CN102579800B - Phenformin hydrochloride and preparation process thereof - Google Patents
Phenformin hydrochloride and preparation process thereof Download PDFInfo
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- CN102579800B CN102579800B CN201210067273.9A CN201210067273A CN102579800B CN 102579800 B CN102579800 B CN 102579800B CN 201210067273 A CN201210067273 A CN 201210067273A CN 102579800 B CN102579800 B CN 102579800B
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Abstract
The invention relates to a compound phenformin hydrochloride and a preparation process thereof. The compound phenformin hydrochloride is prepared from the following raw materials in parts by weight: 1 part of phenformin hydrochloride, 25 parts of membranous milkvetch root, 22 parts of Chinese yam, 20 parts of Chinese atractylodes, 15 parts of figwort, 10 parts of Chinese angelica and 7 parts of dwarf lilyturf turber. The compound phenformin hydrochloride can be produced into capsules, tablets, granules and other formulations by adding pharmaceutical excipients, such as starch and edible cellulose according to an ordinary pharmacy method. A compound phenformin hydrochloride pharmaceutical composition disclosed by the invention has the advantages of treating both manifestation and root cause of diabetes, being non-toxic and harmless to a human body, having no side effect, being low in price, being simple and convenient to manufacture and having broad application prospects.
Description
Technical field
The invention belongs to medical technical field, be specifically related to treat the Chinese-western medicine preparation of diabetes, the application of the compound medicine that the Western medicine phenformin hydrochloride of particularly take is made as main and Chinese herbal medicine in treatment diabetes.
Background technology
Diabetes are a kind of multiple complication diseases, are the worldwide diseases of current serious harm human health.By inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, the various virulence factors of Nervous and Mental Factors etc. act on body and cause hypoinsulinism, insulin resistant etc. and the sugar that causes, protein, fat, a series of metabolism disorder syndromes such as power and water Xie Zhi, take hyperglycemia clinically as main feature, can there is polyuria in model case, polydipsia, polyphagia, the performance such as become thin, i.e. " three-many-one-little " symptom, diabetes (blood glucose) cause complication once control bad meeting, cause kidney, eye, the exhaustion pathological changes at the positions such as foot, and cannot cure.According to WHO, the prevalence of diabetes is positive increase year after year in the whole world.At present, diabetes have become the third-largest Chronic Non-Communicable Diseases after tumor, cardiovascular disease.Existing 1.5 hundred million diabeticss in the whole world, expect patient's number in 2025 and will reach 300,000,000.Closely 20Nian Lai， China diabetes prevalence is multiple growth, greatly affects people's health quality.In the last few years, its sickness rate rose year by year, and had the trend of morbidity rejuvenation, had become the principal disease of current threat human health, therefore effectively it was prevented and treated to tool and was of great significance.
Phenformin hydrochloride, for for 1-(2-phenethyl) biguanide hydrochloride, is biguanides oral hypoglycemic, and its structural formula is:
Mechanism of action is: increase the sensitivity of surrounding tissue to insulin, increase the glucose utilization of insulin-mediated; Increase the utilization of noninsulin dependent tissue to glucose, as brain, hemocyte, renal medulla, intestinal, skin etc.; Suppress gluconeogenesis function of liver, reduce glycogen output; Suppress intestinal wall cellular uptake glucose; Suppress biosynthesis and the storage of cholesterol, reduce blood triglyceride, total cholesterol level.Although diabetes treatment by western medicine has quick, the effective feature of blood sugar lowering, but to take three large metabolism disorders as main animal economy function adjustment and immunologic function adjusting, can not be satisfactory, and prolonged application each tool untoward reaction and limitation, as hypoglycemia, hepatorenal damage, lactic acidosis, gastrointestinal reaction etc., affected therapeutic effect, thereby with regard to, late result obtained in the recent period with regard to it, result is unsatisfactory.
Motherland's medical science thinks that diabetes are the category of the traditional Chinese medical science " diabetes ", and the understanding of the traditional Chinese medical science to diabetes is with a long history, of long standing and well established.In < < Huang di's Canon of Medicine > >, think the substantial connection that has of the factors such as surfeit delicious food, disorder of emotion, the five internal organs be weak and primary disease, sick opinion > > meaning as strange in < < Plain Questions: " this person must count the sweet and refreshing and many fertilizer of food also; overeating greasy food bringing about internal heat; over-eating the food with sweet flavor bringing about abdominal distension; therefore its gas overflow transfers to and quenching one's thirst." < < Ling Shu Miraculous Pivot or Divine Axis five becomes a piece of writing > > and says: " and rage causing upward adverse flow of liver-QI is contrary, accumulates in the heart, and vim and vigour retrograde stationary, hip skin fills flesh, and blood vessels are not all right, then with hot, and the heat skin that disappears, therefore be diseases due to endogenous heat of ZANG FU organs." aspect pathogeny, from gold dollar Liu's interchannel in period, Zhang Zihe etc., " three types of diabetes " theory has been proposed, take yearningly as main person on disappear, the famine of take disappears in main person claims, take to urinate as main person to disappear under meaning, and advocates the scorching theory of three types of diabetes.Chinese medicine is little to actual bodily harm, can improve the fluctuation of blood glucose, repairs the function of islets of langerhans.Stomach, liver, kidney are had to good protective effect, and effect is steadily effective, applicable crowd is wide, more without the toxic and side effects of Western medicine.Chinese medicine is thought, liver controlling conveyance and dispersion, the lifting that is related to human functional activity of vital energy is smooth with tune, the defeated cloth of ascending or descending movement of vital Qi is disorderly for irritability stasis, the liver failing to maintain the normal flow of QI the cereal nutrient such as blood glucose can not be with the gas of clear sun defeated be distributed in the whole body and stasis in blood, occur that the defeated cloth of hyperglycemia or cereal nutrient is disorderly, instead see blood sugar increasing, further cause other cereal nutrient such as blood fat, albumen disorderly, cause other complication.Treatment be take soothing the liver regulating QI as main, and along liver bar soothing the liver, to recover its physiological function, irritability bar reaches, and QI movement being in harmonious way is precise and tinyly able to defeated cloth, and sugar is utilized and blood glucose declines naturally.Rational hypoglycemic drug matching has promoting the production of body fluid to quench thirst, recovers patient's islet function and the affinity of receptor, makes blood glucose be fully absorbed the effect of utilization.
At present, constantly have clinically the medicine (comprising Western medicine and Chinese patent medicine) of new treatment diabetes to occur, but these all fail to reach real gratifying effect.The Chinese medicine and western medicine compound drug of developing a kind of high-efficiency low-toxicity, treating both the principal and secondary aspects of a disease is still clinical eager needs.
Summary of the invention
The object of this invention is to provide that a kind for the treatment of both the principal and secondary aspects of a disease, side effect are little, safe ready, cheap compound hydrochloric acid phenformin medicine.Its objective is in order to solve treatment diabetes, overcome that Western medicine phenformin hydrochloride toxic and side effects is large, drug withdrawal easily repeatedly, the inapparent problem of therapeutic effect, reach the object for the treatment of both the principal and secondary aspects of a disease.
Present inventor is according to forefathers' experience and oneself medical practice for many years, and by the research to Chinese medicine, from integral body, primary disease is " void ", " warm " and " stasis of blood " mainly due to.Therefore in the middle for the treatment of, with the body resistance strengthening and constitution consolidating, enhancing immunity, attach most importance to, benefiting QI and nourishing blood heat clearing away, blood circulation promoting and blood stasis dispelling is promoted blood circulation, and should notice that benefiting QI for activating blood circulation dredging collateral takes stopgap measures, and also will pay attention to tonifying kidney and effect a permanent cure.On this basis, the inventor is in conjunction with dialectical demonstration, in many ways collect the length of many families, seek therapeutic regimen, from motherland's medical treasure-house, filter out the natural Chinese medicine of the treatment diabetes of the merit that the body resistance strengthening and constitution consolidating, benefiting QI and nourishing blood, activating blood circulation to dissipate blood stasis promote blood circulation, by theory of Chinese medical science prescription, the compound hydrochloric acid phenformin pharmaceutical composition that is meticulously mixed with treatment diabetes of the present invention in conjunction with Traditional Chinese Medicine technology, has the effect of taking stopgap measures and effecting a permanent cure to diabetes.
For achieving the above object, the technical solution used in the present invention is as follows:
A compound hydrochloric acid phenformin pharmaceutical composition, is characterized in that it is obtained by the preparation of following weight proportioning raw material,
1 part of phenformin hydrochloride, 25 parts of the Radixs Astragali, 22 parts of Rhizoma Dioscoreaes, 20 parts of Rhizoma Atractylodis, 15 parts of Radix Scrophulariaes, 10 parts of Radix Angelicae Sinensis, 7 parts of Radix Ophiopogonis.
Wherein said phenformin hydrochloride can commercially availablely be bought, and preferably preparation method is:
1, charge ratio
Phenethylamine 35.8kg
Hydrochloric acid 33kg
Dicyandiamide 25kg
2, production technology
2,1 adds phenethylamine 35.8kg in the retort of 100L, stirs the lower hydrochloric acid that drips, and keeps temperature 45-50 ℃, within about 1-1.5 hour, drip and finish, adjust PH to 5, then slowly steam water, when temperature rises to 132-136 ℃, steam the water yield while reaching 10kg simultaneously, stop distillation, add dicyandiamide, while being rapidly heated to 138-139 ℃, add diluted acid water, be warming up to 141-144 ℃, be incubated 1.5 hours, react complete, be cooled to 120 ℃, put into the bucket of having contained diluted acid water, stir, decrease temperature crystalline, below cold preservation to 5 ℃, centrifugal, 5 ℃ of following washings 2 times, obtain crude product.
2,2 is refining: crude product (giving money as a gift): water: active carbon=1: (weight ratio) stirred evenly the water of amount of calculation and active carbon in cylinder in 1.5: 0.03, in suction retort, under stirring, add crude product, be warming up to 80-90 ℃, insulation decolouring 30 minutes, adjust PH6-7 to filter, active carbon is washed with 10kg.Filtrate is placed crystallization under room temperature, below cold preservation to 5 ℃, centrifugal, washes 2 times, each 3kg, and 75-80 ℃ is dry, obtains phenformin hydrochloride.
Pharmaceutical composition of the present invention can add one or more pharmaceutically acceptable carriers and be mixed and made into clinically any or pharmaceutically acceptable dosage form, preferred oral preparation.While being applied in the mode of oral administration the patient who needs this treatment, can be made into conventional solid preparation, as tablet, capsule, soft capsule etc.
When medicine of the present invention is made preparation, can adopt the conventional method in existing pharmaceutical field to produce, when needing, can add various pharmaceutically acceptable carriers.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.
Medicine of the present invention is when making oral formulations, and selectable filler has: starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Selectable binding agent has: sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Selectable disintegrating agent has: dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Selectable lubricant has: magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
Preferably, get phenformin hydrochloride 1g, Radix Astragali 25g, Rhizoma Dioscoreae 22g, Rhizoma Atractylodis 20g, Radix Scrophulariae 15g, Radix Angelicae Sinensis 10g, Radix Ophiopogonis 7g.Through pulverizing, make capsule according to a conventional method, every 0.5g, through being up to the standards as finished product.
Compound medicine of the present invention can increase the sensitivity of target cell to insulin, recovers islet cell function, promotes the utilization of peripheral tissues to glucose; Adjust immune system, strengthen sugared homeostasis, improve animal economy function.This compound medicine also has the effect that reduces blood fat and urine protein.Obviously improve insulin sensitivity, recover islet cell function, promote the utilization of peripheral tissues to glucose, thereby reduce blood glucose, blood fat, diabetes and complication thereof are had to certain therapeutical effect, to overcome, adopt a kind of Western medicine, Chinese medicine or the not good defect of other composition effects, therapeutic effect is more stable simultaneously, has no side effect, without medicine Drug resistance.The present invention is a kind of compound Western medicine preparation for the treatment of diabetes, the motherland's Chinese medicine of extensive knowledge and profound scholarship of take is theoretical basis, optimum organization, by enhancing body insulin sensitivity, recover islet cell function, comprehensive enhancing body sugar homeostasis, decrease blood lipid, urine protein, improve animal economy function.
Technical solutions according to the invention are on the clinical experience basis of TCM treatment of diabetes, the compound preparation with Chinese medicine and western medicine combination of developing in conjunction with modern pharmacy achievement.By Chinese medicine and Western medicine combination effectively, under unique instruction of Chinese Medicine theory, focus on the equilibrium between yin and yang of conditioning human body, not only there is certain blood sugar reducing function, and can eliminate clinical symptoms, and improve the immunologic function of body, particularly improving aspect the complication such as microcirculation, prevent and avoid microangiopathies, curative effect certainly, is accepted and welcomes and obtain extensive patients.Overcome that prior art Chinese medicine and toxicity are large, the easy shortcoming such as repeatedly of drug withdrawal, reach the object for the treatment of both the principal and secondary aspects of a disease.
Advantage of the present invention is:
1, the present invention is prepared simply, and cheap, curative effect is reliable, and treatment time is short, should not recur, and by Chinese medicine and Western medicine combination effectively, reduces toxic and side effects.
2. each component meets pharmacopeia method relevant regulations, utilizes the compatibility effect of each taste Chinese medicine, and not containing chemical components,, containing hormone, treating both the principal and secondary aspects of a disease, does not reach better hypoglycemic effect;
3. this medicament short treating period, total effective rate is high, is difficult for more afterwards recurrence;
4. technique of the present invention is simple, has reduced production cost, has alleviated patient's financial burden.
The specific embodiment
Embodiment 1
A compound hydrochloric acid phenformin pharmaceutical composition, is characterized in that it is obtained by the preparation of following weight proportioning raw material,
1 part of phenformin hydrochloride, 25 parts of the Radixs Astragali, 22 parts of Rhizoma Dioscoreaes, 20 parts of Rhizoma Atractylodis, 15 parts of Radix Scrophulariaes, 10 parts of Radix Angelicae Sinensis, 7 parts of Radix Ophiopogonis.
Wherein said phenformin hydrochloride can commercially availablely be bought, and preferably preparation method is:
1, charge ratio
Phenethylamine 35.8kg
Hydrochloric acid 33kg
Dicyandiamide 25kg
2, production technology
2,1 adds phenethylamine 35.8kg in the retort of 100L, stirs the lower hydrochloric acid that drips, and keeps temperature 45-50 ℃, within about 1-1.5 hour, drip and finish, adjust PH to 5, then slowly steam water, when temperature rises to 132-136 ℃, steam the water yield while reaching 10kg simultaneously, stop distillation, add dicyandiamide, while being rapidly heated to 138-139 ℃, add diluted acid water, be warming up to 141-144 ℃, be incubated 1.5 hours, react complete, be cooled to 120 ℃, put into the bucket of having contained diluted acid water, stir, decrease temperature crystalline, below cold preservation to 5 ℃, centrifugal, 5 ℃ of following washings 2 times, obtain crude product.
2,2 is refining: crude product (giving money as a gift): water: active carbon=1: (weight ratio) stirred evenly the water of amount of calculation and active carbon in cylinder in 1.5: 0.03, in suction retort, under stirring, add crude product, be warming up to 80-90 ℃, insulation decolouring 30 minutes, adjust PH6-7 to filter, active carbon is washed with 10kg.Filtrate is placed crystallization under room temperature, below cold preservation to 5 ℃, centrifugal, washes 2 times, each 3kg, and 75-80 ℃ is dry, obtains phenformin hydrochloride.
After being added to edible cellulose pharmaceutic adjuvant as alive in starch according to common pharmaceutical methods, above-mentioned composition makes the dosage forms such as capsule, tablet, granule.
Preferably, get phenformin hydrochloride 1g, Radix Astragali 25g, Rhizoma Dioscoreae 22g, Rhizoma Atractylodis 20g, Radix Scrophulariae 15g, Radix Angelicae Sinensis 10g, Radix Ophiopogonis 7g.Through pulverizing, make capsule according to a conventional method, every 0.5g, through being up to the standards as finished product.
Recommend to take every day above-mentioned compound hydrochloric acid phenformin pharmaceutical composition twice, each 2.
Zoopathology experiment
Experimental animal: 50 of Wistar rats, male, 180-200g.Rat adapts to and feeds after 7 days at Animal House, randomly draws 10 and feeds with the common feedstuff that maintains as Normal group.High glucose and high fat feed formula: rat normal feedstuff 68%, sucrose 10%, yolk powder 9%, Adeps Sus domestica 8%, cholesterol 1%, cholate 0.2%.
Embodiment: all the other 40 adopt high glucose and high fat forage feed 4 weeks.Rat is after fasting 18h after 4 weeks, streptozotocin (STZ) intravenous injection 20mg/Kg, and every two days are once, use after twice, and the high person of blood pressure and blood lipoid is modeling success.Choose 30 of the successful rats of modeling, be divided at random 3 groups, 10 every group, i.e. model group (not using any medicine), the embodiment of the present invention 1 medicine group, control drug group: use gliclazide, method of application is oral, and one hour ante cibum of every day takes.Take continuously and detect afterwards for 10 days.
Statistical analysis: data information adopts x ± s to represent, is used SPSS17.0 statistical software to carry out data analysis, relatively adopts variance analysis between many groups, relatively adopts t check between two groups.P < 0.05 has statistical significance.
Therapeutic effect: detected fasting glucose (FPG), 2h-plasma glucose (2hPG) biochemical indicator, unit is mmol/L.
| Group | FPG | 2hPG |
| Normal group | 5.31±0.47 | 7.68±0.25 |
| Simulation group | 21.21±4.03 | 27.19±4.92 |
| Control drug group | 7.58±1.27 | 8.52±0.86 |
| Medicine group of the present invention | 6.39±0.28 | 7.64±0.39 |
Embodiment 2
Clinical data
Clinical trial:
Data and method: choose physical data outpatient service type ii diabetes patient totally 120 examples, male 68 examples wherein, female's 52 examples, patient age 38～75 years old, is divided into two groups immediately, experimental group 60 examples, matched group 60 examples, take respectively the compound hydrochloric acid phenformin pharmaceutical composition of embodiment 1 preparation and commercially available metformin, take continuously 10 days, observe clinical efficacy result, during treatment, stop other western medicines in treatment.
Diagnostic criteria: the standard rating curative effect of " guideline of clinical investigations of the treatment diabetes " defined in the < < new Chinese medicine guideline of clinical investigations > > formulating for 1993 with reference to Ministry of Public Health.Effective: after treatment, symptom disappears substantially, FPG (fasting glucose) < 7.0mmol/L, P2hPG (2 hours blood glucoses after the meal) < 8.3mmol/L or blood glucose are front to decline more than 30%; Effective: after treatment, symptom is obviously improved, FPG < 8.3mmol/L, P2hPG < 10.0mmol/L, or the front decline 10%～29% of blood glucose; Invalid: after treatment, symptom is not improved, blood glucose declines and does not reach above-mentioned standard.
Result is as follows:
As seen from the above table: treatment group is all obviously better than matched group to diabetes obvious effective rate and total effective rate, has significant difference.
Embodiment 3
Exemplary embodiments
55 years old patient of Zhang female suffered from diabetes more than 3 years, and the antidiabetic drugs such as oral administration of metformin, glipizide are low when high during blood glucose, the companion body weary unable, become thin, easily irritable, rare when dry during stool, sleep is few, thirsty but polydipsia not.Corpulent tongue, there is indentation on limit, and color is dark red, yellow and thin fur, deficient and rapid pulse, takes described in the embodiment of the present invention 1 that medicine is dry after one month to be alleviated yearningly, muscle power is recovered to some extent, continue to take after one month, stable disease, glucose in urine is turned out cloudy, look into fasting glucose 5.6mmol/l, post-prandial glycemia 6.1mmol/l, the state of an illness is basicly stable, and physical recovery is normal.
Qiao Yang, man, 49 years old, since nearly one month, thirsty, polyuria suddenly, pleasantly sweet in mouthful, again and again, many persons one day and night can more than ten times for urine meaning, and total volume of urine was everlasting more than 2～3L on 1st.Due to polyuria dehydration, always feel excessive thirst, the amount of drinking water and increased frequency, at examination in hospital glucose in urine (++), fasting glucose 12.5mmol/L, 2 hours after the meal 14.8mmol/L, are diagnosed as type ii diabetes.After taking glyburide, metformin and diabetes pill by doctor's advice, glucose in urine turns (+), and blood glucose declines to some extent, but still feels that oropharynx is very thirsty, have no appetite, and fatigue and asthenia, red tongue is dark, indentations at the margin of the tongue, the few Tianjin of white and thin fur, or few tongue, thready and weak pulse.Change the compound hydrochloric acid phenformin compositions that takes the embodiment of the present invention 1 preparation, serve on one month, dryly yearningly alleviate, in mouthful, sweet taste disappears, hypourocrinia, and muscle power is recovered to some extent.Continue to take one month, stable disease, glucose in urine is turned out cloudy, fasting glucose 6.0mmol/l, 2 hours after the meal 9.6mmol/L, it is normal that health recovers substantially.
In view of current Western medicine oral antidiabetic drug and insulin exist side effect in clinical application, and the limitation such as expensive, therefore give with therapy of combining Chinese and Western medicine diabetes wide development space is provided.Chinese medicine is with the quality of its pure natural, under unique instruction of Chinese Medicine theory, focus on the equilibrium between yin and yang of conditioning human body, not only there is certain blood sugar reducing function, and can eliminate clinical symptoms, and improve the immunologic function of body, particularly improving aspect the complication such as microcirculation, prevent and avoid microangiopathies, curative effect certainly, is accepted and welcomes and obtain extensive patients.Above-mentioned each Chinese medicine and western medicine that the present invention adopts is made compatibility mutually, can bring into play its collaborative effect of curing the disease, between each composition of raw material of Chinese medicine used, having drug effect is interweaved and mutually promotes and coordinate usefulness, through clinical verification, diabetes are had to good therapeutic effect, in the applicant's medical practice for many years, the case number of curing is numerous, all obtain good effect, and with low cost, alleviate patient's burden.
The compound hydrochloric acid phenformin pharmaceutical composition of the application's treatment diabetes is with low cost, evident in efficacy, has broad application prospects.
Claims (1)
1. the compound hydrochloric acid phenformin pharmaceutical composition for diabetes, it is characterized in that it obtains 1 part of phenformin hydrochloride, 25 parts of the Radixs Astragali, 22 parts of Rhizoma Dioscoreaes, 20 parts of Rhizoma Atractylodis, 15 parts of Radix Scrophulariaes, 10 parts of Radix Angelicae Sinensis, 7 parts of Radix Ophiopogonis by the preparation of following weight proportioning raw material.
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