A kind of modified-release tablets of potassium chloride and preparation method thereofTechnical field
The invention belongs to technical field of medicine, in particular to a kind of slow releasing tablet containing potassium chloride and preparation method thereof.
Background technology
Potassium chloride is clinical conventional electrolyte balance regulating, and clinical efficacy is definite, is widely used in clinical departments room.Be used for the treatment of and prevent the hypokalemia that a variety of causes (hypoalimentation, vomiting, severe diarrhea, application row's potassium diuretic or prolonged application sugar cortex stimulin and adrenal cortex stimulin, lose potassium nephropathy, Bartter syndrome etc.) causes, frequent, the polyphyly premature beat that also can be used for that the poisoning by cardiotonic glycoside such as the heart, renal edema and Folium Digitalis Purpureae cause or rapid heart rate not normal.
As everyone knows, potassium chloride is irritant to gastrointestinal tract, usually cause nausea, vomit, abdominal part do not accommodate diarrhoea.Weakness, weakness, confusion, hypotension, dizzy, heart block may be caused time heavy dose of, even cause death.Often occur poisoning signal when taking potassium chloride, administration that therefore must be very careful for ordinary preparation, in order to reach therapeutic purposes, every day, the potassium chloride dosage of 1-2g usually needed point to take for 2-6 time, and the compliance of patient is very poor.Therefore, potassium chloride can be considered to make sustained-release preparation.The slow releasing tablet listing of existing potassium chloride at home, but because potassium chloride water solublity is very good, existing slow releasing preparation is usually difficult to the release controlling medicine preferably, often there is the prominent generation releasing phenomenon, there is larger potential risk, as released because of prominent the cation potassium causing high local concentrations in gastrointestinal system, cause the symptoms such as gastrointestinal ulceration, hemorrhage and perforation.In addition, existing slow releasing tablet belongs to individual unit system, and stimulating gastrointestinal when Gastrointestinal Obstruction, esophageal stricture, diverticulum, intestinal atonia increases further, can increase the weight of the state of an illness.
CN103006696B discloses a kind of manufacture method of modified-release tablets of potassium chloride, and with hypromellose E15 for slow-release material prepares slow release label, with acrylic resin RS100, acrylic resin RL100 for slow-release material bag is by extended release coatings, and bag is by sugar-coat.
CN102961363B discloses a kind of potassium chloride slow release capsule, the content of described potassium chloride slow release capsule is slow-release micro-pill, slow-release micro-pill is by the supplementary material potassium chloride 70 ~ 97% of percentage by weight, moulding material 0 ~ 10%, slow-release material 2 ~ 20%, plasticizer 0.5 ~ 5% and antiplastering aid 0 ~ 10% form.By potassium chloride and moulding material mix homogeneously, dry granulating machine is adopted to be prepared into medicine carrying micropill; Then slow-release material, plasticizer and antiplastering aid are mixed with into slow release layer coating solution; Medicine carrying micropill is placed in fluid bed, and is injected in fluid bed by the slow release layer coating solution be prepared into, medicine carrying micropill is conventionally carried out coating, prepares slow-release micro-pill, slow-release micro-pill incapsulates, preparation cost invention product potassium chloride slow release capsule.
CN102144985A relates to formula and the technique of Potassium chloride controlled release tablet, adopt ethyl cellulose, polyvinylpyrrolidone, hypromellose etc. for release blocker, in addition with inert excipient acceptable in pharmacy, lubricant, coloring agent according to certain ratio, label is prepared by suitable technique, again with cellulose acetate and be equipped with suitable coating additive prepare parcel label semipermeable membrane, and on film, produce release path, form monocompartment osmotic pump-type controlled release system, the Zero order release of potassium chloride is provided.
The main method reaching slow release in prior art is the diffusion rate being controlled medicine by matrix diffusion, coating membrane diffusion or the use in conjunction of the two, thus reaches slow effect.Widely used potassium chloride slow releasing preparation comprises matrix tablet, film controlled release tablet, slow-release micro-pill etc. clinically, the matrix type release that its slow release releasing mechanism is main or traditional or film controlling type release.There is release heterogeneity, easily prominent releasing or the incomplete problem of release occur in matrix sustained release tablet.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of drug release steadily, high, the simple modified-release tablets of potassium chloride of preparation method of good stability, bioavailability.
In order to realize object of the present invention, inventor is studied by lot of experiments and updates, and finally obtains following technical scheme:
A kind of modified-release tablets of potassium chloride, it is formed by gastric solubleness slow-release micro-pill, enteric sustained-release pellet and other pharmaceutically acceptable adjuvant direct compression, described gastric solubleness slow-release micro-pill is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin IV and surfactant form, and described enteric sustained-release pellet is 1:(0.3-0.5 by mass ratio): (0.3-0.5): the potassium chloride of (0.01-0.03), mesoporous carbon, acrylic resin I-III and surfactant form.
Preferably, modified-release tablets of potassium chloride as above, gastric solubleness slow-release micro-pill wherein and the weight ratio of enteric sustained-release pellet are 1:(2-4), preferred weight ratio is 1:3.
Preferably, modified-release tablets of potassium chloride as above, acrylic resin I-III is wherein selected from one or more of acrylic resin I, acrylic resin II and acrylic resin III.
Further preferably, modified-release tablets of potassium chloride as above, pharmaceutically acceptable adjuvant wherein comprises filler, disintegrating agent and lubricant.Further preferably, described filler is selected from one or more in lactose, microcrystalline Cellulose, pregelatinized Starch and starch; Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium; Described lubricant is selected from one or more in magnesium stearate, silicon dioxide, sodium stearyl fumarate and Pulvis Talci.
Further preferably, modified-release tablets of potassium chloride as above, mesoporous carbon is wherein specific surface area is 1018 ~ 1058m2/ g, pore volume are 0.51 ~ 0.86cm3the mesoporous carbon of/g.
Present invention also offers a kind of preparation method of modified-release tablets of potassium chloride, the method comprises the steps:
(1) preparation of gastric solubleness slow-release micro-pill:
1. potassium chloride is dissolved in 0.05-0.2mol/L hydrochloric acid solution, adds mesoporous carbon and stir, then add acrylic resin IV successively, surfactant is stirred to and dissolves completely;
2. the mixed liquor 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing hydrochloric acid, filters, washing liquid paraffin, dry, obtains gastric solubleness slow-release micro-pill;
(2) preparation of enteric sustained-release pellet:
1. potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, then add acrylic resin I-III successively, surfactant is stirred to and dissolves completely;
2. the mixed solution 1. prepared is added in liquid paraffin, even to emulsifying by the rotating speed rapid stirring of 1000 ~ 1500rpm;
3. the emulsion 2. prepared is heated to 100 DEG C under agitation, Keep agitation removing ammonia, filters, washing liquid paraffin, dry, obtains enteric sustained-release pellet;
(3) will obtain gastric solubleness slow-release micro-pill, enteric sustained-release pellet is mixed homogeneously with other pharmaceutically acceptable adjuvant, tabletting, to obtain final product.
It should be noted that, in the preparation method of modified-release tablets of potassium chloride of the present invention, wherein adopted surfactant is preferably sorbester p17.
Compared with prior art, the modified-release tablets of potassium chloride that the present invention relates to can improve medicine and gastrointestinal contact area, makes drug absorption complete, thus improves bioavailability; Combined by the micropill of several different drug release rate, can obtain desirable rate of releasing drug, drug release is steady, obtains the blood drug level of expection, and can maintain longer action time, and not existing dashes forward releases phenomenon, can avoid untoward reaction such as the stimulations of gastric mucosa; Its drug release behavior is multiple micropill composition compound recipe impact of a composition dosage, and absorption in vivo has good repeatability; Medicine is seldom subject to the impact of gastric emptying change in vivo, and absorption in vivo has good repeatability; Micropill has uniform particle sizes, good fluidity, and not easily the advantage such as crushing, particularly in fine pellet core surface coatings, makes slow releasing preparation, and technique is simple, can avoid tablet etc. due to coating uneven and the risk of medicine pulse may be caused, safety coefficient is high.
Detailed description of the invention
Now further describe preparation process of the present invention and implementation result by following examples, but protection scope of the present invention is not limited to following examples.Those skilled in the art, according to announcement of the present invention, do not depart from improvement that scope makes and amendment all should within protection scope of the present invention.It should be noted that, the mesoporous carbon that embodiment adopts is specific surface area is 1018 ~ 1058m2/ g, pore volume are 0.51 ~ 0.86cm3the mesoporous carbon of/g.
Embodiment 1: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with pregelatinized Starch, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Embodiment 2: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Embodiment 3: the preparation of modified-release tablets of potassium chloride
(1) gastric solubleness slow-release micro-pill
(2) enteric sustained-release pellet
(3) slow releasing tablet
Preparation method:
(1) potassium chloride is dissolved in 0.1mol/L hydrochloric acid solution, adds mesoporous carbon and stir, add acrylic resin IV and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing hydrochloric acid solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride gastric solubleness slow-release micro-pill.
(2) potassium chloride is dissolved in saturated ammonia, adds mesoporous carbon and stir, add acrylic resin I and be stirred to and dissolve completely, add sorbester p17 and be stirred to and dissolve completely; Added by mixed solution in liquid paraffin, rapid stirring is even to emulsifying; The emulsion of preparation is heated to 100 DEG C under agitation, and Keep agitation removing sodium hydroxide solution, filters, with cyclohexane extraction washing liquid paraffin, dry, obtains potassium chloride enteric sustained-release pellet.
(3) gastric solubleness of preparation, enteric sustained-release pellet are mixed homogeneously with lactose, polyvinylpolypyrrolidone, magnesium stearate, the stamping of Φ 20 × 9.5mm scrobicula of bonding, controls about hardness 100-120N, to obtain final product.
Comparative example 1: the preparation of modified-release tablets of potassium chloride
Preparation method:
Potassium chloride pulverized 100 mesh sieves, mixs homogeneously, add alcohol granulation with microcrystalline Cellulose, hypromellose, crossed 18 mesh sieves, 60 DEG C of dryings, cross 18 mesh sieve granulate, add recipe quantity magnesium stearate, mix homogeneously, Φ 12mm stamping, controls about hardness 90-110N, to obtain final product.
Comparative example 2: the preparation of modified-release tablets of potassium chloride
(1) Core formulation
(2) coating prescription
Ethyl cellulose 5g
Hyprolose 1g
Ethanol 100g
Preparation method:
Potassium chloride pulverized 100 mesh sieves, mixed homogeneously with microcrystalline Cellulose, polyvidone, added 50% alcohol granulation, crossed 18 mesh sieves, 60 DEG C of dryings, cross 18 mesh sieve granulate, add recipe quantity magnesium stearate, mix homogeneously, Φ 12mm stamping, controls about hardness 90-110N, obtains label.Ethyl cellulose and hyprolose are dissolved in ethanol, to the label coating of preparation, to weightening finish about 20%.
Embodiment 4: the drug release determination of modified-release tablets of potassium chloride
Get this product, according to drug release determination method (Chinese Pharmacopoeia version annex X D second method in 2010), adopt dissolution method second subtraction unit (Chinese Pharmacopoeia version annex X C in 2010), with 0-2h with pH1.2 hydrochloric acid solution 500ml for solvent, the pH6.8 phosphate buffer solution 400ml of preheating is added after 2h sampling, rotating speed is 75 turns per minute, operate in accordance with the law, when 1,2,4,6 and 8h, get solution 25ml respectively, filter, and instant release medium of supplementing identical temperature, same volume in process container; Get subsequent filtrate as need testing solution; Another potassium chloride reference substance is appropriate, is dissolved in water and dilutes and make, and is dissolved in water and quantitatively dilutes the solution made about containing 80 μ g in every lml, product solution in contrast.Precision measures need testing solution and gets subsequent filtrate 20mL, adds Neutral potassium chromate indicator 4 respectively, and with 0.01mol/L silver nitrate (specification 0.01mol/L, F=1.013) titration, and adopt blank solvent to correct, drug release determination the results are shown in Table.
Table 1: modified-release tablets of potassium chloride drug release determination result (%)
From the experiment statistics result of table 1, modified-release tablets of potassium chloride prepared by embodiment 1-3 is in 2h release about 25%, mainly because gastric solubleness slow-release micro-pill discharges completely under pH1.2 condition, and enteric coated micropill can not discharge in acid condition, therefore slow releasing tablet of the present invention can not exist and prominent releases phenomenon; Enteric coated micropill has good slow release effect under pH6.8 condition, and 8h medicine releases substantially entirely.Comparative example 1 is ordinary gel type slow releasing tablet, and comparative example 2 is film controlling type slow releasing tablet, and all there is the prominent risk released, the result caused is that in drug release determination process, each sample release differs greatly.