CN102512409A - Medical preparation containing levocarnitine and dihydroxybenzenesulphonic acid salt and preparation method of medical preparation - Google Patents
Medical preparation containing levocarnitine and dihydroxybenzenesulphonic acid salt and preparation method of medical preparation Download PDFInfo
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Abstract
The invention relates to medical preparation containing levocarnitine and dihydroxybenzenesulphonic acid salt and a preparation method of the medical preparation, and particularly relates to an orally taken solid medical preparation. The medical preparation contains the levocarnitine, the dihydroxybenzenesulphonic acid salt and pharmacologically receivable excipient, and the levocarnitine and the dihydroxybenzenesulphonic acid salt are separately granulated in a preparation process of the preparation. The invention further relates to the preparation method for the orally taken solid medical preparation and application for treating and/or preventing diseases affecting renal functions, such as primary nephritis, secondary nephritis, renal ischemia/ reperfusion injury, renal insufficiency (for example, chronic renal insufficiency), nephrotic syndrome, renal failure (for example, chronic renal failure), uremia and diabetic nephropathy, and complications caused by the diseases affecting the renal functions, such as cardiovascular disease (for example, myocardial ischemia/reperfusion and chronic cardiac insufficiency) and diabetes mellitus.
Description
Technical field
The present invention relates to pharmaceutical preparation that comprises levocarnitine and hydroxy benzene sulfonate and preparation method thereof.Particularly, the present invention relates to comprise the oral solid pharmaceutical formulation of levocarnitine and hydroxy benzene sulfonate.
Background technology
Chronic renal failure (CRF) is the performance in late period of common clinically multiple kidney disease, the life and health that end stage renal failure and a series of complication thereof are seriously threatening people.Dialysis treatment during end stage renal failure often brings heavy financial burden to the patient.How can reduce its multisystem complication, save patient's residual renal function better, reduce the dialysis number of times, prolong the interval of dialysing, and keep good quality of life of patient, be the problem that the doctor of kidney section is inquiring into always.
Hydroxy benzene sulfonate is 2,5-dihydroxy benzenes sulfonic acid salt, and molecular formula is (C
6H
5O
5S)
xM, structural formula is following:
M wherein
X+Be metal ion, x=1,2 or 3.Hydroxy benzene sulfonate is white or off-white powder, odorless, and bitter in the mouth, chance light is perishable, and hygroscopicity is arranged, and is very easily water-soluble, is soluble in ethanol or acetone, and atomic chloroform or the ether of being dissolved in.
Known hydroxy benzene sulfonate is the blood capillary protective agent, has the platelet adhesion of reduction and blood viscosity, the effect of microcirculation improvement obstacle.This medicine has been used for the treatment of diabetic microvascular complication (especially diabetic renal papillary necrosis) always since the seventies, have good efficacy.Recent study finds, this medicine can obviously improve chronic renal failure patients renal function, delay disease progression, have the effect that reduces serum creatinine, blood urea nitrogen and uric acid.At present, the dosage form used clinically of this medicine comprises tablet, granule, capsule, dispersible tablet etc.
The molecular formula of levocarnitine is C
7H
15NO
3, chemistry (R)-3-carboxyl by name-2-hydroxy-n, N, N-trimethyl-1-propylamine hydroxide.The levocarnitine molecular structural formula of interior salt form is following:
It is white crystals or crystalline powder, and slight special odor is arranged, and hygroscopicity is extremely strong, and being exposed in the air can deliquescence even possibly liquefy, in soluble in water, ethanol, alkaloid solution and the dilution ore deposit acid, and almost insoluble in acetone or ethyl acetate.
Levocarnitine is a kind of amino acid drug, is widely used in diseases such as secular hemodialysis, muscular dystrophy, cardiomyopathy, acute and arrhythmia that chronic myocardial infarction, angina pectoris, tricyclic antidepressant cause, alzheimer disease, presenile dementia.At present, the dosage form used clinically of this medicine comprises injection, freeze-dried powder, oral administration solution and tablet etc.
One Chinese patent application 201010215998.9 discloses the pharmaceutical composition that comprises levocarnitine and hydroxy benzene sulfonate; Show that levocarnitine and hydroxy benzene sulfonate Combined application have cooperative effect; Serum creatinine and/or urea nitrogen levels be can regulate effectively, the disease and/or the disease that influence renal function can be used for treating and/or preventing.
Yet; One Chinese patent application 201010215998.9 adopts the routine techniques pharmaceutical compositions, has some problems, for example: granulate after adopting direct hybrid medicine powder; Mobility of particle difference and cause the sheet difference big, and cause the tablet machine sticking easily and influence normally carrying out of production; Moisture absorption in the drug powder mixed process, the granule that causes processing produces piebaldism when tabletting; The dissolution of slow release and controlled release tablet (particularly slow release and controlled release coat tablet) is undesirable.These problems cause the difficulty when carrying out the production of scale property, thereby have limited its application.
Inventor of the present invention is surprised to find that; In the preparation process of the oral solid pharmaceutical formulation that comprises levocarnitine and hydroxy benzene sulfonate; The technology that employing is separately granulated two kinds of active component, the appearance character of gained preparation and dissolution have obtained significantly improving.
Summary of the invention
Therefore; In first aspect; The present invention relates to oral solid pharmaceutical formulation, said preparation comprises the acceptable excipient of levocarnitine, hydroxy benzene sulfonate and materia medica, and wherein said levocarnitine and said hydroxy benzene sulfonate are separately granulated in the preparation process of said preparation.
In second aspect, the present invention relates to the method for preparing of the oral solid pharmaceutical formulation of first aspect present invention, said method comprises separately granulates said levocarnitine and said hydroxy benzene sulfonate.
In the third aspect; The present invention relates to levocarnitine and hydroxy benzene sulfonate and be used to treat and/or prevent disease such as constitutional nephritis, Secondary cases nephritis, renal ischaemia/reperfusion injury, renal insufficiency (like chronic renal insufficiency), nephrotic syndrome, renal failure (like chronic renal failure), uremia and the diabetic nephropathy that influences renal function in preparation; And the application in the oral solid pharmaceutical formulation of the complication that causes by the disease that influences renal function such as cardiovascular disease (for example myocardial ischemia/perfusion and chronic cardiac insufficiency) again and diabetes; Wherein in the preparation of said preparation, said levocarnitine and said hydroxy benzene sulfonate are separately granulated.
Description of drawings
Fig. 1 shows the stripping curve of the tablet of comparative example 1 and embodiment 1, and wherein Fig. 1 (a) shows the stripping of calcium dobesilate, and Fig. 1 (b) shows the stripping of levocarnitine.
Fig. 2 shows the stripping curve of the slow releasing tablet of comparative example 2 and embodiment 2, and wherein Fig. 2 (a) shows the stripping of calcium dobesilate, and Fig. 2 (b) shows the stripping of levocarnitine.
Fig. 3 shows the stripping curve of the sustained release coating tablet of comparative example 3 and embodiment 3, and wherein Fig. 3 (a) shows the stripping of calcium dobesilate, and Fig. 3 (b) shows the stripping of levocarnitine.
Fig. 4 shows the stripping curve of the dispersible tablet of comparative example 4 and embodiment 4, and wherein Fig. 4 (a) shows the stripping of calcium dobesilate, and Fig. 4 (b) shows the stripping of levocarnitine.
Fig. 5 shows the stripping curve of the capsule of comparative example 5 and embodiment 5, and wherein Fig. 5 (a) shows the stripping of calcium dobesilate, and Fig. 5 (b) shows the stripping of levocarnitine.
Fig. 6 shows the stripping curve of the granule of comparative example 6 and embodiment 6, and wherein Fig. 6 (a) shows the stripping of calcium dobesilate, and Fig. 6 (b) shows the stripping of levocarnitine.
Fig. 7 shows the stripping curve of the controlled release tablet of comparative example 7 and embodiment 7, and wherein Fig. 7 (a) shows the stripping of calcium dobesilate, and Fig. 7 (b) shows the stripping of levocarnitine.
The specific embodiment
First aspect present invention relates to oral solid pharmaceutical formulation, and said preparation comprises the acceptable excipient of levocarnitine, hydroxy benzene sulfonate and materia medica, and wherein said levocarnitine and said hydroxy benzene sulfonate are separately granulated in the preparation process of said preparation.
As used among this paper, chemistry (R)-3-carboxyl by name-2-hydroxy-n, N, N-trimethyl-1-propylamine hydroxide, the acceptable salt of the chemical compound of inner salt and materia medica thereof contained in term " levocarnitine ".In one embodiment, said levocarnitine is the acceptable acid-addition salts of materia medica.In another embodiment, said levocarnitine is the acceptable base addition salts of materia medica.In an embodiment again, said levocarnitine is the form of inner salt.
As used among this paper, term " the acceptable salt of materia medica " comprises acid-addition salts and base addition salts.Said acid-addition salts comprises the salt that medicine is become with acceptable organic acid or the mineral acid of materia medica, like formates, cinnamate, hydrochlorate, hydrobromate, hydriodate, hydrofluoride, sulfate, citrate, maleate, acetate, lactate, nicotinate, succinate, oxalates, phosphate, malonate, Salicylate, phenylacetate, stearate, mesylate, picrate or tartrate.Said base addition salts comprises the salt that medicine is become with acceptable organic base or the inorganic base of materia medica; Like pyridiniujm, ammonium salt, piperazine salt, diethyl amine salt, nicotinoyl amine salt, alkali metal salt, alkali salt, methylamino salt, triethylamine salt, dimethylamino salt or three (methylol) aminomethane salt; Preferred as alkali salt or alkali salt are like sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and lithium salts.It is known for those skilled in the art that other drug is learned acceptable salt.
As used among this paper, the acceptable salt of various materia medicas of phenolsulfonic acid contained in term " hydroxy benzene sulfonate ".In one embodiment, said hydroxy benzene sulfonate is phenolsulfonic acid and alkali metal cation or the formed salt of alkaline earth metal cation.Preferably, said hydroxy benzene sulfonate is a calcium dobesilate.
The implication of term " materia medica can be accepted " is that the composition that limited and other compositions of pharmaceutical preparation are compatible; And be suitable for contacting with the tissue or the organ of humans and animals; And there are not over-drastic toxicity, stimulation, anaphylaxis, immunogenicity or other problems or complication; Match with rational interests/risk ratio (referring to, Remington:The Science and Practice of Pharmacy, the 21st edition; Lippincott Williams & Wilkins:Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, the 5th edition; Volumes such as Rowe, The Pharmaceutical Press and the American Pharmaceutical Association:2005; With Handbook of Pharmaceutical Additives, the 3rd edition; Ash and Ash compile, Gower Publishing Company:2007; Pharmaceutical Preformulation and Formulation, Gibson compiles, CRC Press LLC:Boca Raton, FL, 2004).
Various materia medicas contained in term " the acceptable excipient of materia medica " can accept adjuvant, like filler, disintegrating agent, binding agent, wetting agent, lubricant, fluidizer, porogen, framework material and coating materials etc.
Pharmaceutical preparation of the present invention can be various forms of oral solid pharmaceutical formulations, like capsule, granule or tablet, particularly slow releasing tablet, sustained release coating tablet, dispersible tablet or controlled release tablet.
In the pharmaceutical preparation of the present invention, by weight, the ratio of levocarnitine and hydroxy benzene sulfonate and adjuvant is about 1: 0.001 to 1: 50, is preferably about 1: 0.1 to 1: 10, is preferably about 1: 0.2 to 1: 5 especially.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said filler includes but not limited to: lactose, starch, pregelatinized Starch (amylum pregelatinisatum), glucose, sugar alcohol (like xylitol or mannitol), microcrystalline Cellulose, sucrose, fructose,, dextrin, calcium carbonate, magnesium carbonate, calcium sulfate, calcium hydrogen phosphate, magnesium oxide, aluminium hydroxide, sodium carboxymethyl cellulose, carboxymethylcellulose calcium and any two kinds or more kinds of mixture in them; Be preferably sugar alcohol, pregelatinized Starch, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, microcrystalline Cellulose or any two kinds or more kinds of mixture in them.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said disintegrating agent includes but not limited to: cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, gas-producing disintegrant, surfactant, alginate and any two kinds or more kinds of mixture in them.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said binding agent includes but not limited to: the ethanol-water solution of polyvinylpyrrolidone, hydroxypropyl emthylcellulose, dehydrated alcohol, various concentration and any two kinds or more kinds of mixture in them.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said wetting agent includes but not limited to: the ethanol-water solution of water, dehydrated alcohol and various concentration.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said lubricant includes but not limited to: stearic acid, Pulvis Talci, magnesium stearate and any two kinds or more kinds of mixture in them.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said fluidizer includes but not limited to: micropowder silica gel, Pulvis Talci and their mixture.
As the excipient in the pharmaceutical preparation of the present invention, the instance of said porogen includes but not limited to: sucrose, lactose, mannitol, polyvidone, starch, Pulvis Talci, Polyethylene Glycol and any two kinds or more kinds of mixture in them.
When pharmaceutical preparation of the present invention is slow release or controlled release preparation; For slow release or the controlled release of realizing levocarnitine and hydroxy benzene sulfonate; Can in preparation, add the release that framework material is controlled medicine, perhaps use packaging technique to control the release of medicine, perhaps two kinds of means combined.
The instance of said framework material includes but not limited to:
-cellulose ether derivative is like carboxymethyl cellulose, ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy methocel and Carboxymethyl cellulose sodium etc.;
-non-cellulosic polysaccharide is like glucose, chitosan, chitosan and galactomannan etc.;
-natural gum is like pectin, sodium alginate, potassium alginate, agar, carrageenin, locust bean gum, guar gum and tragcanth etc.;
-polyvinyl or acrylate copolymer are like polyvinyl alcohol and carbomer (carbopol) etc., particularly commercial goods carbomer 934 P, carbomer 971P and carbomer 974P etc.;
-inertia fat or wax are like Cera Flava, hydrogenated vegetable oil, synthetic wax, butyl stearate, stearic acid, Brazil wax, glyceryl stearate, propylene glycol-stearate and octadecanol 6, polyethylene, polypropylene, polysiloxanes and polyoxyethylene;
-polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA);
Any two kinds or more kinds of mixture in-the above-mentioned substance.
The instance of said coating materials includes but not limited to: cellulose acetate, ethyl cellulose, polyacrylic resin, methacrylic acid-methylmethacrylate copolymer, ethyl acrylate-methacrylate copolymer, ethyl acrylate-methyl methacrylate, polyvinyl alcohol, hydroxy methocel, hydroxyethyl-cellulose, methylcellulose and any two kinds or more kinds of mixture in them.
In pharmaceutical preparation of the present invention, by weight, the ratio of levocarnitine and hydroxy benzene sulfonate is about 1: 10 to 10: 1, for example about 1: 10, about 1: 6, about 1: 3, about 1: 2, about 1: 1, about 2: 1, about 3: 1, about 6: 1 or about 10: 1.Preferably; In pharmaceutical preparation of the present invention; The part by weight of levocarnitine and hydroxy benzene sulfonate is about 1: 3 to 3: 1, more preferably about 1: 2 to 2: 1, and for example about 1: 1.25, about 1: 1.5, about 1: 1.75, about 1.25: 1, about 1.5: 1 or about 1.75: 1.Most preferably, in pharmaceutical preparation of the present invention, the part by weight of levocarnitine and hydroxy benzene sulfonate is about 1: 1.
Second aspect of the present invention relates to the method for preparing of the oral solid pharmaceutical formulation of first aspect present invention, and said method comprises separately granulates said levocarnitine and said hydroxy benzene sulfonate.
In the method for preparing of pharmaceutical preparation of the present invention, said granulation can be adopted dry granulation, wet granulation or spray granulation.Preferably, wet granulation is adopted in said granulation.Various granulating process are well-known to those skilled in the art, for example referring to " pharmaceutics " the 4th edition (Bi Dianzhou, People's Health Publisher).
The third aspect of the invention relates to levocarnitine and hydroxy benzene sulfonate is used to treat and/or prevent disease such as constitutional nephritis, Secondary cases nephritis, renal ischaemia/reperfusion injury, renal insufficiency (like chronic renal insufficiency), nephrotic syndrome, renal failure (like chronic renal failure), uremia and the diabetic nephropathy that influences renal function in preparation; And the application in the oral solid pharmaceutical formulation of the complication that causes by the disease that influences renal function such as cardiovascular disease (for example myocardial ischemia/perfusion and chronic cardiac insufficiency) again and diabetes; Wherein in the preparation of said preparation, said levocarnitine and said hydroxy benzene sulfonate are separately granulated.
Skilled person in the art will appreciate that and when administration pharmaceutical preparation of the present invention, can adjust the patient's age that said factor is for example received treatment, health status and body weight to dosage according to known factor; The degree of disease progression; And the type of the other treatment of depositing; Therapeutic frequency; And desirable effect.For example, for treating and/or preventing disease of the present invention and/or disease, the preferred dose of pharmaceutical preparation of the present invention can be levocarnitine 0.25g/ days to 4g/ days, preferred 0.5g/ days to 1g/ days; And hydroxy benzene sulfonate 0.25g/ days to 3g/ days, be preferably 0.75g/ days to 1g/ days.
Pharmaceutical preparation of the present invention is compared with existing preparation (like disclosed preparation in the one Chinese patent application 201010215998.9), and dissolution and outward appearance all are significantly improved.
Below will further set forth the present invention through specific embodiment.Although skilled person in the art will appreciate that through specific embodiment the present invention is specifically set forth, these specific embodiments never should be understood that limitation of the scope of the invention.
Embodiment
Embodiment 1-tablet
Prescription:
Preparation technology:
With levocarnitine, microcrystalline Cellulose and calcium sulfate mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate and microcrystalline Cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed, add polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose, mixing adds magnesium stearate then, mixing, tabletting promptly gets.
Embodiment 2-slow releasing tablet
Prescription:
Preparation technology:
With levocarnitine, hydroxypropyl emthylcellulose, microcrystalline Cellulose and calcium sulfate mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate, hydroxypropyl emthylcellulose and microcrystalline Cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed, add magnesium stearate, mixing, tabletting promptly gets.
Embodiment 3-sustained release coating tablet
Prescription:
Preparation technology:
With levocarnitine, microcrystalline Cellulose and polyvinylpolypyrrolidone mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate, microcrystalline Cellulose and polyvinylpolypyrrolidone mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed, add magnesium stearate, mixing, tabletting.With sealing coat coating material coating, drying is used slow release layer coating material coating then, and drying promptly gets.
Embodiment 4-dispersible tablet
Prescription:
Preparation technology:
With levocarnitine, polyvinylpolypyrrolidone, micropowder silica gel and carboxymethyl starch sodium mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate, polyvinylpolypyrrolidone, micropowder silica gel and carboxymethyl starch sodium mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed, add magnesium stearate, mixing, tabletting promptly gets.
Embodiment 5-capsule
Prescription:
Preparation technology:
With levocarnitine, microcrystalline Cellulose, calcium sulfate, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate, microcrystalline Cellulose, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed evenly, encapsulatedly promptly get.
Embodiment 6-granule
Prescription:
Preparation technology:
With levocarnitine, microcrystalline Cellulose, calcium sulfate, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 3 hours are as the A part.With calcium dobesilate, microcrystalline Cellulose, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mixing, add suitable amount of adhesive system soft material, 50 ℃ of dryings 2 hours are as the B part.A part and B is partially mixed evenly, and packing promptly gets.
Embodiment 7-controlled release tablet
Prescription:
Preparation technology:
With levocarnitine, microcrystalline Cellulose and sodium chloride mixing, add suitable amount of adhesive system soft material, 40 ℃ of dry half an hour are as the A part.With calcium dobesilate, microcrystalline Cellulose and sodium chloride mixing, add suitable amount of adhesive system soft material, 40 ℃ of dry half an hour are as the B part.A part and B is partially mixed, add magnesium stearate, mixing, tabletting, it is subsequent use to make label.
Cellulose acetate, Polyethylene Glycol fully are dissolved in the mixed liquor of acetone and water, make coating solution.Label placed carry out coating in the small-sized coating pan.The coating parameter is: 30～40 ℃ of coating temperature, coating solution flow velocity 7mLmin
-1, rotating speed 25rmin
-1, the product behind the coating 40 ℃ dry 24 hours down, be fit to the drug release hole in aperture at last with the perforating needle preparation, packing promptly gets.
Comparative example 1 to 7
Except with levocarnitine with calcium dobesilate is granulated together and in granulation step, adopt 3 hours the condition of 50 ℃ of dryings, the preparation that adopts prescription identical and method to make comparative example 1 to 7 respectively with embodiment 1 to 7.
Experimental example-dissolution and appearance character
Adopt following dissolution determination method, the dissolution of the preparation of embodiment 1 to 7 and comparative example 1 to 7 is compared, and adopt visual method that its appearance character is compared, the result is shown in Table A and Fig. 1-7.
The stripping assay method:
These article of getting, the photograph dissolution method (" two appendix X of Chinese pharmacopoeia version in 2010 C, second method), be dissolution medium with water 900ml; Rotating speed is that per minute 50 changes; Operation in accordance with the law, through 30 minutes (embodiment 1 with 4-6 and comparative example 1 and 4-6), 8 hours (embodiment 2 with 3 and comparative example 2 and 3) or 10 hours (embodiment 7 and comparative example 7), it is an amount of to get solution; Filter, subsequent filtrate is subsequent use.
It is an amount of that the calcium dobesilate precision is measured subsequent filtrate, and water quantitatively is diluted to the solution that contains calcium dobesilate 25 μ g among every 1ml approximately, the photograph ultraviolet visible spectrophotometry (" two IV A of Chinese pharmacopoeia version appendix in 2010), measure absorbance in the wavelength of 300nm; Other gets the calcium dobesilate reference substance, accurate claims surely, is dissolved in water and quantitatively is diluted to the solution that contains 25 μ g among every 1ml approximately, measures with method, calculates every stripping quantity.
Levocarnitine is got subsequent filtrate as need testing solution, and according to levocarnitine chromatographic condition under the assay item, precision is measured 100 μ l and injected chromatograph of liquid, the record chromatogram; Other gets the levocarnitine reference substance, and accurate the title decides, and also quantitatively is diluted to the solution that contains 90 μ g among every 1ml approximately with water dissolution, and precision is measured 100 μ l, measures with method.By the stripping quantity of external standard method with every middle levocarnitine of calculated by peak area.
The character of Table A preparation and dissolution (release degree)
Can find out from the result of Fig. 1-7 and table 1, in the preparation process, adopt the oral solid pharmaceutical formulation of the present invention of granulating process respectively to realize the obvious raising of dissolution (release degree), and the appearance character of each tablet obtain remarkable improvement.
Test case 1-renal ischaemia/reperfusion injury
Method:
50 of male SD rats (the about 250-270 gram of body weight is provided by Chinese Medical Sciences University experimental animal center) evenly are divided into 5 groups (every group of n=10) at random: sham operated rats (distilled water); Model control group (distilled water); Levocarnitine treatment group (levocarnitine 200mg/kg); Calcium dobesilate treatment group (calcium dobesilate 200mg/kg); Compound treatment group (levocarnitine 200mg/kg+ calcium dobesilate 200mg/kg).
Preceding 30min of each treatment group art and postoperative 12h organize dosage twice and carry out gastric infusion according to each.Sham operated rats and model control group give the distilled water of respective volume.Behind pentobarbital sodium (30mg/kg) intraperitoneal injection of anesthesia, cut the abdominal cavity, separate left kidney artery and vein along the abdomen median line; Harmless vascular clamp folder closes left renal artery; Expose right kidney and excision with quadrat method, decontrol vascular clamp behind the 45min, sew up the abdominal cavity and put back to mouse cage; The normal raising won left kidney after pouring into 24h again.The only capable right kidney of sham operated rats is extractd, and left kidney takes off after exposing 45min.Get blood behind the eye frame before the nephrectomy of a left side; Blood is got serum after centrifugal; Detect blood urea nitrogen (BUN), serum creatinine (Scr) in the serum, adopt SOD, MDA test kit (bio-engineering research institute is built up in Nanjing) to detect renal cortex tissue SOD's vigor and MDA content respectively, left nephridial tissue is carried out pathology section examination.
The result:
BUN, Scr level:
Compare with sham operated rats, blood BUN, Scr have significance to improve (P＜0.01) in the model control group rat body, show the modelling success.Compare with model control group, the BUN of compound treatment group, Scr value obviously reduce (P＜0.05), show that compound medicine has protective effect to renal ischaemia/pour into the kidney of rats function again.The result is as shown in table 1.
Table 1
SOD is active, MDA content:
Compare with sham operated rats, model control group kidney of rats tissue SOD activity has significance to reduce (P＜0.01), and MDA content then has significance to improve (P＜0.01).The compound treatment group is compared with model control group, can obviously improve the SOD vigor, reduces MDA content, and it is all inhibited with the active reduction of SOD to show that compound medicine organizes MDA content to raise to renal ischaemia/pour into again kidney of rats.The result is as shown in table 2.
Table 2
The kidney pathological tissue changes:
Sham operated rats glomerule and renal tubules structural integrity.The pathological change of model control group kidney is obvious, and hydropic degeneration appears in most renal cells swelling, and partial coagulation property is downright bad, come off, and brush border disappears, luminal stenosis, and matter blood vessel height dilatation and congestion between kidney, the part glomerule is downright bad.Each treatment group nephropathy is compared obviously with model control group and is alleviated, the renal cells Mild edema, and how complete basement membrane is, and the renal tubules chamber is slightly narrow, accidental endothelial denudation.
Conclusion
Compound medicine has protective effect to renal ischaemia/reperfusion injury, its mechanism and enhance SOD activity, thus it is relevant to reduce the damage of kidney peroxidating degree antioxidant radical.
Test case 2-chronic renal insufficiency
Method:
According to the principle of correspondence between group, 50 of SPF level Kunming mouses (the about 20-22 of body weight restrains, and male and female half and half are provided by Chinese Medical Sciences University experimental animal center) are divided into 5 groups (every group of n=10) at random, wherein one group as blank control group.(referring to Zheng Pingdong etc., make chronic renal failure animal model, Chinese Journal of Nephrology, 1989,5 (4): 342-344 like document with adenine; Guo Deyu etc., the foundation of chronic renal insufficiency mouse model, Chinese experimental zoology magazine, 2001,11 (3): 142-145; And Sun Shuling etc., the herbs intervention and the pathological observation of mice chronic renal failure animal model, Zhejiang combination of Chinese and Western medicine magazine; 2002; 12 (4): 221-222), except that sham operated rats, be mouse stomach adenine 300mg/kg (20ml/kgd); Continuous once a day three days, cause mice renal insufficiency model thereby set up adenine.
After the modelling success, except that sham operated rats, be divided into four groups with all the other four groups at random again according to the principle of correspondence between group: renal failure model group (distilled water); Levocarnitine treatment group (levocarnitine 200mg/kg); Calcium dobesilate treatment group (calcium dobesilate 200mg/kg); Compound treatment group (levocarnitine 200mg/kg+ calcium dobesilate 200mg/kg).
Except that the renal failure model group, according to given dose to each treatment group mice administration, once a day, around the successive administration.Measure serum BUN value, serum Scr value, kidney index and the nephridial tissue water content of each treated animal subsequently.
The result:
The result is as shown in table 3.
Table 3
Data from table 3 can be found out, compare with sham operated rats, and the Scr value of renal failure model group shows the modelling success apparently higher than sham operated rats.Levocarnitine treatment group, calcium dobesilate treatment group are compared with the renal failure model group, and BUN and Scr value all decrease, and show that levocarnitine, calcium dobesilate all have the effect of treatment renal insufficiency.The compound treatment group is compared with levocarnitine treatment group, calcium dobesilate treatment group respectively; Show compound medicine therapeutic effect better (P＜0.01); The combination that shows levocarnitine and calcium dobesilate is superior to using separately levocarnitine or calcium dobesilate, has synergism aspect adjusting BUN and rising of Scr level and then the treatment renal insufficiency.
Test case 3-diabetic nephropathy (DN)
Method:
Adopt the mode (150mg/kg) of alloxan (Sigma company) MSI to set up the DN rat model.At first to (the about 250-300 gram of body weight of the male SD rat after 1 week that conformed; Provide by Chinese Medical Sciences University experimental animal center) carry out first time injection; Respectively injected 1 time in 2,6 weeks at interval then, investigate the variation of rat erythrocyte sorbitol, glycolated hemoglobin (HbAIC), urine amount, glucose in urine, urine protein therebetween.Include the rat of 8 week back urine protein＞20mg/dL in the DN rat model.DN rat model after 8 weeks of modeling is divided into 4 groups (every group of n=20) at random: model control group (distilled water); Levocarnitine treatment group (levocarnitine 200mg/kg); Calcium dobesilate treatment group (calcium dobesilate 200mg/kg); Compound treatment group (levocarnitine 200mg/kg+ calcium dobesilate 200mg/kg).Other establishes normal control group (n=20, distilled water).Model control group and normal control group are irritated stomach with the distilled water of respective volume every day, amount to for 8 weeks.After 8 weeks of administration, adopt glycolated hemoglobin affinity chromatograph test kit (biological engineering portion of Beijing software company) to measure glycolated hemoglobin; Collect 24h urine amount; Measure urine protein (with urine analyzer 8A reagent paper (east, Guangzhou chemistry Applied Research Laboratory) moistening, detecting) with urine; Calculate renal index (renal index=kidney weight/body weight).
The result:
The result is as shown in table 4.
Table 4
Influence to glycolated hemoglobin
Data from table 4 can find out that the value of model control group glycolated hemoglobin during whole administration is all apparently higher than normal control group (P＜0.001).Each treatment group is compared glycolated hemoglobin with model control group value all obviously reduces.
Influence to the urine amount
Data from table 4 can find out that each treatment group is compared the urine amount and obviously reduced (P＜0.01) with model control group, and the hypourocrinia of compound treatment group is more obvious, and are starkly lower than each treatment group (P＜0.05) of independent medication.
Influence to urine protein
Data from table 4 can find out that each treatment group is compared urine protein with model control group and obviously reduced, and the minimizing of the urine protein of compound treatment group is more obvious, explains that compound medicine can obviously improve renal function.
Influence to renal index
Data from table 4 can be found out; Each treatment group is compared renal index obviously descend (P＜0.05) with model control group; And the compound treatment group is compared renal index decline more obviously (P＜0.05) with model control group, and action effect obviously is superior to each treatment group (P＜005) of independent medication.
Conclusion
Compound medicine can obviously improve the kidney of rats function, is superior to independent medication.
Test case 4-myocardial ischemia (MIRI)
Method:
60 of male SD rats (body weight 280-300 gram is provided by Chinese Medical Sciences University experimental animal center) are divided into 5 groups (every group of n=12) at random: sham operated rats (distilled water); Model control group (distilled water); Levocarnitine treatment group (levocarnitine 200mg/kg); Calcium dobesilate treatment group (calcium dobesilate 200mg/kg); Compound treatment group (levocarnitine 200mg/kg+ calcium dobesilate 200mg/kg); Each organizes basic body weight difference not statistically significant (p＞0.05).
Each treated animal is all with 3% pentobarbital sodium (30mg/kg) intraperitoneal injection of anesthesia, after the success rat lain on the back and is fixed on the operating-table cervical region medisection skin; Passivity is separated throat flesh; Tracheostomize connects the microfauna respirator, gives the Artificial controlled mechanical ventilation support and breathes; 50-60 time/min of frequency, tidal volume 2ml/100g.Isolate a side common carotid artery, be used for the intubate blood sampling.Cut the 4th intercostal along left border of sternum; Cut off pericardium; Exposing heart and left ventricle vascular surface, is sign with ramus descendens anterior arteriae coronariae sinistrae (LAD), 1-2mm place inserting needle below the left auricle root; 4/0Prolene line (ligature) passes cardiac muscle at pulmonary conus branch pin, overlaps people's silk thread ring respectively at the ligature two ends as pouring into backguy again.Except that sham operated rats, all the other each groups are all tightened up ligature and are made LAD blocking-up 30min, to cause myocardial ischemia.Tractive pours into backguy again and makes ligature loosen the back to recover blood flow and pour into 3h at once again, cause Acute Myocardial Ischemia in Rats reperfusion injury model.Sham operated rats is not ligation of threading LAD only, and other all operations are organized with other.Experimental model is successfully set up standard: n leads that the ST section occurs that the back of a bow is upwards raised, the T wave height is alarmmed etc. and shows as the ischemia success after the ligation; After loosening ligature, descending more than 1/2 to pouring into successfully appears in the ST section of raising again.
The medicine of each treatment group art orally give corresponding dosage preceding 5 day every day; Sham operated rats and model control group rat art were irritated stomach in preceding 5 days and are given the equivalent distilled water.
Sample collecting carries out respectively with measuring as follows:
Blood sample is gathered
Except that sham operated rats, when organizing respectively at ischemia-reperfusion 3h, each gathers blood sample.Sham operated rats is taken a blood sample in corresponding time point.The each 1.8ml of blood sampling volume is centrifugal in the anticoagulant test tube that contains 3.8%EDTA 0.2ml, and (4 ℃, 1000rph 10min), gets blood plasma and puts-70 ℃ of ultralow temperature and preserve to be measured.
The cardiac muscle collection of specimens
Each treatment group is got the size 0.3cm * 0.3cm of the following ischemic injuries of ligature district ischemic area (colour-darkening and asystole) cardiac muscular tissue * 0.3cm during respectively at ischemia-reperfusion 3h.Sham operated rats is got corresponding time point, corresponding site cardiac muscular tissue.Do HE dyeing respectively, the TUNEL method detects apoptosis of cardiac muscle.
Biochemical indicator detects
Plasma creatine kinases MB isozyme (CK-MB) detects and carries out with 7170A type automatic clinical chemistry analyzer (Hitachi, Ltd, Japan), and test kit is provided by U.S. Xi Mai company.Malonaldehyde (MDA) detects and carries out with the thiobarbituricacid colorimetry; Superoxide dismutase (SOD) detects and carries out with xanthine oxidase inhibition method; Test kit gathers Lik-Sang thing engineering in medicine institute by Nanjing to be provided.
Apoptosis of cardiac muscle detects
Adopt Brdurd (dUTP) breach end-labelling (the TDT-mediated dUTP end labeling of deoxyribonucleic acid transferase (TdT enzyme) mediation; The TUNEL method) in situ detection apoptosis of cardiac muscle.Get each one of each BIAO and BEN roughly the same position section respectively, with reference to the method detection apoptotic cell of U.S. Santa Cruz Biotechnology company apoptosis test regent box description.The result judges: observe with OLYMPUS BX-50 light microscopic imaging system; The person that has the brown yellow granule in the nucleus is apoptotic cell, and optical microscope high power field (* 400) selects 10 visuals field to calculate apoptosis of cardiac muscle index (AI) at random in the positive apoptosis cells distributed areas.
The result:
The result is as shown in table 5.
Table 5
1) CK-MB, MDA and SOD level are relatively
Before putting to death animal, model control group Plasma CK-MB and MDA level are apparently higher than each treatment group (P＜0.01), and the SOD level then is lower than levocarnitine treatment group (P＜0.01); Each treatment group and sham operated rats compare, MDA, SOD there was no significant difference (P＞0.05), but CK-MB still obviously increases (P＜0.05).
2) apoptosis of cardiac muscle index (AI)
The person that has the brown yellow granule in the nucleus is apoptotic cell.Model control group AI relatively has significant difference (P＜0.01) in twos apparently higher than each treatment group.Each organizes AI and sham operated rats more all has significant difference (P＜0.01).
3) tectology is observed (HE dyeing)
Obvious abnormal change is not seen by sham operated rats cardiac muscular tissue: the cardiac muscle fiber form is normal, and band is clear, and myocardial cell dyeing is clear, and nucleus is complete.The visible cardiac muscle fiber of model control group is partly ruptured and focal dissolving necrosis.Each treatment group cardiac muscular tissue shows as and is dispersed in cardiac muscle fiber swelling, degeneration and arrangement disorder, myocardium interstitial edema, but structure is almost complete.
Conclusion:
This research shows that compound medicine can obviously reduce the apoptosis of ischemic myocardial cells, and its possible mechanism is to improve the metabolic way of ischemic myocardium, makes some damaged cells that reversible transformation take place, thereby reaches the purpose of protection cardiac muscle.
Test case 5-chronic cardiac insufficiency
Method:
50 of male SD rats (body weight 180-200 gram is provided by Chinese Medical Sciences University experimental animal center) are divided into 5 groups (every group of n=10) at random: blank group (distilled water), model control group (distilled water), levocarnitine treatment group (levocarnitine 200mg/kg), calcium dobesilate treatment group (calcium dobesilate 200mg/kg), compound treatment group (levocarnitine 200mg/kg+ calcium dobesilate 200mg/kg).
Except that the blank group, all the other each treated animals in the experiment the 2nd day lumbar injection amycin 2.5mg/kg, the next day once, totally 6 times.Integral dose 15mg/kg.The normal saline of blank group injection Isodose.Each treatment group basis dosage separately is in the 2nd day oral administration gavage administration every day, totally 4 weeks of experiment.The corresponding distilled water that gives equivalent of blank group and model control group.Injection amycin modeling same day, administration 30min before the injection amycin carries out.All rats are all supplied the feedstuff and the drinking-water of capacity.
Sample collecting carries out respectively with measuring as follows:
Blood plasma MDA and whole blood GSH assay
Experiment beginning the 2nd weekend of back and the 6th weekend, 5 groups of rats are all got jugular vein blood, survey MDA and GSH content.MDA measures the thiobarbituricacid method that adopts improvement, and GSH measures and adopts dithio dinitrobenzoic acid method, and method sees Nanjing for details and builds up MDA and the GSH testing cassete description that bio-engineering research provides.
The preparation of BIAO and BEN and the calculating of cardiac index
Tested for 6 weekends, disconnected neck is put to death rat, takes by weighing to open breast after the rat body constitution amount and expose heart, takes out heart; Along the free heart of aortic root, reject the unnecessary connective tissue of trunk wall, with 4 pre-cooling normal saline flushing blood stains; Filter paper blots, and takes by weighing cardiac mass, calculates cardiac mass index (heart weight index; HWI), HWI=cardiac mass/animal body quality is as the judgement index of cardiac hypertrophy.
The result:
1) rat body constitution amount and whole body situation
5 groups of rat body constitution amounts at 6 weekend are respectively: model control group (348.12 ± 13.45) g; Levocarnitine treatment group (353.33 ± 9.67) g; Calcium dobesilate treatment group (331.28 ± 10.30) g; Compound treatment group (347.54 ± 8.91) g; With blank group (361.38 ± 11.26) g there was no significant difference (P＞0.05).Wherein performance such as skin alopecia areata, ascites in various degree all appears in the model control group rat; Levocarnitine treatment group has 4 examples depilation phenomenon to occur; Calcium dobesilate treatment group has 3 examples depilation phenomenon to occur; The compound treatment group has 3 examples depilation phenomenon to occur; Above situation does not then appear in blank group rat.
2) contents of mda and GSH content
The 2nd weekend and the 6th weekend, model control group MDA content all is significantly higher than the blank group, and GSH content significantly is lower than the blank group, and difference all has statistical significance (all P＜0.01).At the 6th weekend, each treatment group MDA content all is higher than the blank group, but is lower than model control group, and difference all has statistical significance (P＜0.05); And GSH content and blank group difference not statistically significant (P＜0.05), but apparently higher than model control group, difference has statistical significance (P＜0.01).The result is as shown in table 6.
Table 6
3) cardiac mass index (HWI)
Model control group HWI is (3.521 ± 0.339), is significantly higher than blank group (2.781 ± 0.333) and levocarnitine treatment group (3.004 ± 0.336), calcium dobesilate treatment group (3.150 ± 0.371) and compound treatment group (2.953 ± 0.345).Difference all has statistical significance (all P＜0.01).Levocarnitine treatment group, calcium dobesilate treatment group and compound treatment group are compared with the blank group, difference not statistically significant (P＞0.05).
Conclusion:
This research shows that compound medicine can effectively improve the myocardial metabolism disorder, removes oxygen-derived free radicals, has antioxidation, can improve the cardiomyopathy degree, thereby can effectively treat cardiac insufficiency.
Although present invention is described with reference to the above specific embodiment, it should be understood that under the situation that does not break away from the spirit and scope of the invention that limits appended claims those skilled in the art can carry out various abreviations, replacement and change.Therefore, these abreviations, replacement and change are contained in the present invention.
Claims (9)
1. oral solid pharmaceutical formulation, said preparation comprises the acceptable excipient of levocarnitine, hydroxy benzene sulfonate and materia medica, and wherein said levocarnitine and said hydroxy benzene sulfonate are separately granulated in the preparation process of said preparation.
2. oral solid pharmaceutical formulation as claimed in claim 1, it is the form of capsule, granule or tablet, particularly slow releasing tablet, sustained release coating tablet, dispersible tablet or controlled release tablet.
3. according to claim 1 or claim 2 oral solid pharmaceutical formulation; Wherein said levocarnitine is selected from acid-addition salts such as levocarnitine formates, cinnamate, hydrochlorate, hydrobromate, hydriodate, hydrofluoride, sulfate, citrate, maleate, acetate, lactate, nicotinate, succinate, oxalates, phosphate, malonate, Salicylate, phenylacetate, stearate, mesylate, picrate or the tartrate of levocarnitine; Base addition salts such as levocarnitine pyridiniujm, ammonium salt, piperazine salt, diethyl amine salt, nicotinoyl amine salt, alkali metal salt, alkali salt, methylamino salt, triethylamine salt, dimethylamino salt or three (methylol) aminomethane salt, and levocarnitine inner salt.
4. according to claim 1 or claim 2 oral solid pharmaceutical formulation; Wherein said hydroxy benzene sulfonate is selected from phenolsulfonic acid pyridiniujm, ammonium salt, piperazine salt, diethyl amine salt, nicotinoyl amine salt, alkali metal salt, alkali salt, methylamino salt, triethylamine salt, dimethylamino salt and three (methylol) aminomethane salt, is preferably selected from phenolsulfonic acid sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and lithium salts.
5. according to claim 1 or claim 2 oral solid pharmaceutical formulation, wherein said granulation is a wet granulation.
6. like each described oral solid pharmaceutical formulation of claim 1-5, the weight ratio of wherein said levocarnitine and said hydroxy benzene sulfonate and the acceptable excipient of said materia medica is 1: 0.001-1: 50, be preferably 1: 0.1-1: 10.
7. each the method for preparing of oral solid pharmaceutical formulation of claim 1-6, said method comprises separately granulates said levocarnitine and said hydroxy benzene sulfonate.
8. method for preparing as claimed in claim 7, wherein said granulation is a wet granulation.
9. levocarnitine and hydroxy benzene sulfonate are used to treat and/or prevent disease such as constitutional nephritis, Secondary cases nephritis, renal ischaemia/reperfusion injury, renal insufficiency (like chronic renal insufficiency), nephrotic syndrome, renal failure (like chronic renal failure), uremia and the diabetic nephropathy that influences renal function in preparation; And the application in the oral solid pharmaceutical formulation of the complication that causes by the disease that influences renal function such as cardiovascular disease (for example myocardial ischemia/perfusion and chronic cardiac insufficiency) again and diabetes; Wherein in the preparation of said preparation, said levocarnitine and said hydroxy benzene sulfonate are separately granulated.
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| CN107693521A (en) * | 2016-08-09 | 2018-02-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | A kind of compound L-carnitine Tablets and preparation method thereof |
| CN113226270A (en) * | 2018-12-20 | 2021-08-06 | 莱雅公司 | Method for treating keratin fibers using a composition comprising a carnitine salt or a carnitine derivative salt comprising an aromatic organic anion |
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| CN102038671A (en) * | 2010-06-29 | 2011-05-04 | 辽宁思百得医药科技有限公司 | Medicinal composition containing levocarnitine and hydroxybenzene sulfonate |
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| CN102038671A (en) * | 2010-06-29 | 2011-05-04 | 辽宁思百得医药科技有限公司 | Medicinal composition containing levocarnitine and hydroxybenzene sulfonate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107693521A (en) * | 2016-08-09 | 2018-02-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | A kind of compound L-carnitine Tablets and preparation method thereof |
| CN113226270A (en) * | 2018-12-20 | 2021-08-06 | 莱雅公司 | Method for treating keratin fibers using a composition comprising a carnitine salt or a carnitine derivative salt comprising an aromatic organic anion |
| CN113226270B (en) * | 2018-12-20 | 2024-05-28 | 莱雅公司 | Method for treating keratin fibres using a composition comprising a carnitine salt or a carnitine derivative salt comprising an aromatic organic anion |
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