CN106606502B - Doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof - Google Patents
Doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides a compound doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and a preparation method thereof, the composition consists of a tablet core containing doxylamine succinate and pyridoxine hydrochloride, a barrier coat, an enteric coat and other medicinal auxiliary materials, the composition has simple process and good stability, is insoluble in stomach and can be quickly released in intestines, and the defect that the product in the prior art is slowly released after being transferred to a neutral environment in the intestines through a gastric acid environment is overcome.
Description
Technical Field
The invention relates to a doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and a preparation method thereof, and belongs to the technical field of medicines.
Background
Vomiting during pregnancy is a natural reaction, and the main symptoms are general weakness, depressed mood, dizziness, nausea, poor appetite, sensitivity to peculiar smell or strong reaction, and are particularly obvious in the early morning or during sleep. These symptoms generally occur in the early fifth week of pregnancy, and after the sixteenth week, the vomiting reaction of most people gradually decreases until naturally disappears, but a few pregnant women have the vomiting reaction during the whole pregnancy, which is painful. The vomiting reaction is not only unfavorable for the pregnant woman to recuperate, but also is important for how to deal with the vomiting and how to reduce the adverse effect of the vomiting on the pregnant woman and the fetus as much as possible because most people have affected appetite during the pregnancy and the nutrition of the fetus comes from the mother.
Doxylamine succinate has the chemical name of N, N-dimethyl-2- [ 1-phenyl-1- (2-pyridine) ethoxy ] ethylamine succinate, is white or milk white powder, is easily soluble in water, ethanol and chloroform, and is very slightly soluble in ether and benzene. The product has antihistaminic and anticholinergic effects, and has remarkable tranquilizing effect, with low intestinal side effect. Antihistamines are a class of drugs that counteract the various pathological responses caused by histamine. The medicines reversibly occupy histamine receptors, competitively block the binding of histamine to the receptors, and thus show an antihistaminic effect. Histamine receptors are of the two types H1 and H2, and produce different effects when activated. Activation of the H1 receptor causes contraction of bronchial and gastrointestinal smooth muscles, relaxation of vascular smooth muscles, enhancement of atrial contraction, slowing of atrioventricular conduction, etc. The H2 receptor can cause gastric acid secretion increase of gastric parietal cells when excited. These two effects are each antagonized by different drugs. The H1 receptor antagonist displaces histamine from the body, competitively antagonizes its action, and does not inactivate histamine and inhibit its synthesis and release. Therefore, it is mainly used to relieve the symptoms of anaphylaxis.
Pyridol hydrochloride, vitamin B6, is 5-hydroxy-6-methyl-3, 4-pyridinedimethanol hydrochloride in the chemical name of white or off-white crystalline powder, is readily soluble in water, sparingly soluble in ethanol, and hardly soluble in diethyl ether. It is stable in air and has good heat resistance, but it is decomposed slowly in sunlight, and is decomposed rapidly in aqueous solution, and its melting point is about 206 deg.C and can be partially decomposed. Is a water-soluble vitamin, is stable in acid solution and is easy to destroy in alkali solution. Is a B vitamin containing pyridoxine, pyridoxal or pyridoxamine. Vitamin B6 is converted to pyridoxal phosphate in erythrocytes and acts as a coenzyme for various metabolic functions of proteins, carbohydrates, lipids. Vitamin B6 is also involved in the conversion of tryptophan to nicotinic acid or 5-hydroxytryptamine. It is absorbed mainly in the jejunum. Vitamin B6 did not bind to plasma proteins and pyridoxal phosphate did bind to plasma proteins completely. The half-life period is 15-20 days. Metabolism in the liver and excretion through the kidney. The pyridoxine hydrochloride is suitable for preventing and treating vitamin B6 deficiency (vitamin B6 deficiency can cause xanthine acid urine, iron granulocyte anemia, nervous system diseases, seborrheic dermatitis and xerocheilia), and preventing and treating isoniazid poisoning; it can also be used for treating emesis and seborrheic dermatitis caused by pregnancy, radiation sickness, and anticancer drugs; treating infantile convulsion or administering to pregnant woman to prevent infantile convulsion.
Doxylamine succinate pyridoxine hydrochloride compound was first developed by dachsiensin, canada (duchenay Inc.) for the treatment of emesis, and its 1995 patent CA2139896 discloses that doxylamine succinate and pyridoxine hydrochloride are combined in approximately equal weight ratios for the prevention and suppression of nausea and vomiting symptoms in anovulatory patients, involving oral, rectal, intravenous, and other dosage forms.
Dacisin corporation's patent ZL01814548.5 (publication No: CN1447694A) provides an enteric coated rapid onset formulation of pyridoxine hydrochloride and doxylamine succinate comprising a disintegrant such that the formulation meets the following dissolution profile when measured at 100rpm in 1000ml of phosphate buffer pH6.8 at 37 ℃: (a) at least about 40% of the total amount of each of pyridoxine hci and doxylamine succinate is dissolved after 30 minutes of measurement; (b) at least about 70% of the total amount of each of pyridoxine hci and doxylamine succinate is dissolved after 60 minutes of measurement; (c) at least about 80% of the total amount of each of pyridoxine hci and doxylamine succinate is dissolved after 90 minutes of measurement; (d) at least about 90% of the total amount of each of pyridoxine hci and doxylamine succinate is dissolved after 120 minutes of measurement. Preferably, the formulation comprises a core coated with at least one enteric coating, said core comprising pyridoxine hydrochloride, doxylamine succinate and the following inactive excipients: fillers or binders, disintegrants, lubricants, silica flow modifiers and stabilizers.
Dacisin patent application CN104136004A discloses a doxylamine succinate pyridoxine hydrochloride oral formulation with both immediate release and sustained release, one embodiment of the tablet formulation comprising: the slow release tablet core contains 7.5mg of doxylamine succinate and 7.5mg of pyridoxine hydrochloride, and the quick release tablet core contains 2.5mg of doxylamine succinate and 2.5mg of pyridoxine hydrochloride.
CN103432126A discloses a pharmaceutical composition for treating vomiting during pregnancy, which contains doxylamine succinate (1-50 mg/granule) or further contains pyridoxine hydrochloride, and is prepared into oral preparations, including enteric coated tablets and capsules, together with pharmaceutically acceptable auxiliary materials.
WO2013082706 discloses a disintegrant-free oral sustained release composition comprising a core and an enteric coating layer, wherein the dissolution rate of the drug is about 95% within 20 minutes as determined by a USP Type ii apparatus at a stirring rate of 100rpm and a ph of 900mL of 6.5 phosphate buffer solution; the active components comprise: doxylamine and/or pyridoxine hydrochloride in an amount of 10mg each.
The inventor finds that when the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet in the prior art is subjected to a dissolution test of 0.1N HCl (in an acid stage) and then a phosphate buffer solution (in an alkali stage) with pH of 6.8, the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet is slowly released in the alkali stage, the release rate of the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet in the alkali stage can only reach about 50%, and when the dissolution test of the alkali stage is directly carried out without the acid stage, the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet can be normally and quickly released, and the release rate of the doxylamine; however, the tablets must pass through the gastric acid environment in vivo and then enter the neutral environment of the small intestine, which is similar to the above dissolution test process of the acid stage before the alkali stage, and if the enteric-coated tablets cannot be well dissolved in the alkali stage after the acid environment, the rapid exertion of the drug effect is inevitably influenced. This is probably due to the fact that some drugs are complexed with the carboxyl groups of the enteric material, and during 2 hours of immersion in acid, the penetration of moisture complexes the core material with the enteric material to form a poorly soluble substance, thereby affecting release.
Disclosure of Invention
In order to solve the defects of the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablets in the prior art, the invention aims to provide a compound doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition which can still be quickly released in a dissolution medium in an alkaline stage after undergoing an acid stage, and has simple process and good stability, and a preparation method thereof.
The invention is realized by the following technical means:
the invention provides a doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition, wherein the enteric-coated tablet is a tablet prepared from a tablet core containing doxylamine succinate, pyridoxine hydrochloride and pharmaceutical excipients, and a first isolation coating, an enteric coating and a second isolation coating layer which are wrapped outside the tablet core;
the tablet core comprises the following components in parts by weight: doxylamine succinate, pyridoxine hydrochloride, a filling agent, a disintegrating agent, a lubricant, a glidant and a flow aid, wherein the weight ratio of doxylamine succinate to pyridoxine hydrochloride to the flow aid is 5-20: 80-160: 1-6: 2-6: 0.5-2;
the weight ratio of each component in the first isolation clothes and the second isolation clothes is as follows: the isolation material comprises an anti-sticking agent and a dispersion medium, wherein the dispersion medium is 1-50: 1-15: 50-500; the first isolation clothes and the second isolation clothes are 8-20% aqueous solution of Kalekang coating powder YS-1-7472 or YS-1-7003;
the enteric coating comprises the following components in percentage by weight: the enteric material comprises a plasticizer, an anti-sticking agent, a defoaming agent, a pH regulator and a dispersion medium, wherein the ratio of the plasticizer to the defoaming agent to the dispersion medium is 30-50: 0.8-2: 4-10: 0.1-1: 0.1-0.3: 15-50.
Further, the filler is selected from one or more of microcrystalline cellulose, lactose, starch and mannitol.
Further, the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
Further, the lubricant is magnesium stearate.
Further, the glidant is silicon dioxide or talcum powder.
Further, the release material is selected from one or more of PVP, HPMC, and PEG 4000.
Further, the enteric material is selected from one or more of acrylic resin Eudragit L, hydroxypropyl methylcellulose phthalate (HPMCP), acrylic resin Kollicoat MAE 100P and Yakeyi 930; the plasticizer is selected from one or more of diethyl phthalate, PEG6000, PEG400 and triethyl citrate; the defoaming agent is dimethyl silicone oil; the pH regulator is sodium hydroxide or sodium bicarbonate.
Further, the antisticking agent is talcum powder; the dispersion medium is water or ethanol or a mixture of the water and the ethanol.
The invention also provides a preparation method of the doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition, which comprises the following steps:
step 1. preparation of tablet core:
(1) respectively drying the filler to the moisture content of less than 1-4% and the flow aid to the moisture content of less than 4-6% at 80 ℃;
(2) pulverizing doxylamine succinate and pyridoxine hydrochloride, and sieving with 100 mesh sieve;
(3) mixing doxylamine succinate and a flow aid, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(5) mixing the disintegrating agent for 2 times by using a filler equivalent dilution method, adding the mixture into the mixture II, and mixing to obtain a mixture III;
(6) adding the rest of the filler and the mixture (c) into a multidirectional motion mixer, and mixing for 20min at the rotating speed of 10 rpm;
(7) adding lubricant and mixing for 5 min;
(8) and (6) tabletting.
Step 2, coating a first isolation coat:
(1) weighing the isolating material and the anti-sticking agent in the prescription amount, dissolving or dispersing in a dispersion medium, or preparing the Carlekang coating powder YS-1-7472 or YS-1-7003 into an aqueous solution with the concentration of 12%, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(2) and adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 4% -5% +/-0.5%.
Step 3, enteric coating:
(1) adding a sodium hydroxide solution or a sodium bicarbonate solution into the enteric-coated material under stirring, and uniformly stirring and dispersing;
(2) adding the dispersion medium into a beaker, adding a plasticizer, an anti-sticking agent and a defoaming agent, homogenizing for 20min, adding the suspension into the enteric material solution under mild stirring, and sieving with a 60-mesh sieve before use;
(3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the enteric coated tablet after the feeding of the coating liquid is finished, and increasing the weight of the coating by 10% -15% +/-0.5%.
And 4, coating a second isolation coat:
(1) weighing the isolating material and the anti-sticking agent in the prescription amount, dissolving or dispersing in a dispersion medium, or preparing the Carlekang coating powder YS-1-7472 or YS-1-7003 into an aqueous solution with the concentration of 12%, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(2) and (3) adding the enteric-coated tablets into a coating pan, adjusting the air inlet temperature to 60 ℃, the temperature of a tablet bed to 30-35 ℃, the atomization pressure to 0.25MPa, the rotation speed of the coating pan to 10-30 rph, the sample injection flow rate to 3-8 g/min, and obtaining the doxylamine succinate pyridoxine hydrochloride enteric-coated tablets after the coating liquid is fed, wherein the weight of the coating is increased by 2.5-4% +/-0.5%.
The doxylamine succinate pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition prepared according to the formula and the preparation method does not release active ingredients in the acid stage, and can quickly release the active ingredients in a dissolving medium in the alkali stage after the acid stage, so that the effect that the doxylamine succinate pyridoxine hydrochloride enteric-coated tablet is insoluble in the stomach and quickly releases the active ingredients in the intestine is achieved, and the defect of the doxylamine succinate pyridoxine hydrochloride enteric-coated tablet in the prior art is overcome; the enteric-coated tablet has the advantages of few auxiliary materials, low cost and simple process, and can be produced by adopting common tablet production equipment; the enteric-coated tablet has good drug stability; the enteric-coated tablet avoids adverse reaction caused by the stimulation of doxylamine to the upper gastrointestinal tract, and has good patient compliance.
Detailed Description
The following detailed description is further illustrative of the invention and should not be taken as limiting the scope of the invention.
EXAMPLE 1 preparation of doxylamine succinate pyridoxine hydrochloride tablets of the present invention
1. Preparation of a tablet core:
preparing materials (1000 tablets) according to the following formula:
the preparation method comprises the following steps:
(1) respectively drying starch at 80 deg.C until the water content is less than 1.5%, and drying pulvis Talci until the water content is less than 5%;
(2) pulverizing doxylamine succinate and pyridoxine hydrochloride, and sieving with 100 mesh sieve;
(3) mixing doxylamine succinate and talcum powder, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(5) mixing low-substituted hydroxypropyl cellulose for 2 times by using a starch equivalent dilution method, adding the mixture into the mixture II, and mixing to obtain a mixture III;
(6) adding the residual starch and the mixture (c) into a multidirectional motion mixer, and mixing for 20min at the rotation speed of 10 rpm;
(7) adding magnesium stearate, and mixing for 5 min;
(8) tabletting to obtain tablet core.
2. First isolation clothes
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing PVP and talcum powder according to the formula amount, dispersing the PVP and the talcum powder in an ethanol aqueous solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the PVP and the talcum powder to obtain a coating solution;
(2) and (3) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 4.5% +/-0.5%.
3. Enteric coating
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) adding 5g of 4% sodium hydroxide solution into Kollicoat MAE 100P under stirring, and uniformly stirring and dispersing;
(2) adding 33mL of water into a beaker, adding diethyl phthalate, talcum powder and simethicone, homogenizing for 20min, adding the suspension into a Kollicoat MAE 100P solution under mild stirring, and sieving with a 60-mesh sieve before use;
(3) and (3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the enteric coated tablet after the coating liquid is fed, wherein the weight of the coating is increased by 13% +/-0.5%.
4. Coated with second barrier coat
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing HPMC (hydroxy propyl methyl cellulose) with the formula amount, dissolving the HPMC in an ethanol water solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the HPMC to prepare a coating solution;
(2) and (3) adding the enteric-coated tablets into a coating pan, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pan to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the doxylamine succinate pyridoxine hydrochloride enteric-coated tablets after the coating liquid is fed, wherein the coating weight is increased by 3% +/-0.5%.
EXAMPLE 2 preparation of doxylamine succinate pyridoxine hydrochloride tablets of the present invention
1. Preparation of a tablet core:
preparing materials (1000 tablets) according to the following formula:
the preparation method comprises the following steps:
(1) respectively drying microcrystalline cellulose PH102 at 80 deg.C until the water content is less than 3% and drying silicon dioxide until the water content is less than 5%;
(2) pulverizing doxylamine succinate and pyridoxine hydrochloride, and sieving with 100 mesh sieve;
(3) mixing doxylamine succinate and silicon dioxide, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(5) mixing sodium carboxymethyl starch for 2 times by mannitol equivalent dilution method, adding into the mixture II, and mixing to obtain a mixture III;
(6) adding the rest mannitol, the mixture (III) and the microcrystalline cellulose PH102 into a multidirectional motion mixer, and mixing for 20min at the rotating speed of 10 rpm;
(7) adding magnesium stearate, and mixing for 5 min;
(8) tabletting to obtain tablet core.
2. First isolation clothes
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing HPMC and talcum powder according to the formula amount, dispersing in an ethanol water solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the HPMC and the talcum powder to obtain a coating solution;
(2) and (3) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 4% +/-0.5%.
3. Enteric coating
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) adding 1.3g of 4% sodium hydroxide solution into HPMCP under stirring, and uniformly stirring and dispersing;
(2) adding 34mL of ethanol aqueous solution into a beaker, adding PEG400, talcum powder and simethicone, homogenizing for 20min, adding the suspension into HPMCP under mild stirring, and sieving with a 60-mesh sieve before use;
(3) and (3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the enteric coated tablet after the coating liquid is fed, wherein the weight of the coating is increased by 10% +/-0.5%.
4. Coated with second barrier coat
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing PEG4000 with the formula amount, dissolving the PEG4000 in ethanol water solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the PEG4000 to prepare coating liquid;
(2) and (3) adding the enteric-coated tablets into a coating pan, adjusting the air inlet temperature to 60 ℃, the temperature of a tablet bed to 30-35 ℃, the atomization pressure to 0.25MPa, the rotation speed of the coating pan to 10-30 rph, the sample injection flow rate to 3-8 g/min, and obtaining the doxylamine succinate pyridoxine hydrochloride enteric-coated tablets after the coating liquid is fed, wherein the weight of the coating is increased by 2.5% +/-0.5%.
EXAMPLE 3 preparation of doxylamine succinate pyridoxine hydrochloride tablets of the present invention
1. Preparation of a tablet core:
preparing materials (1000 tablets) according to the following formula:
the preparation method comprises the following steps:
(1) respectively drying microcrystalline cellulose PH102 at 80 deg.C until the water content is less than 3%, lactose until the water content is less than 1.5%, and silicon dioxide until the water content is less than 5%;
(2) pulverizing doxylamine succinate and pyridoxine hydrochloride, and sieving with 100 mesh sieve;
(3) mixing doxylamine succinate and silicon dioxide, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(5) mixing croscarmellose sodium with lactose equivalent dilution method for 2 times, adding into the mixture II, and mixing to obtain a mixture III;
(6) adding the rest lactose, the mixture (III) and the microcrystalline cellulose PH102 into a multidirectional motion mixer, and mixing for 20min at the rotating speed of 10 rpm;
(7) adding magnesium stearate, and mixing for 5 min;
(8) tabletting to obtain tablet core.
2. First isolation clothes
Preparing materials (1000 tablets) according to the following formula:
kalekang coating powder YS-1-74727.5 g
55mL of water
The method comprises the following operation steps:
(1) weighing the Carlekang coating powder YS-1-7472 according to the prescription amount to prepare an aqueous solution with the concentration of 12%, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(2) and (3) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 4.5% +/-0.5%.
3. Enteric coating
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) adding 4% sodium hydroxide into acrylic resin Eudragit L30D-55 under stirring;
(2) adding water into a beaker, adding triethyl citrate, talcum powder and dimeticone, homogenizing for 20min, adding the suspension into Uygur under mild stirring, and sieving with a 60-mesh sieve before use;
(3) and (3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the enteric coated tablet after the coating liquid is fed, wherein the weight of the coating is increased by 12.5% +/-0.5%.
4. Coated with second barrier coat
Preparing materials (1000 tablets) according to the following formula:
kalekang coating powder YS-1-70038.5 g
62.5mL of water
The method comprises the following operation steps:
(1) weighing the Carlekang coating powder YS-1-7003 according to the prescription amount to prepare an aqueous solution with the concentration of 12 percent, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(2) and (3) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 3% +/-0.5%.
EXAMPLE 4 preparation of doxylamine succinate pyridoxine hydrochloride tablets of the present invention
1. Preparation of a tablet core:
preparing materials (1000 tablets) according to the following formula:
the preparation method comprises the following steps:
(1) respectively drying starch at 80 deg.C until the water content is less than 1.5%, and drying silicon dioxide until the water content is less than 5%;
(2) pulverizing doxylamine succinate and pyridoxine hydrochloride, and sieving with 100 mesh sieve;
(3) mixing doxylamine succinate and silicon dioxide, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(5) mixing crospovidone for 2 times by using a mannitol equivalent dilution method, adding the mixture into the mixture II, and mixing to obtain a mixture III;
(6) adding the rest mannitol, the mixture (the third step) and the starch into a multi-directional motion mixer, and mixing for 20min at the rotating speed of 10 rpm;
(7) adding magnesium stearate, and mixing for 5 min;
(8) tabletting to obtain tablet core.
2. First isolation clothes
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing PVP and talcum powder according to the formula amount, dispersing the PVP and the talcum powder in an ethanol aqueous solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the PVP and the talcum powder to obtain a coating solution;
(2) and (3) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the barrier coat after the coating liquid is fed, and increasing the weight of the coating by 5% +/-0.5%.
3. Enteric coating
Preparing materials (1000 tablets) according to the following formula:
yake Yi 93050 g
50ml of water
The method comprises the following operation steps:
(1) weighing Yake Yi930 according to the formula amount, dispersing the Yake Yi930 in water, performing electromagnetic stirring for more than 2 hours to fully disperse the Yake Yi930 to prepare a coating solution, and sieving the coating solution with a 60-mesh sieve before use;
(3) and (3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the enteric coated tablet after the coating liquid is fed, wherein the weight of the coating is increased by 15% +/-0.5%.
4. Coated with second barrier coat
Preparing materials (1000 tablets) according to the following formula:
the method comprises the following operation steps:
(1) weighing HPMC (hydroxy propyl methyl cellulose) with the formula amount, dissolving the HPMC in an ethanol water solution, and performing electromagnetic stirring for more than 2 hours to fully disperse the HPMC to prepare a coating solution;
(2) and (3) adding the enteric-coated tablets into a coating pan, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotation speed of the coating pan to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the doxylamine succinate pyridoxine hydrochloride enteric-coated tablets after the coating liquid is fed, wherein the coating is increased by 4% +/-0.5%.
Example 5 in vitro Release test
In order to examine the enteric effect of the present invention, according to the second method (for enteric formulation) in the second part appendix X. D release degree determination of the chinese pharmacopoeia 2010 version, the following studies were performed:
taking the product, respectively placing in glass tubes of a lifting disintegration apparatus, checking in 0.1mol/L hydrochloric acid solution, stopping after 120 minutes, taking out the product, and observing. The basket was then removed, washed with a small amount of water, and 1 block of baffle was added to each tube, followed by examination in phosphate buffer (pH 6.8). The results of examination of disintegration time of the samples in hydrochloric acid solution and phosphate buffer are shown in table 1:
TABLE 1 examination results of disintegration time of samples of examples in hydrochloric acid solution and phosphate buffer solution
| Medium | Hydrochloric acid solution (after 120 minutes) | Phosphate buffer |
| Example 1 | Without cracking, disintegrating or softening phenomena | Totally disintegrate after 12 minutes |
| Example 2 | Without cracking, disintegrating or softening phenomena | Totally disintegrate after 11 minutes |
| Example 3 | Without cracking, disintegrating or softening phenomena | Totally disintegrate after 12 minutes |
| Example 4 | Without cracking, disintegrating or softening phenomena | Totally disintegrate after 15 minutes |
In order to further examine the enteric effect of the present invention, according to the second method of XC release assay (paddle method) in the second part of the chinese pharmacopoeia 2010 edition, the following studies were performed using the release of doxylamine succinate as an index:
taking the product, respectively placing in a rotary basket of a dissolution instrument, taking 750mL of 0.1mol/L hydrochloric acid solution as a dissolution medium, rotating at 100 revolutions per minute, operating according to the method, taking a proper amount of solution at 120 minutes, filtering, and taking the subsequent filtrate as a test solution; adding 250mL of 0.2mol/L sodium phosphate solution into the acid solution, adjusting the pH to 6.8 by using 2mol/L hydrochloric acid or 2mol/L sodium hydroxide solution, operating for 45 minutes, taking a proper amount of solution, filtering, and taking the continuous filtrate as a test solution. Taking a proper amount of the product, grinding, precisely weighing fine powder of Xiangdang Dang in average amount, respectively adding the hydrochloric acid solution and the phosphate buffer solution, performing ultrasonic treatment to fully dissolve the doxylamine succinate, and filtering to obtain a subsequent filtrate as a control solution. The operation is carried out according to the quality standard. The dissolution results of the samples in hydrochloric acid solution and phosphate buffer are shown in table 2:
TABLE 2 dissolution results of the samples of examples in hydrochloric acid solution and phosphate buffer solution
| Dissolution media | Hydrochloric acid solution | Phosphate buffer |
| Dissolution time | 120 minutes | 45 minutes |
| Example 1 | 1.36％ | 92.73％ |
| Example 2 | 0.79％ | 90.80％ |
| Example 3 | 1.05％ | 93.09％ |
| Example 4 | 0.42％ | 92.28％ |
| Example 5 | 0.99％ | 90.40％ |
The examples in tables 1 and 2 all have significant enteric characteristics: in hydrochloric acid solution, no crack, disintegration or softening phenomenon exists after 120 minutes, and the released doxylamine succinate amount is less than 10 percent; in a phosphate buffer solution, the enteric-coated tablet is completely disintegrated after 11-15 minutes, and is released more than 70% in 45 minutes, thereby meeting the requirements of Chinese pharmacopoeia 2010 edition on disintegration time limit and release rate of the enteric-coated tablet.
The inventor also prepares samples of doxylamine succinate and pyridoxine hydrochloride enteric-coated tablets of each example according to the methods provided in specifications of CN1447694A, CN104136004A, CN103432126A and WO2013082706, carries out in-vitro release tests together with commercial products, and directly carries out release test in phosphate buffer solution with pH6.8, so that each sample can normally and rapidly release, and the release rate of 1h can reach more than 70% (the release rate of the sample of WO2013082706 can reach more than 90% within 20 minutes); then, the samples are subjected to a release degree test of 0.1N HCl (acid stage) and then a phosphate buffer solution (alkali stage) with pH of 6.8, and the results show that the samples are basically not disintegrated or slightly disintegrated in the acid stage and basically not release active ingredients, the release is slow after the acid stage and the alkali stage are carried out, the release degree can only reach about 50% after 1 hour, the samples can be gradually dissolved along with the increase of the dissolution time, and finally about 90% can be dissolved after 6-8 hours.
Therefore, the doxylamine succinate pyridoxine hydrochloride enteric-coated tablet can still quickly release active ingredients in a neutral environment (alkali phase) after undergoing an acidic environment (acid phase), ensures quick exertion of drug effect, and has obvious advantages compared with the prior art in terms of dissolution characteristics.
Claims (2)
1. The doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition is characterized in that the enteric-coated tablet is a tablet prepared from a tablet core containing doxylamine succinate, pyridoxine hydrochloride and pharmaceutical excipients, and a first isolating coat, an enteric coat and a second isolating coat layer which are wrapped outside the tablet core;
the tablet core comprises the following components in parts by weight: doxylamine succinate, pyridoxine hydrochloride, a filling agent, a disintegrating agent, a lubricant, a glidant and a flow aid, wherein the weight ratio of doxylamine succinate to pyridoxine hydrochloride to the flow aid is 5-20: 80-160: 1-6: 2-6: 0.5-2;
the weight ratio of each component in the first isolation clothes and the second isolation clothes is as follows: the isolation material comprises an anti-sticking agent and a dispersion medium, wherein the dispersion medium is 1-50: 1-15: 50-500; the first isolation clothes and the second isolation clothes are 8-20% aqueous solution of Kalekang coating powder YS-1-7472 or YS-1-7003;
the enteric coating comprises the following components in percentage by weight: the enteric material comprises a plasticizer, an anti-sticking agent, a defoaming agent, a pH regulator and a dispersion medium, wherein the ratio of the plasticizer to the defoaming agent to the dispersion medium is 30-50: 0.8-2: 4-10: 0.1-1: 0.1-0.3: 15-50;
the filler is selected from one or more of microcrystalline cellulose, lactose, starch and mannitol;
the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone;
the lubricant is magnesium stearate;
the glidant is silicon dioxide or talcum powder;
the release material is selected from one or more of PVP, HPMC and PEG 4000;
the enteric material is selected from one or more of acrylic resin Eudragit L, hydroxypropyl methylcellulose phthalate (HPMCP), acrylic resin Kollicoat MAE 100P and Yakewei 930; the plasticizer is selected from one or more of diethyl phthalate, PEG400 and triethyl citrate; the defoaming agent is dimethyl silicone oil; the pH regulator is sodium hydroxide;
the anti-sticking agent is talcum powder;
the dispersion medium is water or ethanol or a mixture of the water and the ethanol.
2. A process for the preparation of a doxylamine succinate pyridoxine hci enteric tablet pharmaceutical composition according to claim 1, characterized in that it comprises the steps of:
(1) preparation of a tablet core:
(1.1) respectively drying the filler to the moisture content of less than 1-4% and the flow aid to the moisture content of less than 4-6% at 80 ℃;
(1.2) crushing doxylamine succinate and pyridoxine hydrochloride, and sieving with a 100-mesh sieve for later use;
(1.3) mixing doxylamine succinate with a flow aid, sieving with a 40-mesh sieve for dispersion, and mixing to obtain a mixture I;
(1.4) adding pyridoxine hydrochloride into the mixture I, and mixing to obtain a mixture II;
(1.5) mixing the disintegrating agent for 2 times by using a filler equivalent dilution method, adding the mixture into the mixture II, and mixing to obtain a mixture III;
(1.6) adding the residual filler and the mixture (c) into a multidirectional motion mixer, and mixing for 20min at the rotating speed of 10 rpm;
(1.7) adding a lubricant and continuously mixing for 5 min;
(1.8) tabletting;
(2) coating a first isolation coat:
(2.1) weighing the isolating material and the anti-sticking agent with the prescription amount, dissolving or dispersing in a dispersion medium, or preparing the Carlekang coating powder YS-1-7472 or YS-1-7003 into an aqueous solution with the concentration of 12 percent, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(2.2) adding the tablet core into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the tablet core coated with the isolation coating after the coating liquid is fed, and increasing the weight of the coating by 4% -5% +/-0.5%;
(3) coating enteric coating:
(3.1) adding the sodium hydroxide solution into the enteric-coated material under stirring, and uniformly stirring and dispersing;
(3.2) adding the dispersion medium into a beaker, adding a plasticizer, an antisticking agent and a defoaming agent, homogenizing for 20min, adding the suspension into the enteric material solution under mild stirring, and sieving by a 60-mesh sieve before use;
(3.3) adding the tablet core coated with the isolation coating into a coating pot, adjusting the air inlet temperature to be 60 ℃, the temperature of the tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pot to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, obtaining the enteric coated tablet after the feeding of the coating liquid is finished, and increasing the weight of the coating by 10-15% +/-0.5%;
(4) coating a second isolation coat:
(4.1) weighing the isolating material and the anti-sticking agent with the prescription amount, dissolving or dispersing in a dispersion medium, or preparing the Carlekang coating powder YS-1-7472 or YS-1-7003 into an aqueous solution with the concentration of 12 percent, and performing electromagnetic stirring for more than 2 hours to fully disperse the coating solution to prepare a coating solution;
(4.2) adding the enteric-coated tablets into a coating pan, adjusting the air inlet temperature to be 60 ℃, the temperature of a tablet bed to be 30-35 ℃, the atomization pressure to be 0.25MPa, the rotating speed of the coating pan to be 10-30 rph, the sample injection flow rate to be 3-8 g/min, and obtaining the doxylamine succinate pyridoxine hydrochloride enteric-coated tablets after the coating liquid is fed, wherein the weight of the coating is increased by 2.5-4% +/-0.5%.
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| AR121619A1 (en) * | 2020-03-25 | 2022-06-22 | Inibsa Ginecologia S A | A MULTIPLE MODIFIED RELEASE UNIT ORAL DOSAGE FORM OF DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE AND A PROCEDURE FOR THEIR PREPARATION |
| CN115078556B (en) * | 2021-03-11 | 2023-10-24 | 远大生命科学(武汉)有限公司 | Method for simultaneously measuring content of doxylamine and pyridoxine |
| WO2022254277A1 (en) * | 2021-05-31 | 2022-12-08 | Maneesh Pharmaceuticals Ltd | Extended release composition and its process for the preparation |
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| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric tablet and preparation method thereof |
| CN103432126A (en) * | 2013-08-05 | 2013-12-11 | 北京阜康仁生物制药科技有限公司 | Drug composition for treating vomiting during pregnancy |
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| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric tablet and preparation method thereof |
| CN103432126A (en) * | 2013-08-05 | 2013-12-11 | 北京阜康仁生物制药科技有限公司 | Drug composition for treating vomiting during pregnancy |
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