CN109316452B - Clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet - Google Patents
Clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
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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
Provides a preparation method of clopidogrel hydrogen sulfate orally disintegrating tablets. The orally disintegrating tablet adopts freeze-drying process, and the stability of clopidogrel hydrogen sulfate is well guaranteed.
Description
Technical Field
The invention relates to a preparation method of an orally disintegrating tablet of clopidogrel hydrogen sulfate. The orally disintegrating tablet adopts freeze-drying process, and the stability of clopidogrel hydrogen sulfate is fully ensured. Belongs to the field of medicine technology.
Background
Thrombi are the cause of many cardiovascular and cerebrovascular diseases. With the increase of human age, the blood lipid content of human blood increases and thickens, the blood vessel wall gradually thickens and becomes hard, and the thrombus is easy to form more and more. Diseases with extremely high lethality rate such as coronary syndrome, myocardial infarction, cerebral arterial thrombosis and the like are closely related to thrombus.
Clopidogrel bisulfate is an anticoagulant and antithrombotic tap type medicine, is widely and massively applied to various cardiovascular and cerebrovascular diseases caused by thrombus, and has almost no substitution in the medication status of related fields. Marketed under the name boliwei by the company Sonofield in 1999®English trade name PLAVIX®Chinese domestic medicine is on the market in 2005. The dosage form of the marketed product is a tablet, and the specification of the tablet comprises 25mg and 75mg (calculated by clopidogrel), which is equivalent to 32.63mg and 97.88mg of clopidogrel hydrogen sulfate.
Clopidogrel bisulfate has been used to prevent atherosclerotic thrombotic events such as myocardial infarction (from days to less than 35 days), ischemic stroke (from 7 days to less than 6 months) or confirmed diagnosis of peripheral arterial disease, acute coronary syndrome (including unstable angina or non-Q wave myocardial infarction). When used with aspirin, the composition can be used for maintaining and treating stent after percutaneous coronary intervention, and thrombolysis for patients with acute coronary syndrome.
The disclosed technology shows that clopidogrel hydrogen sulfate tablets developed by sunofil are prepared by a dry granulation process, which comprises the steps of mixing, lubricating, compacting, crushing and screening, granulating, drying, adding additional auxiliary materials, uniformly mixing, tabletting and coating. Compared with the traditional dry granulation process, the drying process has one more step, which is related to the characteristic of strong moisture absorption of clopidogrel hydrogen sulfate. It is well known that clopidogrel bisulfate has a series of problems and difficulties in the preparation of conventional oral solid tablets. The clopidogrel bisulfate is prepared into the freeze-dried orally disintegrating tablet, so that the problems and difficulties can be almost perfectly solved.
In the traditional pressing process, the addition of a lubricant is inevitable, and clopidogrel bisulfate has compatibility problems with the traditional lubricants such as magnesium stearate and zinc stearate. Patents such as US5520928, US4591592, WO0001364, WO2005070464, CN200610063151, etc. are designed to solve this problem, and are not ideal. PLAVIX®In order to solve the problem of lubricant compatibility, polyethylene glycol 6000 and hydrogenated castor oil are adopted for lubrication. Although the method relieves the problem of compatibility of clopidogrel hydrogen sulfate and a lubricant, the melting point of polyethylene glycol 6000 at about 60 ℃ and the melting point of hydrogenated castor oil at about 75 ℃ are lower. Such low melting points are difficult to adapt to the heavy pressure and thus heat generation in the tabletting process, sticking is often caused in the tabletting process, and the sticking time and degree are difficult to control. The freeze-drying process selected by the invention does not need adding a lubricant at all.
The strong moisture absorption effect of clopidogrel hydrogen sulfate is well known, and is a problem which is difficult to overcome in the preparation process of common tablets. Such as additional drying steps during the manufacturing process, coating, etc., are used to reduce the adverse effects of moisture absorption on the tablets. The clopidogrel bisulfate is prepared into the freeze-dried orally disintegrating tablet, and the influence of moisture absorption on the procedures is very little in the whole preparation process, or in a solution state, or in a frozen vacuum state, or in a closed package.
Clopidogrel bisulfate is easily hydrolyzed under the action of water, and the hydrolysis reaction tends to be severe along with the increase of temperature. Although water is directly used when the clopidogrel hydrogen sulfate solution is prepared before freeze-drying, the solution is prepared at low temperature and enters a frozen state within a short time, and after freeze-drying, the moisture of the finished tablet can be prepared to be below 2 percent or even lower, and the occurrence of hydrolysis in the state is very little. In the traditional process, the moisture in the finished tablet is difficult to control to be less than or equal to 3 percent due to the extremely strong moisture absorption characteristic of clopidogrel hydrogen sulfate in the wet method and the dry method and the fact that the conventional process is not suitable for the objective condition of drying at a higher temperature. The temperature of a material system is also increased in various links such as mixing, tabletting and the like in the traditional tablet pressing process, so that the stability is further deteriorated. The freeze-drying process does not have the process links, and the stability is easier to guarantee.
Polymorphic forms of clopidogrel hydrogen sulfate exist, as described in detail in CN99807458, wherein the marketed products are used or often discussed as form 1 and form 2. The freeze-dried orally disintegrating tablet prepared by the invention belongs to different amorphous states, and has better and faster dissolution performance compared with the crystal form 1 and the crystal form 2.
The clopidogrel bisulfate tablets are mostly taken by old patients, and are often injured by the heart or brain, and certain obstacles often exist in thinking and swallowing actions. The freeze-dried orally disintegrating tablet can be automatically dissolved into liquid along with the infiltration of saliva after being placed into the oral cavity, and the clopidogrel hydrogen sulfate and the freeze-dried tablet can slightly stimulate the secretion of saliva when being adjusted to the weak acid state, so that the orally disintegrating tablet has no taking obstacle. The orally disintegrating tablets or dispersible tablets prepared by the common pressing process can be quickly dispersed in oral cavities, but cannot be completely dissolved, a large amount of sediments exist, gritty feeling, strong adhesive feeling and the like are formed in the oral cavities, and the experience feeling is completely inferior to that of freeze-dried tablets.
Disclosure of Invention
The basic composition of the invention comprises clopidogrel hydrogen sulfate, gelatin, a pH regulator, a flavoring agent and a propping agent. Clopidogrel bisulfate is an active ingredient, has a wide dosage application range, and can be prepared into orally disintegrating tablets from 0-100 mg. According to the conventional treatment needs, the application range of the selected medicine is 20-100 mg. It is recommended that clopidogrel bisulfate of 25mg and 75mg (calculated as clopidogrel) in two different amounts is prepared into an orally disintegrating tablet, so that the clinical use of the medicament can be very convenient.
Besides clopidogrel hydrogen sulfate, other suitable clopidogrel salts can also be prepared into similar freeze-dried orally disintegrating tablets, such as clopidogrel hydrochloride, clopidogrel benzene sulfonate, clopidogrel hydrogen bromide and the like.
The use of the gelatin can greatly improve the properties of the orally disintegrating tablet. Considering that the clopidogrel bisulfate in the freeze-dried orally disintegrating tablet has larger mass and is easy to cause the over-loosening or powdering of the freeze-dried tablet, the existence of the gelatin has important significance for keeping enough strength and toughness of the freeze-dried tablet and maintaining the complete structure. The gelatin improves the properties of the orally disintegrating tablet, and is reflected in that the tablet strength is increased, the tablet is convenient to take and use, and the toughness is enhanced and the tablet is not easy to break. The gelatin may be selected from common biogenic gelatin, and may also be selected from hydrolyzed or partially hydrolyzed gelatin. In consideration of the dissolution property of gelatin, gelatin is often dissolved and swollen first in the preparation process. To accelerate this process, it is often facilitated by means of heat. In the invention, the concentration of the gelatin in the aqueous solution is 0.5-10%, and the preferable use concentration is 1-8%. Specifically, the content range of the gelatin in the orally disintegrating tablet is 1 mg-20 mg per tablet.
The proppant used in the present invention can be in principle any safe, pharmaceutically acceptable, water-soluble solid material. However, the inventors have limited the selection of proppants to sugars, sugar alcohols, amino acids, water-soluble celluloses, povidone, etc. in view of the taste impact and the quality of the tablet form of the final product.
Sugars such as sucrose, glucose, fructose, xylose, lactose, maltose, mannose, sorbose, etc., and oligosaccharides or homoglycans may also be used. Oligosaccharides such as malto-oligosaccharide and fructo-oligosaccharide, and high polysaccharides such as dextran (dextran). Sugar alcohols such as xylitol, sorbitol, isosorbide, mannitol, erythritol, maltitol, isomalt, lactitol and the like. Amino acids such as glycine and sodium glycine can also be used as a proppant, but are not recommended in view of cost. Small molecule salts, small molecule organic acids may also be used as proppants, such as sodium chloride, sodium phosphate salts, citrate salts, citric acid, tartaric acid, and the like.
The polyvidone and water soluble cellulose include hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose. The freeze-drying process can improve the properties of tablets, but the products often have obvious sticky effect. When the dosage is more, the tablet product has increased viscosity after entering water, and is not favorable for quick dissolution and quick release of active ingredients in the tablet product. Furthermore, too much viscous material is not conducive to the final lyophilisate falling out of the pack, i.e. the lyophilisate may stick too firmly on the contact surface of the pack.
In the invention, the concentration of the propping agent in the aqueous solution is 0.2-10%, and the preferable use concentration is 0.5-5%. Specifically, the content range of the proppant in the orally disintegrating tablet is 2 mg-30 mg per tablet.
In the present invention, if sugar or sugar alcohol is used as a proppant, the tablet will have a certain sweet taste, but this is often not enough to correct the significant sour taste caused by clopidogrel hydrogen sulfate. The addition of flavors is desirable to improve mouthfeel, and sweetness is the preferred flavor option. In the non-sugar high-potency sweetener, saccharin and its sodium salt, aspartame, sodium cyclamate, sucralose, etc. can be selected.
Clopidogrel bisulfate has strong acidity, and the solubility of clopidogrel bisulfate is accompanied by obvious pH dependence. Without adjustment, clopidogrel bisulfate is very soluble in water, and the pH value of the aqueous solution is less than 1. The peracid solution causes strong corrosivity and irritation, is not acceptable in taste, and cannot be taken by patients, so the solution needs to be adjusted to an acceptable range for oral administration in the preparation process, and researches show that patients with weak acidic environment are acceptable, for example, when the pH is more than or equal to 2.5, and more preferably when the pH is more than or equal to 3.0.
Supersaturated clopidogrel hydrogen sulfate solution is placed for 12 hours under different pH environments to determine solubility
| pH value | 1.0 | 2.0 | 3.0 | 3.5 | 4.0 |
| Equilibrium solubility (mg/ml) | 944 | 137 | 41 | 18 | 7 |
Determination of solubility of clopidogrel hydrogen sulfate solution by standing at different temperatures for 12 hours at pH3
| Temperature (. degree.C.) | 5 | 10 | 20 |
| Equilibrium solubility (mg/ml) | 55 | 48 | 41 |
The pH value of the inclusion solution is adjusted from 1 to 3.5, and the solubility of clopidogrel hydrogen sulfate is measured at different times
| Time (min) | 1 | 10 | 30 | 60 | 120 |
| Solubility (mg/ml) | 418 | 241 | 180 | 147 | 107 |
The detection mode is as follows: high performance liquid chromatography.
The dissolving mode is as follows: dissolving clopidogrel bisulfate in water to prepare supersaturated solution.
The pH adjusting mode is as follows: unidirectional adjustment with sodium hydroxide.
Solubility measurement mode: in solution, the solution is directly taken, filtered and tested.
Equilibrium solubility assay format: the saturated solution was allowed to stand for 24 hours, and then the supernatant was taken, filtered and tested.
The lower the pH, the better the solubility of clopidogrel hydrogen sulfate, but the product which is too acidic is not suitable for direct administration. The greater the pH, the poorer the solubility of clopidogrel hydrogen sulfate, which is not favorable for the formation of high-concentration solution and the preparation of freeze-dried products. The pH value of 2.5-4.0 is suitable for preparing the freeze-dried orally disintegrating tablet, wherein the preferable pH value of 3.0-3.5 is the optimal range, and the requirements of combining taste and solubility are better.
The effect of temperature reduction on clopidogrel bisulfate dissolution is limited.
Dissolving clopidogrel bisulfate in water to form a relatively strong acidic aqueous solution, then adjusting alkali, and freezing the solution before the clopidogrel bisulfate is separated out. The concentration range of the prepared clopidogrel bisulfate solution for freeze-drying is 20 mg/ml-150 mg/ml, and the more suitable concentration is 40 mg/ml-100 mg/ml. Larger solution concentrations, requiring faster pre-freezing operations, and may even precipitate as a suspended product.
The technological process recommended by the present invention is that firstly, the gelatin is dissolved by warm or hot water, and then the aqueous solution of the gelatin is dissolved with the proppant and the flavoring agent to prepare a blank solution. And cooling the blank solution to room temperature, and adding clopidogrel hydrogen sulfate to completely dissolve. Adding a pH regulator to adjust the pH to the target range.
The solution is quickly subpackaged into a sheet-shaped mould and frozen at low temperature. Vacuum state, and freeze drying. In the basic procedure, the pH regulator is selected from alkaline substances or solutions, and is added after the clopidogrel hydrogen sulfate is completely dissolved, so that the problem that the solvent is alkaline due to advanced addition is avoided, and the dissolving efficiency of the clopidogrel hydrogen sulfate is limited. The addition of the pH regulator needs to ensure that the solution system has enough stirring or dispersing efficiency, so that excessive local alkalinity for a long time and large precipitation of clopidogrel hydrogen sulfate can be avoided. Inorganic bases, organic bases or basic salts which can be used in pharmacy can be used as pH regulators in the present invention.
In the present invention, the addition of a small amount of a water-soluble viscous substance is allowed to consolidate the strength and stability of the lyophilized tablet form. Povidone and water-soluble cellulose can be added into the prescription.
During the solution preparation process, if bubble generation is found or suspected, the solution needs to be degassed. Since the presence of air bubbles tends to disrupt the morphology of the lyophilized product.
The content range of the solid in the solution is 5-30% (w/v), the preferable content range of the solid is 10-25%, and the solution comprises clopidogrel hydrogen sulfate, gelatin, a propping agent, a flavoring agent and other possibly added components.
The shorter the time from dissolution to compaction, the better the clopidogrel hydrogen sulfate solution. Generally, the amount of the solution to be dispensed into the sheet-shaped mold package is limited, and therefore, the freezing time is often short. The time for the solution to exist depends on the volume of the solution and the dispensing speed, and the dispensing speed depends on the number of the dispensing heads and the dispensing efficiency. The shorter solution existence time is beneficial to the stability of the clopidogrel hydrogen sulfate. Meanwhile, clopidogrel bisulfate is adjusted from low pH to high pH in the solution, and the amount of clopidogrel bisulfate which can be contained in the solution is reduced along with the time lapse after the adjustment, so that the longer the time is, the greater the risk that the clopidogrel bisulfate is possibly separated out is. When the concentration of clopidogrel hydrogen sulfate in the solution reaches 100mg/ml, the total time from the pH adjustment to the completion of subpackaging and the freezing compaction is controlled within 2 hours. And after the pH value of the solution is adjusted, subpackaging the solution into a sheet type packaging mold for quick freezing.
When the amount of the solution is large, the dispensing time is unacceptably short. The split charging preparation mode or the online pH adjustment mode can be adopted to avoid the limitation of the split charging time.
The split-tank preparation method comprises preparing the solution in a larger container, dividing part of the solution into a relatively smaller container, adjusting pH value of the small container, and discharging the solution with adjusted pH value from the container for split-charging. The small container has small solution amount and can complete packing fast.
The mode of online pH adjustment means that the clopidogrel hydrogen sulfate solution and the pH adjustment solution are not directly added to each other, but are mixed in a pipeline route. The mixing uniformity is ensured by controlling the discharge capacity, the force, the length of a pipeline and the like of the solution. The components are not mixed before being subpackaged, and are subpackaged quickly after being mixed, and a small-sized mixing cavity can be added in the operation if necessary. During production, the accuracy of the pH amount and the flow rate needs to be fully considered according to the condition of field equipment, and full production verification is carried out.
The volume of the solution distributed into the sheet-shaped mold is 0.1 ml-1.5 ml, and the optimal volume is 0.2 ml-0.6 ml. Such tablet dies are typically in the form of blister packs and may be round or oval, square-like, or other non-round shapes. Larger tablets may limit the ease of access, while smaller tablets may significantly increase the efficiency requirements for dispensing the solution. The packaging amount of the solution and the solid content of 5-30% are comprehensively planned, so that the better orally disintegrating tablet has the mass of 30-150 mg after being freeze-dried, and the better mass range is 35-120 mg.
The solution is frozen rapidly in the invention, laboratories are often realized by low-temperature refrigerators or low-temperature cold traps, and laboratories and production can be realized by low-temperature channels. The low-temperature channel is a way of rapidly cooling the solution in the process of conveying the solution after being distributed to the sheet-shaped molds, and the cooling mode of the channel is severe, so that more refrigerants such as liquid nitrogen, hydrofluoroalkane, chlorofluoroalkane and the like are required to be used. If liquid nitrogen is used, the liquid nitrogen circulation is used for rapid temperature reduction, and if alkane refrigerants are used, the liquid nitrogen circulation is used for rapid temperature reduction, and the alkane refrigerants are used for rapid temperature reduction, and the liquid nitrogen circulation is used for rapid temperature reduction. After the quick freezing is completed, the frozen liquid is generally not stored but directly transferred or transferred to a drying oven for freeze-drying unless the ultralow temperature state can be guaranteed to be maintained all the time, which causes severe load on the consumption of liquid nitrogen or energy consumption on the preparation line. The temperature in the sheet is required to be less than-40 deg.C, preferably less than-50 deg.C.
The drying box is an important component of the freeze dryer, and after the freeze drying is started, the equipment is vacuumized, the vacuum degree is less than or equal to 10bar, and the preferred vacuum degree is less than or equal to 1 bar. The prefreezing material is kept under vacuum to remove water in a sublimation form, and in the process, the water sublimation absorbs heat to maintain the low temperature state of the material, which is primary drying. The temperature adjusting function of the freeze dryer can heat or reduce the temperature of the material container, so as to ensure that the temperature of the product material is always within a set range. Therefore, the freeze dryer with temperature regulation function is important in the preparation process of the orally disintegrating tablet. The whole primary drying time is controlled to be less than or equal to 5 percent based on moisture control, the optimized control index is that the moisture is less than or equal to 2 percent, and the parameters can be set by time after necessary verification is carried out in production. Lower moisture content, and reduced secondary drying time and difficulty. To achieve this level of moisture control, the primary drying may be within 20 hours. The excellent process can control the primary drying time within 8 hours.
After the primary drying is completed, the freeze dryer is kept in a vacuum state, and the temperature is gradually increased to remove a very small amount of water which cannot be removed by sublimation initially, which is secondary drying. The secondary drying temperature may eventually rise to no more than 60 ℃. And secondary drying, wherein the product still uses the moisture as a control index, and finally drying until the moisture content of the product is less than or equal to 2%.
And (4) finishing secondary drying, namely finishing the freeze-drying step after the preparation of the orally disintegrating tablet, and then transferring the orally disintegrating tablet out of a freeze dryer for packaging.
All materials in the clopidogrel bisulfate orally disintegrating tablet are water-soluble materials, and after freeze-drying is completed, the tablet structure is loose, so that the moisture-attracting property of the product is enhanced. Therefore, the mold package carrying the clopidogrel bisulfate solution and performing freeze-drying needs to have not only excellent deformation resistance but also better moisture isolation capability. The packaging material is generally selected from metal materials as basic structure, such as stainless steel, aluminum, etc., and special film layer is added to isolate the direct contact between metal and medicine. The film material is selected from medicinal materials, such as polyethylene, polyvinyl chloride, polyvinylidene chloride, polytetrafluoroethylene, polyethylene terephthalate, epoxy resin and the like.
After the freeze-drying is completed, the packaging material carrying the freeze-dried orally disintegrating tablet is removed from the freeze-dryer, and then is covered with a sealing material, such as an aluminum foil, an aluminum-containing paper film and the like. The attached material must meet the requirement that the product be completely isolated from the outside.
The quality control of the freeze-dried clopidogrel hydrogen sulfate orally disintegrating tablet is that the most important thing is the reduction of the clopidogrel hydrogen sulfate content, namely the degradation of active ingredients is controlled. And secondly, the freeze-drying forming effect is excellent, the freeze-drying sheet is required to be complete, and the freeze-drying sheet has certain physical strength and toughness, is convenient to take out from a packing material, and is convenient for a patient or a nursing staff to hold without breaking, collapsing and the like. Then a fast dissolution profile, the requirement for 1 minute dissolution or disintegration of the orally disintegrating tablet is relatively low.
The clopidogrel bisulfate orally disintegrating tablet prepared by the freeze-drying process exists in an amorphous form, and is shown in figure 1.
Through accelerated tests (40 ℃), the stability of a commercial clopidogrel bisulfate ordinary compressed tablet (brivudine) and a clopidogrel bisulfate freeze-dried orally disintegrating tablet is compared, and the percentage content is evaluated relative to the mark.
| Time | Common clopidogrel hydrogen sulfate tablet (%) | Clopidogrel acid content (%) | (example 1) lyophilized orally disintegrating tablet | Example 1 clopidogrel acid content in product (%) |
| New purchase/preparation | 100.4 | 0.031 | 99.1 | 0.053 |
| 1 month | 100.6 | 0.074 | 99.0 | 0.066 |
| 3 months old | 99.5 | 0.132 | 98.5 | 0.082 |
| 6 months old | 99.3 | 0.204 | 98.7 | 0.129 |
Clopidogrel acid is calculated by an area normalization method, and the percentage of the peak area is expressed.
Example 1
| Components | Dosage is g/1000 tablets |
| Clopidogrel hydrogen sulfate | 32.6 |
| Gelatin | 12 |
| |
3 |
| Aspartame | 0.10 |
| Sodium hydroxide | Adjusting pH to 3.2 |
| Dissolving water (eventually volatilize) | 400ml |
The gelatin with the prescription dose is added into 300ml of water, heated to 80 ℃, and stirred to be completely dissolved. Adding mannitol and aspartame according to the prescription amount, and stirring to completely dissolve. Cooling the solution to about 25 ℃, adding clopidogrel hydrogen sulfate, and stirring to completely dissolve. The pH was adjusted to 3.2 by adding 1mol/L sodium hydroxide solution. The solution was dispensed into plastic-aluminum blisters at 300. mu.l/tablet. And (3) rapidly freezing to ensure that the temperature of the clopidogrel hydrogen sulfate solution is rapidly reduced to minus 50 ℃ to minus 80 ℃, and completely freezing. And (5) ensuring the temperature of the frozen product to be in the original range, and transferring the pre-frozen tablets to a freeze dryer. Vacuumizing, starting freeze-drying, wherein the vacuum requirement is less than 1 bar. And (4) continuously freeze-drying for 7 hours until the time is up, stopping freeze-drying refrigeration, maintaining vacuum, and after the sample is naturally heated to 25 ℃, continuously heating to 40 ℃ for 20 minutes, and heating until the moisture is less than 2%, and then taking out of the cabinet. And (7) sealing and packaging.
The lyophilized tablet was subjected to powder diffraction test, see FIG. 1.
And comparing the solubility evaluation of the common clopidogrel hydrogen sulfate compressed tablet with that of the clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet.
| (Mode) | Common clopidogrel hydrogen sulfate pressed tablets | (example 1) lyophilized orally disintegrating tablet |
| 2ml static observation in water | Failure to completely collapse and largeSediment measuring | Complete melting in 38 seconds |
| Static observation in 200ml water | 12 minutes and 57 seconds are completely disintegrated, and a large amount of dregs are settled | Complete dissolution in 17 seconds |
Example 2
| Components | Dosage is g/1000 tablets |
| Clopidogrel hydrogen sulfate | 97.9 |
| |
20 |
| Glucan | 10 |
| Saccharin sodium salt | 0.06 |
| Sodium hydroxide | Adjusting pH to 3.0 |
| Dissolving water (eventually volatilize) | 1000ml |
Example 3
| Components | Dosage is g/1000 tablets |
| Clopidogrel hydrogen sulfate | 32.6 |
| Gelatin | 18 |
| Mannitol | 15 |
| Acesulfame potassium | 0.1 |
| Sodium hydroxide | Adjusting pH to 3.5 |
| Dissolving water (eventually volatilize) | 400ml |
Claims (1)
1. A clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet comprises the following components in percentage by weight:
clopidogrel hydrogen sulfate 32.6g
Gelatin 12g
Povidone K303 g
Aspartame 0.10g
Adjusting pH to 3.2 with sodium hydroxide
Dissolving water 400ml
Making into 1000 pieces;
adding gelatin in the formula amount into 300ml of water, heating to 80 ℃, and stirring to completely dissolve and clear; adding mannitol and aspartame according to the prescription amount, and stirring to completely dissolve; cooling the solution to 25 ℃, adding clopidogrel hydrogen sulfate, and stirring to completely dissolve; adding 1mol/L sodium hydroxide solution to adjust the pH value to 3.2; subpackaging the solution into plastic-aluminum foam cells at 300 μ l/tablet; rapidly freezing to rapidly reduce the temperature of the clopidogrel hydrogen sulfate solution to-50 to-80 ℃, and completely freezing; ensuring the temperature of the frozen product to be in the original range, and transferring the pre-frozen slices to a freeze dryer; vacuumizing, starting freeze-drying, wherein the vacuum requirement is less than 1 bar; continuously freeze-drying for 7 hours until the time is up, stopping freeze-drying refrigeration, maintaining vacuum, naturally heating the sample to 25 ℃, continuously heating to 40 ℃ for 20 minutes, heating until the moisture is less than 2%, and taking out of the cabinet; and (7) sealing and packaging.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811042608.5A CN109316452B (en) | 2018-09-07 | 2018-09-07 | Clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811042608.5A CN109316452B (en) | 2018-09-07 | 2018-09-07 | Clopidogrel hydrogen sulfate freeze-dried orally disintegrating tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109316452A CN109316452A (en) | 2019-02-12 |
| CN109316452B true CN109316452B (en) | 2021-07-30 |
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