CN102188399B

CN102188399B - Torasemide gastric-floating tablet and preparation method thereof

Info

Publication number: CN102188399B
Application number: CN 201110082398
Authority: CN
Inventors: 徐卓业
Original assignee: NANJING ZENKOM PHARMACEUTICAL CO Ltd
Current assignee: NANJING ZHENGKE PHARMACEUTICAL CO., LTD.
Priority date: 2011-04-02
Filing date: 2011-04-02
Publication date: 2012-12-12
Anticipated expiration: 2031-04-02
Also published as: CN102188399A

Abstract

The invention discloses a torasemide gastric-floating tablet and a preparation method thereof, which belong to the field of new medicament technology and relate to new torasemide preparation formulation. After being contacted with gastric juice at body temperature and containing various hydrophilic polymer gel, the novel preparation formulation is hydrated into gel on the surface, so that the volume is swelled, the weight of the tablet is lighter than the buoyant force of the gastric juice so as to lead the tablet to float on the gastric juice, thus prolonging the retention time in the stomach.

Description

Torasemide's intra-gastric floating tablet and preparation method thereof

Technical field

The invention belongs to medical manufacturing field, relate to a kind of novel form of torasemide, be specifically related to a kind of torasemide intra-gastric floating tablet and preparation method thereof.

Background technology

Torasemide is the efficient loop diuretic of a new generation.Went on the market in Belgium first in 1993.In succession in countries such as Italy, Belgium, the U.S. and Britain get permission listing thereafter.In December, 2003 gets into China.First torasemide's hydro-acupuncture preparation (Te Suni) in China SFDA approval manufacturing country in 2004 has been filled up the blank during this medicine is clinical at home.Be used to treat the edema due to congestive heart failure, the kidney floss hepatic disease.Also can be used for treating hypertension, both orally-ingestible also can quietly be annotated.Compare with other diuretic such as furosemide (furosemide).These article diuresis is strong.Bioavailability is high.Persistent, untoward reaction is less.Patient tolerability is good.

1. pharmacological action

There are diuresis, row Na in torasemide ⁺With row C1 ^-Effect, but significantly do not change glomerular filtration rate, RPF and acid-base balance.Act on ascending thick limb of Henle's loop, disturb the Na of tube chamber cell membrane ⁺, K ⁺, 2C1 ^-The symport system suppresses Cl ^-And Na ⁺Heavily absorption, the concentration of liquid lumen NaCl is increased, osmotic pressure increases, the NaCl of renal medulla interstitial fluid reduces, osmotic pressure gradient reduces, thereby disturbs the concentration process of urine, makes urine Na ⁺, Cl ^-Increase with the drainage of water.The human research confirms that also these article act on this position, and is still indeterminate to the influence at other positions, kidney unit.The resisting hypertension mechanism of these article is the same with other diuretic not to be understood as yet fully, possibly be because it has reduced total peripheral resistance.

Diuresis: human trial confirms that the diuresis of 10mg torasemide and 20～40mg furosemide (furosemide) and 1mg bumetanide (bumetanide) are suitable, its diuresis threshold dose 2.5mg.40min diuresis in several hours in oral back is obvious, and the urine amount is dose dependent to be increased, urine peak in Dary in the 4h, and drug effect weakens subsequently, but pressure decay rate is considerably slower than furosemide.Healthy subjects vein and oral medication, effect can be kept 6～8h.

Row Na ⁺Effect: torasemide suppresses the Heng Shi loop to Na ⁺And Cl ^-Heavily absorption, and far-end kidney section can not be compensatory fully, so the row of generation Na ⁺And diuresis.Row Na ⁺Threshold dose be 2.5mg.In the therapeutic dose scope, urine Na ⁺And be logarithm one linear response curve between the discharge rate of torasemide.These article 20mg significantly increases total row Na of each time period and 24h ⁺Amount, and these article 10mg or furosemide 40mg only obviously increase row Na in the pro-4h ⁺Amount.The quiet notes of healthy volunteer 20mg torasemide begins to arrange Na in the 1h ⁺, l～2h reaches the peak, Na in the 6h ⁺Discharge at most, after this arrange Na ⁺Reduce, be lower than basis row Na ⁺Amount

Row K ⁺Effect: the row K of torasemide ⁺Effect is weaker than other loop diuretics.Torasemide lacks in the heavily absorption activity of proximal convoluted tubule to phosphorus or saccharide, and K ⁺Heavily absorption also at proximal convoluted tubule, infer row K thus ⁺Amount reduces.On the other hand, also maybe be relevant with the aldosterone antagonist effect of these article, it arranges K ⁺Effect is weaker than its row Na relatively ⁺Therefore effect urinates Na ⁺/ K ⁺Increase.The row K of furosemide ⁺Effect is 3 times of these article.But monitor blood K clinically ⁺And urine row K ⁺Amount, torasemide and furosemide do not have significant difference.

Other effects: with the long-term treatment blood Mg of torasemide ²⁺The variation of no clinical meaning, Mg in the back 24h that takes medicine ²⁺Variation directly with row K ⁺Relevant, therefore, at present to Mg ²⁺Effect still do not have final conclusion.In torasemide is between action period, urine Ca ²⁺With urine Cl ^-Lose with urine Na ⁺Drainage parallel.Urine Ca in the 24h ²⁺And C1 ^-Excretion rate between 10.20mg of torasemide and furosemide 40mg, do not have significant difference, blood Ca ²⁺With blood Cl ^-Do not have and become.Discharge to uric acid, carbamide, creatinine does not also have obvious influence.

2 pharmacokineticss

The bioavailability of oral torasemide is about 80%, and onset is rapid, and intravenous administration got final product onset in 10 minutes, and peak time is 1～2 hour, advances altogether with food, selects peak time to delay slightly, and with homaluria 20%, all the other are at intrahepatic metabolism with the medicine original shape.Plasma half-life bumetanide 1～1.5h, furosemide 2h, this medicine can reach 3～4h.1 time/d of administration, hepatic and kidney function obstacle person do not produce usually yet and accumulate.Dose-effect relationship is stable: in sizable dosage range, can keep good dose-effect relationship.Unique aldosterone antagonism makes K ⁺Obviously reduce Deng the electrolyte excretion amount, clinically to Mg ²⁺, uric acid, sugar and lipid do not have obvious influence.Prolonged application is difficult for producing the diuresis opposing, and patient tolerability is good.

3 clinical practices

Torasemide is used for the edema patient due to congestive heart failure, cirrhotic ascites, the kidney disease; Also can be used for primary hypertension patient.Main component is a torasemide, and chemistry is by name: 1-isopropyl-3-[(toluidino between 4--3-pyridine radicals) sulfonyl] urea, be sulfonylureas pyridines diuretic, and it acts on the Heng Lishi ascending thick limb of Henle's loop, suppresses Na ⁺/ K ⁺/ 2Cl ^-Carrier system makes Na in the urine ⁺, K ⁺, Cl ^-Increase with the drainage of water, but acid-base balance in glomerular filtration rate, RPF or the body is not made significant difference.The low potassium that can cause can increase the weight of the untoward reaction of heart tonifying glycoside.Can strengthen the potassium consumption effect of salt and glucocorticoid and aperient.Nonsteroidal antiinflammatory drug (like indometacin) and probenecid can reduce the diuresis and the hypotensive effect of these article.Can strengthen the effect of antihypertensive drug.Continuous use or beginning and a kind of angiotensin converting enzyme inhibitor drug combination may make blood pressure excessively reduce.Can reduce the effect of antidiabetic medicine., may increase the weight of high dose the ototoxicity and the nephrotoxicity of aminoglycosides antibiotics (like kanamycin, gentamycin, tobramycin), cisplatin class preparation, cephalo-type when using.Can strengthen the effect of curare appearance muscle relaxant and theophylline class medicine.Can reduce norepinephrine and adrenergic effect.When using heavy dose of these article of Salicylate time-like, patient can increase the toxicity of salicylic acid salt.

Common adverse reactions has headache, dizzy, tired, loss of appetite, muscle spasm, nausea and vomiting, hyperglycemia, hyperuricemia, constipation and diarrhoea; The fluid and electrolyte balance imbalance possibly take place in long-term a large amount of use.Polyuria often takes place in treatment initial stage and older patient; Individual patient causes that owing to blood concentrates hypotension, abalienation, thrombotic complications and the heart or cerebral ischemia cause cardiac arrhythmia, angina pectoris, acute myocardial infarction or faintness etc., and hypokalemia can occur in low potassium diet, vomiting, diarrhoea, too much use the parafunctional patient of cathartic regulating liver-QI.Skin allergy can appear in individual patient, accidental pruritus, erythra, photosensitivity reaction, rare xerostomia, acroparesthesia, visual disorder.Renal failure anuria patient, hepatic precoma or hepatic coma patient, to these article and sulfonylurea autopath, hypotension, Hypovolemia, low potassium or hyponatremia patient, serious dysuria (like prostate hyperplasia) patient is forbidden these article.

The dosage form of present domestic torasemide has agent such as tablet, capsule, soft capsule, injection powder pin, injection, powder pin, but all there is tachytrophism in this type of medicine, needs multiple dosing, has increased the fluctuation of blood drug level, has amplified the untoward reaction of torasemide.Therefore developing a kind of intra-gastric floating tablet that discharges with 0 stage speed is imminent.

Summary of the invention:

The object of the present invention is to provide a kind of good stability, quality is high, and is evident in efficacy; Untoward reaction is little is tablet of processing of principal agent and preparation method thereof with torasemide; Use torasemide's intra-gastric floating tablet that this method processes and it is characterized in that this intra-gastric floating tablet owing to contain multiple hydrophilic macromolecule gel, with after gastric juice contacts, surface water changes into gel in body temperature; And make volumetric expansion; The weight of slice, thin piece floats on the gastric juice slice, thin piece less than the buoyancy of gastric juice at this moment, must be through prolonging gastric transit time.A kind of intra-gastric floating tablet that contains torasemide of the present invention is made up of following component:

A kind of intra-gastric floating tablet that contains torasemide of the present invention is realized through following technical scheme: behind torasemide of recipe quantity, chitosan, Compritol 888 ATO, calcium carbonate, magnesium carbonate, mannitol mix homogeneously; 80 mesh sieves are even; The micropowder silica gel, the sodium lauryl sulphate mix homogeneously that add recipe quantity; The dry method direct compression promptly gets.

Description of drawings

Fig. 1 be in embodiment 1 torasemide's intra-gastric floating tablet torasemide water, in hydrochloric acid (pH=1.0), phosphate buffer (pH=7.2), acetate buffer (pH=5.0) releasing curve diagram.

The specific embodiment

The intra-gastric floating tablet that contains torasemide that the present invention obtains has that method is simple, good stability, characteristics that quality is high.Below implement explanation the present invention, but do not limit the present invention in any way.

Embodiment 1: 10000 in batches

Prescription:

Method for making: behind torasemide of recipe quantity, chitosan, Compritol 888 ATO, calcium carbonate, magnesium carbonate, mannitol mix homogeneously, 80 mesh sieves are even, add micropowder silica gel, the sodium lauryl sulphate mix homogeneously of recipe quantity, and the dry method direct compression promptly gets.

The release degree of torasemide's intra-gastric floating tablet is investigated: the torasemide's intra-gastric floating tablet to processing carries out drug release determination.

Dissolution test method: drug release determination: getting torasemide's intra-gastric floating tablet, adopt 2010 editions two appendix XD drug release determinations of Chinese Pharmacopoeia method, second method, is solvent with hydrochloric acid solution (pH=1.0), water, acetate buffer (pH=5.0), phosphate buffer (pH=7.2) 1000ml respectively; Rotating speed is 75rpm, gets solution 10ml respectively at 1h, 2h, 4h, 8h, 12h, adds the release medium of uniform temp, equal volume simultaneously; Institute's sample thief filters immediately, gets subsequent filtrate as need testing solution, and other gets torasemide's reference substance; Add the reference substance solution that mobile phase is made into 5 μ g/ml; According to HPLC, (4.6mm * 250mm, 5 μ m) are chromatographic column with Kromasil C18 chromatographic column; Mobile phase is 0.02mol/L potassium dihydrogen phosphate (pH3.0): acetonitrile (volume ratio 3: 1), and flow velocity is 1.0ml/min; Detecting wavelength is that 291nm measures.Measure the result and see table 1, Fig. 1.

Table 1 torasemide intra-gastric floating tablet release degree is investigated table

	1h	2h	4h	8h	12h
						Water	21.7％	31.5％	59.6％	78.6％	99.5％
Acetate buffer (pH=5.0)	14.2％	26.4％	55.5％	75.6％	96.5％
						Hydrochloric acid solution (pH=1.0)	20.5％	33.9％	61.8％	81.4％	98.3％
Phosphate buffer (pH=7.2)	17.4％	28.9％	57.8％	80.2％	97.5％

Claims

1. torasemide's intra-gastric floating tablet, it is characterized in that: this intra-gastric floating tablet is to be the preparation that main component is processed with torasemide, this intra-gastric floating tablet is owing to contain multiple hydrophilic macromolecule gel; In body temperature with after gastric juice contacts; Surface water changes into gel, and makes volumetric expansion, and the weight of slice, thin piece is less than the buoyancy of gastric juice at this moment; Slice, thin piece is floated on the gastric juice, must be through prolonging gastric transit time; This intra-gastric floating tablet is made up of following component:

2. torasemide according to claim 1 intra-gastric floating tablet is characterized in that: this intra-gastric floating tablet prescription is:

3. the method for preparing of the described torasemide of claim 2 intra-gastric floating tablet; It is characterized in that: method for preparing may further comprise the steps; Behind torasemide of recipe quantity, chitosan, Compritol 888 ATO, calcium carbonate, magnesium carbonate, mannitol mix homogeneously, 80 mesh sieves are even, add micropowder silica gel, the sodium lauryl sulphate mix homogeneously of recipe quantity; The dry method direct compression promptly gets.