CN114767642A - Clopidogrel hydrogen sulfate tablet and preparation method thereof - Google Patents
Clopidogrel hydrogen sulfate tablet and preparation method thereof Download PDFInfo
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- CN114767642A CN114767642A CN202210301950.2A CN202210301950A CN114767642A CN 114767642 A CN114767642 A CN 114767642A CN 202210301950 A CN202210301950 A CN 202210301950A CN 114767642 A CN114767642 A CN 114767642A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The application provides a preparation method of a clopidogrel bisulfate tablet. The preparation method of the clopidogrel bisulfate tablet comprises the following steps of: mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles, and then mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine; adding an alcoholic solution of a binder into the premixed liquid medicine, and performing wet granulation operation to obtain clopidogrel bisulfate wet granules; adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operations on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles; mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture; and tabletting the pre-pressed mixture to obtain the clopidogrel hydrogen sulfate tablet. The preparation method of the clopidogrel hydrogen sulfate tablet can effectively solve the sticking problem and improve the stability of the clopidogrel hydrogen sulfate tablet.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a clopidogrel bisulfate tablet and a preparation method thereof.
Background
Clopidogrel bisulfate is a platelet aggregation inhibitor, selectively inhibits the binding of Adenosine Diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Clopidogrel bisulfate must be biotransformed to inhibit platelet aggregation. Besides ADP, clopidogrel bisulfate can block the enhancement of platelet activity caused by releasing ADP of other agonists, thereby inhibiting platelet aggregation caused by the agonists.
At present, the main problems in the production process of the clopidogrel bisulfate tablet are as follows: (1) the stability is poor: clopidogrel bisulfate has a carboxylic ester structure, is unstable to moist heat, and is easy to hydrolyze and degrease to form clopidogrel acid. In particular, US6914141 teaches that magnesium stearate, a lubricant, can accelerate clopidogrel degradation; (2) easy sticking and punching: clopidogrel hydrogen sulfate is easy to be adsorbed on the metal surface, and can be rapidly bonded under friction and overstock to cause sticking and poor product quality.
In order to overcome the problem that clopidogrel bisulfate is easy to stick, a technical worker selects a proper lubricant and dosage. For example, the Plavix tablet on the market uses hydrogenated vegetable oil and polyethylene glycol 6000 as lubricants, and the clopidogrel tablet disclosed in US6914141 uses stearic acid, zinc stearate, and sodium fumarate as lubricants, but the hydrogenated vegetable oil, zinc stearate, and sodium fumarate stearate have no pharmaceutical approval at home and cannot be produced. The clopidogrel tablet disclosed in CN1935119A uses glyceryl palmitostearate as a lubricant, the tablet is prepared by dry tabletting, in order to sufficiently mix the drugs, a large amount of auxiliary materials are added, and a tablet with a specification of 25mg is finally prepared by a very complicated process, which undoubtedly increases the drug production cost and cycle. In addition, the conventional clinical administration dosage of the clopidogrel tablet is 75 mg/time, which is equivalent to three tablets taken at one time by a tablet with the specification of 25mg, and obviously, the clopidogrel tablet is not beneficial to improving the compliance of a patient.
A great difficulty in preparing clopidogrel tablets in the preparation technology is that clopidogrel salts including bisulfate are extremely easy to adsorb on the metal surface in the production process and are rapidly bonded by friction and extrusion, so that the tablets are rapidly bonded on the punches and the dies of a tablet press by the extrusion of the upper punches and the lower punches and the extrusion of the punches and the dies during tabletting, and the problems of sticking and surface irregularity of other various tablets are caused more and more seriously, so that the quality of finished products is poor.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides the clopidogrel hydrogen sulfate tablet which is good in stability and can avoid sticking phenomenon and the preparation method thereof.
The purpose of the invention is realized by the following technical scheme:
a preparation method of clopidogrel hydrogen sulfate tablets comprises the following steps:
mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles;
mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine;
adding an alcohol solution of a binder into the premixed liquid medicine, and performing wet granulation to obtain clopidogrel hydrogen sulfate wet granules;
adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles;
mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture;
and tabletting the pre-pressed mixture to obtain the clopidogrel hydrogen sulfate tablet.
In one embodiment, the method for preparing a clopidogrel bisulfate tablet further comprises the steps of, after the step of adding talc powder to the clopidogrel bisulfate wet granules and then subjecting the clopidogrel bisulfate wet granules to a drying and sizing operation to obtain dried clopidogrel bisulfate granules and before the step of subjecting the dried clopidogrel bisulfate granules to a mixing operation with a lubricant and a disintegrant to obtain a pre-pressed mixture:
adding second micropowder silica gel and magnesium stearate into the clopidogrel bisulfate dry particles.
In one embodiment, the weight of the first micropowder silica gel is 0.3-0.8% of the weight of the clopidogrel hydrogen sulfate powder.
In one embodiment, the weight of the second micropowder silica gel is 0.1-0.5% of the weight of the clopidogrel hydrogen sulfate powder.
In one embodiment, the first micropowder silica gel has an average particle size of 10 to 25 μm and a specific surface area of 100 to 500 m/g.
In one embodiment, the diluent is at least one of spray dried lactose, pregelatinized starch, microcrystalline cellulose, modified starch, inorganic salts, and sugar alcohols.
In one embodiment, the lubricant is at least one of polyethylene glycol 4000, polyethylene glycol 6000, talc, hydrogenated vegetable oil, and hydrogenated castor oil.
In one embodiment, the disintegrant is at least one of sodium starch glycolate, crospovidone, croscarmellose sodium, and low substituted hydroxypropylcellulose.
In one embodiment, after the step of performing a tabletting operation on the pre-pressed mixture to obtain the clopidogrel bisulfate tablet, the preparation method of the clopidogrel bisulfate tablet further comprises the following steps:
and (3) coating the clopidogrel bisulfate tablet to form a coated tablet.
The application provides a clopidogrel bisulfate tablet which is prepared by adopting the preparation method of the clopidogrel bisulfate tablet disclosed by any one embodiment.
Compared with the prior art, the invention has at least the following advantages:
in the preparation method of the clopidogrel bisulfate tablet, the clopidogrel bisulfate powder and the first micropowder silica gel are mixed to form clopidogrel bisulfate pre-mixed particles, so that the first micropowder silica gel can be uniformly distributed on the clopidogrel bisulfate powder, and the micropowder silica gel has good fluidity, thereby reducing the contact surface area of the clopidogrel bisulfate powder and the metal surface of a tabletting mold, reducing the probability of the clopidogrel bisulfate adsorbing on the metal surface, reducing the adsorption force and further increasing the fluidity of the clopidogrel bisulfate. In addition, the adsorption of the micropowder silica gel can be utilized to destroy drug powder agglomerates, and the talcum powder is utilized to eliminate charge adsorption, so that the flowability of the raw material drugs is increased, the drugs are fully dispersed, the powder agglomerates of the drugs are reduced, the viscosity of clopidogrel hydrogen sulfate is reduced, the sticking phenomenon is avoided, and the stability of the clopidogrel hydrogen sulfate tablet is improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Fig. 1 is a flow chart of a method for preparing clopidogrel bisulfate tablets according to an embodiment of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully hereinafter with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
It will be understood that when an element is referred to as being "secured to" another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present. The terms "vertical," "horizontal," "left," "right," and the like as used herein are for illustrative purposes only and do not denote a single embodiment.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The application provides a preparation method of a clopidogrel bisulfate tablet. The preparation method of the clopidogrel hydrogen sulfate tablet comprises the following steps: mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles; mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine; adding an alcoholic solution of a binder into the premixed liquid medicine, and performing wet granulation operation to obtain clopidogrel bisulfate wet granules; adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles; mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture; and tabletting the pre-pressed mixture to obtain the clopidogrel bisulfate tablet.
In the preparation method of the clopidogrel bisulfate tablet, the clopidogrel bisulfate powder and the first micropowder silica gel are mixed to form clopidogrel bisulfate pre-mixed particles, so that the first micropowder silica gel can be uniformly distributed on the clopidogrel bisulfate powder, and the micropowder silica gel has good fluidity, thereby reducing the contact surface area of the clopidogrel bisulfate powder and the metal surface of a tabletting mold, reducing the probability of the clopidogrel bisulfate adsorbing on the metal surface, reducing the adsorption force and further increasing the fluidity of the clopidogrel bisulfate. It is understood that the root cause of the sticking of the tablets on the punches and dies of the tablet press is the extremely strong adsorption of clopidogrel hydrogen sulfate. The clopidogrel bisulfate particles are easy to adsorb on the metal surface, and the clopidogrel bisulfate raw material particles are easy to adsorb with each other, so that the clopidogrel bisulfate particles adhered to the surfaces of the punch and the die are extruded by the upper punch and the lower punch and are rubbed and extruded between the punch and the die in the production process, the adhesion is formed on the punch and the die of the tablet press, and the adhesion is more serious, various surface irregularities such as sticking and the like are caused, and the quality of finished products is poor. Therefore, clopidogrel bisulfate adsorption and adhesion due to adsorption must be prevented. And through mixing clopidogrel bisulfate powder and first micropowder silica gel in this application, reduce the external surface area of clopidogrel bisulfate contact to reduce its surface area and mutual area of contact with the metal, can reduce the area of contact of clopidogrel bisulfate and moisture in the air simultaneously, so both can reduce its adsorptivity, prevent the bonding of tablet on tablet press drift and mould in the preforming process, can prevent again that clopidogrel bisulfate from producing the degradation because of the moisture contact with the air, prevent the production of clopidogrel acid. In addition, the preparation method of the clopidogrel hydrogen sulfate tablet can also utilize the adsorbability of the micro-powder silica gel to destroy the drug powder groups, and then utilize the talcum powder to eliminate the charge adsorption, so that the fluidity of the raw material drugs is increased, the drugs are dispersed fully, the powder groups of the drugs are reduced as much as possible, the viscosity of the clopidogrel hydrogen sulfate is reduced, the sticking phenomenon is avoided, and the stability of the clopidogrel hydrogen sulfate tablet is improved.
Referring to fig. 1, in order to better understand the method for preparing clopidogrel hydrogen sulfate tablets of the present application, the following further explains the method for preparing clopidogrel hydrogen sulfate tablets of the present application, and the method for preparing clopidogrel hydrogen sulfate tablets of one embodiment includes the steps of:
s100, mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles.
It will be appreciated that the root cause of tablet adhesion to the tablet press punches and dies is the extremely strong adsorption of clopidogrel hydrogen sulfate. The clopidogrel bisulfate particles are easy to adsorb on the metal surface, and the clopidogrel bisulfate raw material particles are easy to adsorb with each other, so that the clopidogrel bisulfate particles adhered to the surfaces of the punch and the die are extruded by the upper punch and the lower punch and are rubbed and extruded between the punch and the die in the production process, the adhesion is formed on the punch and the die of the tablet press, and the adhesion is more serious, various surface irregularities such as sticking and the like are caused, and the quality of finished products is poor. In order to prevent the problem of adhesion of tablets on a punch and a die of a tablet press during tabletting, in the embodiment, the clopidogrel bisulfate powder is mixed with the first micropowder silica gel to reduce the external surface area of the clopidogrel bisulfate, thereby reducing the surface area of the clopidogrel bisulfate in contact with metal and the contact area of the clopidogrel bisulfate and moisture in the air, so that the adsorbability of the clopidogrel bisulfate can be reduced, the adhesion of the tablets on the punch and the die of the tablet press during tabletting can be prevented, the clopidogrel bisulfate can be prevented from being degraded due to the contact with the moisture in the air, and the clopidogrel acid can be prevented from being generated.
S200, mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine.
As can be appreciated. The primary purpose of the diluent is to increase the weight and volume of the tablet. For convenience in application and manufacture, the diameter of the tablet is generally not less than 6mm, and the total weight of the tablet is generally not less than l00mg, so when the dosage of the drug is less than l00mg, a diluent is usually added. The addition of the diluent not only ensures a certain volume size, but also reduces the dosage deviation of the main ingredients, improves the compression moldability of the medicament, and the like. When the tablet contains oily components, absorbent is added to absorb the oily components to keep the oily components in a dry state, so as to facilitate the preparation of the tablet. In the present embodiment, the compression moldability of the clopidogrel hydrogen sulfate premixed particles can be improved by mixing the clopidogrel hydrogen sulfate premixed particles with a diluent, thereby improving the stability of the clopidogrel hydrogen sulfate tablet.
S300, adding an alcohol solution of the adhesive into the premixed liquid medicine, and performing wet granulation to obtain the clopidogrel bisulfate wet granules.
In this embodiment, the adhesive is a pharmaceutical excipient with viscosity, and the two separate materials are connected together by virtue of the viscosity of the adhesive, and the alcoholic solution of the adhesive has no physiological activity, and the property of the alcoholic solution is stable without reacting with the drug and affecting the content determination of the drug. By adding the alcoholic solution of the adhesive into the premixed liquid medicine, the tablet forming of the clopidogrel bisulfate can be facilitated, and meanwhile, the stability of the clopidogrel bisulfate tablet formulation is improved. Furthermore, the premixed liquid medicine added with the alcoholic solution of the adhesive is subjected to wet granulation operation, so that the clopidogrel hydrogen sulfate is firstly subjected to surface wetting and then is granulated, and thus clopidogrel hydrogen sulfate wet granules with strong wear resistance, good compression formability and beautiful appearance are obtained.
S400, adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles.
It can be understood that the clopidogrel hydrogen sulfate powder and the first micropowder silica gel are mixed to form clopidogrel hydrogen sulfate premixed particles, so that the first micropowder silica gel can be uniformly distributed on the clopidogrel hydrogen sulfate powder, and the micropowder silica gel has good fluidity, thereby reducing the contact surface area of the clopidogrel hydrogen sulfate powder and the metal surface of the tabletting mold, reducing the adsorption probability of clopidogrel hydrogen sulfate on the metal surface, reducing the adsorption force and further increasing the fluidity of clopidogrel hydrogen sulfate. Meanwhile, the adsorption of the micropowder silica gel is utilized to destroy the drug powder agglomerates, but electrostatic adsorption is easy to exist among drug particles formed after the drug powder agglomerates are destroyed, so that the problems of small amount of sticking and poor stability of clopidogrel hydrogen sulfate still exist. In the implementation, the talcum powder is added into the clopidogrel bisulfate wet particles, so that the charge adsorption among the drug particles can be eliminated by the talcum powder, the flowability of the raw material drug is increased, the drug is fully dispersed, and the powder agglomerates of the drug are reduced, so that the viscosity of the clopidogrel bisulfate is reduced, the sticking phenomenon is avoided, and the stability of the clopidogrel bisulfate tablet is improved. Furthermore, drying and granule finishing operations are carried out on the clopidogrel bisulfate wet granules, so that the flowability and compressibility of the clopidogrel bisulfate granules are improved, and the clopidogrel bisulfate tablets after tabletting and forming are more stable.
S500, mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture.
It will be appreciated that the disintegrant enables the tablet to be rapidly broken from an integral tablet into a plurality of fine particles which facilitate dissolution and absorption of the principal drug in the tablet. Lubricants are excipients which reduce the friction between the granules or tablets and the die wall to prevent high friction forces which make tabletting difficult. In order to improve the solubility and compressibility of clopidogrel bisulfate, in the implementation, the clopidogrel bisulfate dry particles are mixed with a lubricant and a disintegrating agent, so that the clopidogrel bisulfate tablets are promoted to be rapidly disintegrated into small particles in gastrointestinal fluids, and the drugs are easy to absorb. Furthermore, the clopidogrel hydrogen sulfate material is wetted by the lubricant to generate viscosity with enough strength, and the material is integrated under the action of the auxiliary adhesive, so that the subsequent tabletting is facilitated. Meanwhile, the lubricant can also change the performance of tabletting and reduce the sticking phenomenon.
S600, tabletting the pre-pressed mixture to obtain the clopidogrel bisulfate tablet.
In this example, the precompacted mixture was tableted using a tablet press to give clopidogrel hydrogen sulfate tablets with a tablet hardness of 96N, a friability of < 1%, and a weight of 250.57 mg/tablet.
In one embodiment, the preparation method of the clopidogrel bisulfate tablet further comprises the following steps of adding talcum powder into the clopidogrel bisulfate wet particles, then carrying out drying and granule finishing operations on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles, and mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture, wherein the steps are as follows: adding second micropowder silica gel and magnesium stearate into the clopidogrel bisulfate dry particles. In the embodiment, the second micropowder silica gel is added into the clopidogrel bisulfate dry particles, so that the flowability and the dispersibility of the clopidogrel bisulfate dry particles can be enhanced, the clopidogrel bisulfate dry particles are prevented from being bonded or forming powder agglomerates, and the clopidogrel bisulfate dry particles can be effectively prevented from sticking when being tableted. Furthermore, magnesium stearate is added into the clopidogrel bisulfate dry particles, so that the clopidogrel bisulfate dry particles have better anti-sticking property and lubricating effect before tabletting, and the second micropowder silica gel and the magnesium stearate have synergistic effect, so that the flowability of the clopidogrel bisulfate dry particles can be further improved, the sticking phenomenon is further prevented, and the stability of the clopidogrel bisulfate tablets is improved.
In one embodiment, the weight of the first micropowder silica gel is 0.3-0.8% of the weight of the clopidogrel bisulfate powder. It can be understood that the first micropowder silica gel and the clopidogrel bisulfate powder can be uniformly distributed on the clopidogrel bisulfate powder after being mixed, and the micropowder silica gel has better fluidity, so that the surface area of the clopidogrel bisulfate powder in contact with the metal surface of the tabletting mold is reduced, the probability of the clopidogrel bisulfate being adsorbed on the metal surface is reduced, the adsorption force is reduced, and the fluidity of the clopidogrel bisulfate is further increased. And the adsorption of the micropowder silica gel can destroy the drug powder agglomerates, and the talcum powder is utilized to eliminate the charge adsorption, so that the flowability of the raw material drug is increased, the drug is fully dispersed, and the powder agglomerates of the drug are reduced, thereby reducing the viscosity of clopidogrel hydrogen sulfate, avoiding the sticking phenomenon and improving the stability of the clopidogrel hydrogen sulfate tablet. However, if the addition amount of the first micropowder silica gel is too large, the drug effect of the clopidogrel bisulfate tablet is easily influenced; if the addition amount of the first micropowder silica gel is too small, the viscosity of clopidogrel hydrogen sulfate cannot be reduced well, and the sticking problem is still easy to occur. In order to further effectively reduce the viscosity of clopidogrel hydrogen sulfate and avoid the sticking phenomenon, in the embodiment, the weight of the first micropowder silica gel is controlled to be 0.3-0.8% of the weight of the clopidogrel hydrogen sulfate powder, so that the first micropowder silica gel can fully destroy drug powder agglomerates and further enhance the flowability of the clopidogrel hydrogen sulfate powder, thereby reducing the surface area of the clopidogrel hydrogen sulfate powder in contact with the metal surface of a tabletting mold, simultaneously reducing the viscosity of the clopidogrel hydrogen sulfate and further effectively solving the sticking problem of the clopidogrel hydrogen sulfate tablet.
In one embodiment, the weight of the second micropowder silica gel is 0.1-0.5% of the weight of the clopidogrel bisulfate powder. It can be understood that the second micropowder silica gel is added into the clopidogrel bisulfate dry particles, so that the fluidity and the dispersity of the clopidogrel bisulfate dry particles can be enhanced, the clopidogrel bisulfate dry particles are prevented from being bonded or forming powder groups, and the clopidogrel bisulfate dry particles can be effectively prevented from sticking when being tabletted. However, if the addition amount of the second micropowder silica gel is too large, the drug effect of the clopidogrel bisulfate tablet is easily influenced; if the addition amount of the second micropowder silica gel is too small, the viscosity of clopidogrel hydrogen sulfate cannot be reduced well, and the sticking problem is still easy to occur. In order to further effectively reduce the viscosity of clopidogrel hydrogen sulfate and avoid the sticking phenomenon, in the embodiment, the weight of the second micropowder silica gel is controlled to be 0.1-0.5% of the weight of the clopidogrel hydrogen sulfate powder, so that the second micropowder silica gel can be uniformly dispersed in the clopidogrel hydrogen sulfate dry particles, the flowability and the dispersibility of the clopidogrel hydrogen sulfate dry particles are further improved, the surface area of the clopidogrel hydrogen sulfate powder in contact with the metal surface of the tabletting mold is reduced, the viscosity of the clopidogrel hydrogen sulfate is reduced, and the sticking problem of the clopidogrel hydrogen sulfate tablet is further effectively solved.
In one embodiment, the first micropowder silica gel has an average particle size of 10 to 25 μm and a specific surface area of 100 to 500 m/g. In the embodiment, the particle size of the clopidogrel bisulfate powder is 30-90 μm, the average particle size of the first micropowder silica gel is controlled to be 10-25 μm by combining the particle size of the clopidogrel bisulfate powder, and the specific surface area is 100-500 m/g, so that the flowability of the first micropowder silica gel in the clopidogrel bisulfate powder can be improved, and the first micropowder silica gel is uniformly distributed in the clopidogrel bisulfate powder. Furthermore, the average particle size of the first micropowder silica gel is 10-25 μm, and the specific surface area is 100-500 m/g, so that the first micropowder silica gel can be stably and uniformly distributed on the clopidogrel bisulfate particles with dozens of micrometers, the surface area of the clopidogrel bisulfate particles in contact with the metal surface is reduced, the probability of the clopidogrel bisulfate adsorbing on the metal surface is reduced, the adsorption force is reduced, and the fluidity is increased.
In one embodiment, the diluent is at least one of spray dried lactose, pregelatinized starch, microcrystalline cellulose, modified starch, inorganic salts, and sugar alcohols. It is understood that the addition of the diluent not only ensures a certain volume size but also reduces the dosage deviation of the main ingredient, improves the compression moldability of the drug, etc. When the tablet contains oily components, an absorbent is added to absorb the oily components and keep the oily components in a dry state, so that the tablet can be conveniently prepared. In order to further improve the compression moldability of clopidogrel hydrogen sulfate, in the present example, the diluent is at least one of spray-dried lactose, pregelatinized starch, microcrystalline cellulose, modified starch, inorganic salts, and sugar alcohols. Spray-dried lactose is formed by fluidized bed treatment of ground lactose monohydrate to form lactose monohydrate agglomerates. The mixture of the lactose accumulation and clopidogrel bisulfate premixed particles has better fluidity and compaction characteristics, and is beneficial to improving the tabletting stability of clopidogrel bisulfate. The pregelatinized starch can increase the fluidity and compressibility of clopidogrel hydrogen sulfate, and can also have the effects of adhesion and self-lubrication, so that the tabletting stability of clopidogrel hydrogen sulfate is improved. Microcrystalline cellulose is a rod-like or granular crystal obtained by hydrolyzing natural fibers with a strong acid under heating and removing amorphous fibers from the natural fibers. Hydrogen bonds exist among microcrystalline cellulose molecules, and are associated when being pressed, so that the microcrystalline cellulose has high compressibility and can play a good bonding role; when the pressed tablet meets body fluid, water rapidly enters the tablet containing microcrystalline cellulose, and hydrogen bonds are immediately broken, so that the tablet can also have a good disintegration effect. In addition, the microcrystalline cellulose has lower density, larger specific volume and wider particle size distribution, and can improve the compression formability of the clopidogrel hydrogen sulfate. The modified starch is convenient for subsequent mixing operation in production, can also be used as a disintegrating agent, and has a large surface area which is beneficial to absorbing water.
Furthermore, the inorganic salts are mainly inorganic calcium salts, such as calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate, magnesium oxide and aluminum hydroxide gel powder, and the usage amount is about 10%. The calcium sulfate has stable property, no smell and odor, slightly water solubility, no hygroscopicity and strong oil absorption capacity. The prepared tablet has smooth appearance, good hardness and disintegration, and no adsorption effect on the medicine. The calcium hydrogen phosphate is alkalescent, has no hygroscopicity, is a good absorbent for Chinese medicine extract and oil, and has good hardness for tabletting. Sugar alcohols such as mannitol sorbitol are in the form of granules or powder, absorb heat when dissolved in the mouth, thus having a cool feeling, at the same time having a certain sweet taste, without gritty feeling in the mouth, and at the same time having a better compressibility.
In one embodiment, the lubricant is at least one of polyethylene glycol 4000, polyethylene glycol 6000, talc, hydrogenated vegetable oil, and hydrogenated castor oil. It will be appreciated that the lubricant will reduce the friction between the granules or tablets and the die wall to prevent the friction from being so great that tabletting is difficult. In order to further improve the compressibility of clopidogrel hydrogen sulfate, in the present embodiment, the lubricant is at least one of polyethylene glycol 4000, polyethylene glycol 6000, talc, hydrogenated vegetable oil, and hydrogenated castor oil. Polyethylene glycol 4000 has very strong plasticity, film forming property and capability of improving the drug release capacity of the tablet, can make the surface of the tablet glossy and smooth, is not easy to damage and adhere, and can be used as a suppository matrix by adding liquid polyethylene glycol to adjust the consistency. Polyethylene glycol 6000 has good lubricating effect, and can be used as a carrier of a solid dispersant to achieve the purpose of solid dispersion. Talc powder has excellent physical and chemical properties such as lubricity, fire resistance, acid resistance, insulation, high melting point, chemical inertness, good covering power, softness, good gloss, strong adsorption power and the like, and has a tendency to be easily broken into flakes and a special lubricating property because talc has a layered crystal structure.
In one embodiment, the disintegrant is at least one of sodium starch glycolate, crospovidone, croscarmellose sodium, and low substituted hydroxypropylcellulose. It will be appreciated that the disintegrant enables the tablet to be rapidly broken from an integral tablet into a plurality of fine particles of material which facilitate dissolution and absorption of the principal drug in the tablet. In order to further improve the disintegrability of the clopidogrel bisulfate, the disintegrant is at least one of carboxymethyl starch sodium, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
In one embodiment, after the step of performing a tabletting operation on the pre-compressed mixture to obtain the clopidogrel bisulfate tablet, the method for preparing the clopidogrel bisulfate tablet further comprises the following steps: and (3) coating the clopidogrel hydrogen sulfate tablet to form a coated tablet. In the embodiment, after the clopidogrel bisulfate is tableted, the prepared tablet is coated, the coating process is carried out in a coating pan, the solid content of a coating solution is 8-12%, the air inlet temperature is controlled at 40-60 ℃, the rotating speed of the coating pan is 3-5 rpm, and the coating weight gain is controlled at 2-3%. And packaging with double aluminum bubble caps after coating.
In one embodiment, the method for preparing a clopidogrel bisulfate tablet, after the step of mixing the clopidogrel bisulfate dry particles with the lubricant and the disintegrant to obtain a pre-compressed mixture and before the step of tabletting the pre-compressed mixture to obtain a clopidogrel bisulfate tablet, further comprises the steps of: the precompacted mixture is subjected to a hot precompression operation. In the present embodiment, by performing a pre-pressing operation on the pre-pressed mixture, the pre-pressed mixture is compressed to one-half of the predetermined thickness of the clopidogrel bisulfate tablet, thereby effectively removing excess moisture in the pre-pressed mixture. When the prepressing operation is carried out on the prepressing mixture, the prepressing mixture is slightly heated by carrying out hot air blowing operation on the prepressing mixture, on one hand, the hot air blowing can improve the heating uniformity, on the other hand, the bonding problem caused by the direct heating of the surfaces of the die and the punch can be avoided, so that when the punch performs prepressing on the prepressing mixture, the water at the contact interface of the clopidogrel bisulfate and the punch as well as the die is volatilized in time, and the clopidogrel bisulfate particles adhered to the surfaces of the punch and the die are prevented from being extruded by the upper punch and the lower punch and from being rubbed and extruded between the punch and the die, bonding is formed on the punch and the die of the tabletting machine, and the stability of the clopidogrel bisulfate tablet is improved. In addition, hot prepressing operation and tabletting operation are carried out on the clopidogrel hydrogen sulfate, so that irregular tablet shape caused by one-time tabletting can be reduced or avoided, and the regularity and the yield of the clopidogrel hydrogen sulfate are improved.
Further, while the hot pre-pressing operation is performed on the pre-pressed mixture, the first shaking operation is simultaneously performed on the pre-pressed mixture. It can be understood that, in the present embodiment, when the hot pre-pressing operation is performed on the pre-pressed mixture, the excess moisture in the pre-pressed mixture can be effectively removed, and the pre-pressed mixture is compressed to be half of the predetermined thickness of the clopidogrel bisulfate tablet, and at this time, dry particles or small adhesive blocks are easily generated on the prototype surface of the formed clopidogrel bisulfate tablet, so that the regularity and the smoothness of the clopidogrel bisulfate tablet are affected, and the sticking problem is also easily caused. In the embodiment, the mould is used for carrying out primary vibration operation on the pre-pressed mixture, so that dry particles or small bonding blocks formed in the hot pre-pressing process of the pre-pressed mixture are separated from the surface of the pre-pressed mixture and fall off, and then tabletting operation is carried out, so that the regularity and the flatness of the clopidogrel hydrogen sulfate tablet can be improved, and the sticking problem is solved.
Further, while the preliminary pressed mixture is subjected to the tabletting operation, the preliminary pressed mixture is simultaneously subjected to the second shaking operation. It can be understood that the pre-pressed mixture is subjected to a hot pre-pressing operation to form a preliminary blank clopidogrel bisulfate tablet, and in this embodiment, the pre-pressed mixture subjected to the hot pre-pressing operation is subjected to an overturning operation and then a tabletting operation, while the pre-pressed mixture is subjected to a second shaking operation. The prepressing mixture is subjected to primary vibration operation in the hot prepressing process, substances in the prepressing mixture are precipitated downwards, and the problem of uneven tabletting of the clopidogrel bisulfate tablets is easily caused.
In one embodiment, the drying and granulating operation is a segmented temperature control operation. In this embodiment, the segmented temperature control operation includes a first temperature-raising stage, a second temperature-raising stage, a first temperature-lowering stage and a second temperature-lowering stage, which are sequentially performed, wherein the temperature of the first temperature-raising stage is 30 ℃ to 50 ℃ and the time is 3min to 8 min; the temperature of the second temperature rise stage is 60-80 ℃, and the time is 2-5 min; the temperature of the first cooling stage is 50-70 ℃, and the temperature of the second cooling stage is 25-45 ℃. Through the segmented temperature control operation, firstly, the drying effect can be improved, and the situation that partial clopidogrel bisulfate particles are easy to remain moisture is prevented, so that the partial viscosity is large in the tabletting process and is adhered to a punch and a die of a tabletting machine, and the situation of partial coking caused by one-time drying is avoided; and secondly, the stability of the environmental humidity can be better controlled through the segmented temperature control operation, the drying process is divided into a temperature rising stage and a temperature reducing stage, and the temperature rising stage and the temperature reducing stage are changed in a stepped manner, so that the clopidogrel bisulfate particles have better stability in the drying process, the problem that the clopidogrel bisulfate particles form powder lumps or the viscosity is increased is prevented, and the sticking problem of the clopidogrel bisulfate tablets can be effectively avoided.
Example 1
Mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles, wherein the weight of the first micropowder silica gel is 0.3 percent of that of the clopidogrel bisulfate powder, the average particle size of the first micropowder silica gel is 10 mu m, the specific surface area is 100m/g, and the particle size of the clopidogrel bisulfate powder is 30 mu m. And then mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine. And then adding an alcohol solution of the adhesive into the premixed liquid medicine, and performing wet granulation operation to obtain clopidogrel bisulfate wet granules. Adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles. And mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture. And (3) tabletting the pre-pressed mixture to obtain clopidogrel hydrogen sulfate tablets, wherein the hardness of the tablets is 96N, the friability is less than 1%, and the weight is 250.57 mg/tablet.
Example 2
Mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles, wherein the weight of the first micropowder silica gel is 0.8 percent of that of the clopidogrel bisulfate powder, the average particle size of the first micropowder silica gel is 25 mu m, the specific surface area is 500m/g, and the particle size of the clopidogrel bisulfate powder is 90 mu m. And then mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine. And then adding an alcoholic solution of the adhesive into the premixed liquid medicine, and performing wet granulation operation to obtain the clopidogrel bisulfate wet granules. Adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operations on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles. And mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture. And (3) tabletting the pre-pressed mixture to obtain clopidogrel hydrogen sulfate tablets, wherein the hardness of the tablets is 96N, the friability is less than 1%, and the weight is 250.57 mg/tablet.
Example 3
Mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles, wherein the weight of the first micropowder silica gel is 0.5 percent of that of the clopidogrel bisulfate powder, the average particle size of the first micropowder silica gel is 15 mu m, the specific surface area is 250m/g, and the particle size of the clopidogrel bisulfate powder is 50 mu m. And then mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine. And then adding an alcohol solution of the adhesive into the premixed liquid medicine, and performing wet granulation operation to obtain clopidogrel bisulfate wet granules. Adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles. And mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture. And (3) tabletting the pre-pressed mixture to obtain clopidogrel bisulfate tablets, wherein the hardness of the tablets is 96N, the friability is less than 1%, and the weight is 250.57 mg/tablet.
Example 4
Mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles, wherein the weight of the first micropowder silica gel is 0.2 percent of that of the clopidogrel bisulfate powder, the average particle size of the first micropowder silica gel is 18 mu m, the specific surface area is 300m/g, and the particle size of the clopidogrel bisulfate powder is 60 mu m. And then mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine. And then adding an alcohol solution of the adhesive into the premixed liquid medicine, and performing wet granulation operation to obtain clopidogrel bisulfate wet granules. Adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles. And mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture. And (3) tabletting the pre-pressed mixture to obtain clopidogrel hydrogen sulfate tablets, wherein the hardness of the tablets is 96N, the friability is less than 1%, and the weight is 250.57 mg/tablet.
Compared with the prior art, the invention has at least the following advantages:
in the preparation method of the clopidogrel bisulfate tablet, the clopidogrel bisulfate powder and the first micropowder silica gel are mixed to form clopidogrel bisulfate pre-mixed particles, so that the first micropowder silica gel can be uniformly distributed on the clopidogrel bisulfate powder, and the micropowder silica gel has good fluidity, thereby reducing the contact surface area of the clopidogrel bisulfate powder and the metal surface of a tabletting mold, reducing the probability of the clopidogrel bisulfate adsorbing on the metal surface, reducing the adsorption force and further increasing the fluidity of the clopidogrel bisulfate. In addition, the adsorbability of the micropowder silica gel can be utilized to destroy drug powder agglomerates, and the talcum powder is utilized to eliminate charge adsorption, so that the fluidity of the raw material drugs is increased, the drugs are fully dispersed, and the powder agglomerates of the drugs are reduced, thereby reducing the viscosity of clopidogrel hydrogen sulfate, avoiding the sticking phenomenon and improving the stability of clopidogrel hydrogen sulfate tablets.
The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Claims (10)
1. The preparation method of the clopidogrel hydrogen sulfate tablet is characterized by comprising the following steps of:
mixing clopidogrel bisulfate powder with first micropowder silica gel to form clopidogrel bisulfate premixed particles;
mixing the clopidogrel bisulfate premixed particles with a diluent to obtain premixed liquid medicine;
adding an alcohol solution of a binder into the premixed liquid medicine, and performing wet granulation to obtain clopidogrel hydrogen sulfate wet granules;
adding talcum powder into the clopidogrel bisulfate wet particles, and then carrying out drying and granule finishing operation on the clopidogrel bisulfate wet particles to obtain clopidogrel bisulfate dry particles;
mixing the clopidogrel bisulfate dry particles with a lubricant and a disintegrating agent to obtain a pre-pressed mixture;
and tabletting the pre-pressed mixture to obtain the clopidogrel bisulfate tablet.
2. The method for producing clopidogrel bisulfate tablets as claimed in claim 1, which is characterized in that after the step of adding talc powder to the wet clopidogrel bisulfate particles and then subjecting the wet clopidogrel bisulfate particles to a drying and sizing operation to obtain dry clopidogrel bisulfate particles and before the step of subjecting the dry clopidogrel bisulfate particles to a mixing operation with a lubricant and a disintegrant to obtain a pre-pressed mixture, the method for producing clopidogrel bisulfate tablets further comprises the steps of:
and adding second micropowder silica gel and magnesium stearate into the clopidogrel bisulfate dry particles.
3. The method for preparing a clopidogrel hydrogen sulfate tablet according to claim 1, wherein the weight of the first aerosil is 0.3 to 0.8 percent of the weight of the clopidogrel hydrogen sulfate powder.
4. The method for preparing clopidogrel hydrogen sulfate tablets according to claim 2, wherein the weight of the second aerosil is 0.1 to 0.5 percent of the weight of the clopidogrel hydrogen sulfate powder.
5. The method for preparing clopidogrel bisulfate tablets according to claim 1, wherein the first aerosil has an average particle size of 10 to 25 μm and a specific surface area of 100 to 500 m/g.
6. The method for preparing clopidogrel hydrogen sulfate tablets according to claim 1, wherein the diluent is at least one of spray-dried lactose, pregelatinized starch, microcrystalline cellulose, modified starch, inorganic salts, and sugar alcohols.
7. The method for preparing clopidogrel hydrogen sulfate tablets according to claim 1, wherein the lubricant is at least one of polyethylene glycol 4000, polyethylene glycol 6000, talc, hydrogenated vegetable oil and hydrogenated castor oil.
8. The method for preparing a clopidogrel hydrogen sulfate tablet according to claim 1, wherein the disintegrant is at least one of carboxymethyl starch sodium, crospovidone, croscarmellose sodium and low substituted hydroxypropylcellulose.
9. The method for preparing a clopidogrel bisulfate tablet according to claim 1, which is characterized by further comprising the steps of, after the step of subjecting the precompacted mixture to a tableting operation to obtain a clopidogrel bisulfate tablet:
and (3) coating the clopidogrel hydrogen sulfate tablet to form a coated tablet.
10. A clopidogrel bisulfate tablet, characterized by being prepared by the method for preparing a clopidogrel bisulfate tablet according to any one of claims 1 to 9.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| US20170157098A1 (en) * | 2015-12-04 | 2017-06-08 | Shenzhen Salubris Pharmaceuticals Co., Ltd | Clopidogrel Hydrogen Sulfate Solid Preparation and Its Preparation Method |
| CN107951847A (en) * | 2017-11-20 | 2018-04-24 | 湖南天济草堂制药股份有限公司 | A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| US20170157098A1 (en) * | 2015-12-04 | 2017-06-08 | Shenzhen Salubris Pharmaceuticals Co., Ltd | Clopidogrel Hydrogen Sulfate Solid Preparation and Its Preparation Method |
| CN107951847A (en) * | 2017-11-20 | 2018-04-24 | 湖南天济草堂制药股份有限公司 | A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application |
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