CN114762681A - Boshentan freeze-dried orally disintegrating tablet and preparation method thereof - Google Patents
Boshentan freeze-dried orally disintegrating tablet and preparation method thereof Download PDFInfo
- Publication number
- CN114762681A CN114762681A CN202011596458.XA CN202011596458A CN114762681A CN 114762681 A CN114762681 A CN 114762681A CN 202011596458 A CN202011596458 A CN 202011596458A CN 114762681 A CN114762681 A CN 114762681A
- Authority
- CN
- China
- Prior art keywords
- disintegrating tablet
- orally disintegrating
- freeze
- bosentan
- lyophilized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title abstract description 28
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims abstract description 105
- 229960003065 bosentan Drugs 0.000 claims abstract description 99
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- 238000007710 freezing Methods 0.000 claims abstract description 18
- 239000000796 flavoring agent Substances 0.000 claims abstract description 17
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- 229960003421 bosentan anhydrous Drugs 0.000 claims abstract description 8
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- 238000004806 packaging method and process Methods 0.000 claims abstract description 8
- -1 bosentan anhydrous compound Chemical class 0.000 claims abstract description 3
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- 239000000203 mixture Substances 0.000 claims description 16
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Images
Classifications
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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
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physiology (AREA)
- Pulmonology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Zoology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a bosentan freeze-dried orally disintegrating tablet and a preparation method thereof, belonging to the field of pharmaceutical preparations, wherein the bosentan freeze-dried orally disintegrating tablet is composed of 8 parts by weight of an active ingredient bosentan anhydrous compound contained in each tablet, 1-10 parts by weight of an adhesive, 0-10 parts by weight of a filler and 0-5 parts by weight of a flavoring agent. The preparation method of the freeze-dried orally disintegrating tablet comprises the steps of dissolving, injection molding, quick freezing, freeze-drying and product packaging. The bosentan freeze-dried orally disintegrating tablet is simple and convenient to take, does not need water for taking, and is fast to absorb.
Description
Technical Field
The invention relates to the field of oral preparations, in particular to a bosentan freeze-dried orally disintegrating tablet and a preparation method thereof.
Background
Pulmonary Arterial Hypertension (PAH) is arterial hypertension connecting the heart to the lungs, with or without malignant pulmonary vascular disease characterized by small pulmonary artery disease, often leading to right heart failure and even death. It may be an independent disease, a complication, or a syndrome. Can lead to shortness of breath, fatigue, syncope, chest pain, and edema of the legs and ankles. Patients with pulmonary hypertension are called "blue lips" because of cyanosis of the lips due to long-term hypoxia.
Bosentan (Bosetan) belongs to the class of endothelin receptor antagonists. Is suitable for treating patients with Pulmonary Arterial Hypertension (PAH) of WHO grade II-IV to improve the exercise capacity and reduce clinical deterioration of the patients. Bosentan Chinese chemical name: n- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide monohydrate of formula: c27H29N5O6S·H2O, the chemical structural formula is as follows:
bosentan was developed by Actelion, switzerland and was first approved by the FDA in the united states for the treatment of pulmonary hypertension in 11 months in 2001. Since the first time of the pulmonary hypertension drug market, the drug can reduce pulmonary and systemic vascular resistance, thereby increasing cardiac output without increasing heart rate and improving the motor ability and hemodynamic index of patients with idiopathic pulmonary hypertension. Approved for entry into china in 2006, month 10.
US5292740 describes a process for the synthesis of bosentan, and the composition and preparation of bosentan tablets, capsules and injections.
ZL200680016611.9 describes a dispersible bosentan tablet which can be completely decomposed in water at 15-22 deg.C for no more than 5 minutes, and which contains, in addition to bosentan, fillers, glidants, acidifying agents, flavouring agents, sweeteners, lubricants and the like. The tablet solves the problem of clinical adaptability of children through dispersion, has a complex preparation process, requires the dispersion treatment of raw material medicines and then tabletting, needs various high-quality auxiliary materials for meeting the relevant requirements of dispersion and tabletting and ensuring that the product does not have related quality problems during storage, and has high product cost.
ZL201210396980.2 describes a bosentan pharmaceutical composition and a preparation method thereof, the composition consists of bosentan, a diluent, a disintegrating agent and an adhesive, the dissolution rate of the composition is effectively increased, and the stability of the preparation is improved.
ZL201010573886.0 describes a preparation method of a bosentan capsule, and the capsule formula contains a proper amount of bosentan, polyethylene glycol 6000, lactose, sodium hydroxymethyl starch, 5% of povidone K30 and magnesium stearate, so that the capsule has the characteristics of stable quality, simplicity and convenience in use, good fluidity and small filling quantity difference.
The existing preparation is easy to cause chocking cough in the process of taking by children, and a bosentan oral preparation suitable for children is yet to be developed.
Disclosure of Invention
The invention discloses a bosentan freeze-dried orally disintegrating tablet and a preparation method thereof.
The freeze-dried orally disintegrating tablet is a novel oral preparation, and has the greatest advantages of quick oral absorption and high bioavailability; the oral liquid is taken without water, and no obvious gravel feeling is generated at the entrance; avoid the first pass effect of the liver.
The invention aims to provide a bosentan freeze-dried orally disintegrating tablet convenient for oral administration, which is prepared by adopting a freeze-drying technology, does not need water for administration in the administration process, and is convenient for the old or children to take. The bosentan is bosentan monohydrate containing one crystal water, and the bosentan anhydrate is a compound of bosentan without one crystal water.
The invention provides a bosentan freeze-dried orally disintegrating tablet which consists of bosentan and an auxiliary material and is characterized in that the auxiliary material of the freeze-dried orally disintegrating tablet contains an adhesive. The bosentan is a main drug of the orally disintegrating tablet and plays a role in treating pulmonary hypertension, other components in the bosentan freeze-dried orally disintegrating tablet are used as auxiliary materials, and the bosentan freeze-dried orally disintegrating tablet is added for solving the problems of formability, effectiveness, stability, safety and the like of the preparation during the design of a preparation prescription, the safety is reasonably evaluated, and the quality reliability and diversity of the bosentan freeze-dried orally disintegrating tablet ensure the advancement of dosage forms and preparations.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized in that each freeze-dried orally disintegrating tablet contains bosentan anhydrous compound:8 parts by weight of (based on bosentan anhydrous compound C)27H29N5O6S meter); each freeze-dried orally disintegrating tablet contains a binder: 1 to 10 parts by weight.
The bosentan freeze-dried orally disintegrating tablet is prepared by proportioning a main drug bosentan and an auxiliary material adhesive or other auxiliary materials according to a weight ratio and preparing the bosentan freeze-dried orally disintegrating tablet by a corresponding preparation method.
According to the requirements of patients on different dosages of the bosentan freeze-dried orally disintegrating tablets in clinical treatment, different specifications of the bosentan freeze-dried orally disintegrating tablets are prepared, and currently in experiments, 8mg, 16mg, 32mg and 64mg (in terms of bosentan anhydrous compound C) are prepared27H29N5O6Spimeter) and the like to meet the requirements of patients in clinic.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized in that an adhesive is one or more of gelatin, hydrolyzed gelatin, pullulan, polyvinyl alcohol and dextran.
The adhesive or skeleton propping agent mainly obtains a loose and porous skeleton structure in the freeze-dried orally disintegrating tablet to support the shape of the freeze-dried orally disintegrating tablet so as to prevent the tablet from collapsing.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized by also comprising a filling agent.
In order to improve the disintegration of the bosentan freeze-dried orally disintegrating tablet in water, the porosity of the freeze-dried orally disintegrating tablet is increased, and a proper amount of bulking agents such as sugar alcohols, polysaccharides and the like are added. Can effectively improve the appearance plumpness of the freeze-dried orally disintegrating tablet and reduce the phenomena of fragments, top cracks, cracks and the like.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized in that 0-10 parts by weight of a filler is filled in the freeze-dried orally disintegrating tablet.
In a mixture containing 8 parts by weight of (as bosentan anhydrous compound C)27H29N5O6S) bosentan and 1-10 parts by weight of adhesive, and 0-10 parts by weight of filler is added into bosentan freeze-dried orally disintegrating tablets, so that the porosity of the bosentan freeze-dried orally disintegrating tablets can be remarkably improved, and the stability is improvedIt is also good.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized in that a filling agent is one or more of mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, xylose, galactose, trehalose, dextrin and glycine.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized by further comprising 0-5 parts by weight of a flavoring agent.
In a mixture containing 8 parts by weight of (as bosentan anhydrous compound C)27H29N5O6S) 0-5 parts by weight of flavoring agent is added into the bosentan freeze-dried orally disintegrating tablet containing bosentan and 1-10 parts by weight of adhesive, so that the taste of the bosentan orally disintegrating tablet can be effectively improved, and the compliance of a patient during taking is improved.
In a mixture containing 8 parts by weight of (as bosentan anhydrous compound C)27H29N5O6S) bosentan, 1-10 parts by weight of adhesive and 0-10 parts by weight of filler, and 0-5 parts by weight of flavoring agent is added into the bosentan freeze-dried orally disintegrating tablet, so that the taste of the bosentan orally disintegrating tablet can be effectively improved, and the compliance of a patient in taking can be improved.
The invention provides a bosentan freeze-dried orally disintegrating tablet which is characterized in that a flavoring agent is as follows: one or more of sucralose, aspartame, milk flavor, chocolate flavor, orange flavor and strawberry flavor.
Bosentan is bitter in taste and has low solubility in water, and the solubility is increased with the increase of ph. The flavoring agent is added into the bosentan freeze-dried orally disintegrating tablet to improve the taste of a patient when the patient takes the tablet, and the physical and chemical properties of the bosentan freeze-dried orally disintegrating tablet are not influenced.
The invention provides a preparation method of a bosentan freeze-dried orally disintegrating tablet, which is characterized in that the freeze-dried orally disintegrating tablet is prepared by a decompression freeze-drying method. The preparation process adopts a physical method to evaporate or sublimate a solvent (such as water and the like) in the bosentan orally disintegrating tablet to obtain the bosentan freeze-dried orally disintegrating tablet.
The invention also provides a preparation method of the bosentan freeze-dried orally disintegrating tablet, which comprises the following steps:
dissolving: adding the adhesive into water, mixing and heating to 40 ℃, and continuously mixing until the adhesive is completely dissolved; adding the uniformly mixed filler and the mixture of other auxiliary materials and bosentan, and stirring uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into the mold according to the dosage;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 to-90 ℃;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and preserving heat for 1-2 hours when the vacuum degree is below 10-20 Pa;
raising the temperature of the shelf to 0 to-10 ℃, and keeping the temperature for 3 to 4 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3-4 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 1-2 hours;
and (3) product packaging: laminating, cutting and printing batch numbers and production dates under the condition of strictly controlling humidity.
For the quick-freezing step: in order to make the concentration of the medicine uniform, liquid nitrogen is adopted for quick freezing when the freeze-drying orally disintegrating tablet is prepared, so that the liquid medicine is quickly frozen into solid, and the uniform dispersion of the medicine in the tablet is facilitated. The temperature of the liquid nitrogen is not easy to control, so that the quick freezing is finished in a wider temperature range.
Drawings
FIG. 1: the dissolution curves of the home-made bosentan freeze-dried orally disintegrating tablet in a 0.1% SDS aqueous medium are compared with the dissolution curves of the commercially available bosentan dispersible tablets.
FIG. 2: the dissolution curves of the home-made bosentan freeze-dried orally disintegrating tablet in a 0.1% SDS pH1.2 medium are compared with the dissolution curves of the commercially available bosentan dispersible tablets.
FIG. 3: the dissolution curves of the home-made bosentan freeze-dried orally disintegrating tablet in a 0.1% SDS pH4.5 medium are compared with the dissolution curves of the commercially available bosentan dispersible tablets.
FIG. 4: comparing dissolution curves of the home-made bosentan freeze-dried orally disintegrating tablet in a medium with pH6.8 with the commercially available bosentan dispersible tablet.
Detailed Description
The following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.
Example one
| Composition (I) | Content (g) | |
| Bosentan (bosentan) | 33.05 | With bosentan anhydrate (C)27H29N5O6S) 32g |
| |
20 | |
| Mannitol | 12 | |
| Sucralose | 0.4 |
The preparation steps of the freeze-dried orally disintegrating tablet are as follows:
dissolving: adding hydrolyzed gelatin into 300ml water, mixing and heating, and continuously mixing until completely dissolving; adding the uniformly mixed mixture of mannitol and bosentan, stirring uniformly, continuously adding sucralose, stirring uniformly, adding water to a constant volume of the mixed solution to 400ml, and stirring and mixing uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.4 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 deg.C;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mold filled with the liquid medicine into the freeze dryer, vacuumizing, and preserving heat for 2 hours when the vacuum degree reaches 10-20 Pa;
raising the temperature of the shelf to 0-minus 10 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 2 hours;
and (3) product packaging: and (3) laminating, shearing and printing the batch number and the production date under the condition of strictly controlling the humidity.
The lyophilized oral disintegrating tablet contains 32mg of bosentan.
Example two
| Composition (A) | Content (g) | |
| Bosentan (bosentan) | 8.26 | With bosentan anhydrate (C)27H29N5O6S) |
| Gelatin | ||
| 10 | ||
| |
10 | |
| Strawberry flavor essence | 5 |
The preparation steps of the freeze-dried orally disintegrating tablet are as follows:
dissolving: adding gelatin into 200ml water, mixing and heating, and continuously mixing until the gelatin is completely dissolved; adding the uniformly mixed mixture of mannitol and bosentan, stirring uniformly, continuously adding the strawberry flavor essence, stirring uniformly, adding water to a constant volume of the mixed solution to 300ml, and stirring and mixing uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.6 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 deg.C;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and keeping the temperature for 2 hours when the vacuum degree reaches 10-20 Pa;
raising the temperature of the shelf to 0-minus 10 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 2 hours;
and (3) product packaging: laminating, cutting and printing batch numbers and production dates under the condition of strictly controlling humidity.
The lyophilized oral disintegrating tablet contains bosentan 16 mg.
EXAMPLE III
| Composition (A) | Content (g) | |
| Bosentan | 8.26 | With bosentan anhydrate (C)27H29N5O6S) 8g |
| Polyvinyl alcohol | 1 | |
| Mannitol | 8 | |
| Milk flavor essence | 3 |
The preparation steps of the freeze-dried orally disintegrating tablet are as follows:
dissolving: adding polyvinyl alcohol into 150ml of water, mixing and heating, and continuously mixing until the polyvinyl alcohol is completely dissolved; adding the uniformly mixed mixture of mannitol and bosentan, stirring uniformly, continuously adding the milk flavor essence, stirring uniformly, adding water to a constant volume of the mixed solution to 200ml, and stirring and mixing uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.2 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 deg.C;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and keeping the temperature for 2 hours when the vacuum degree reaches 10-20 Pa;
raising the temperature of the shelf to 0 to-10 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 2 hours;
and (3) product packaging: laminating, cutting and printing batch numbers and production dates under the condition of strictly controlling humidity.
The lyophilized oral disintegrating tablet contains bosentan 8 mg.
Example four
| Composition (A) | Content (g) | |
| Bosentan (bosentan) | 16.52 | With bosentan anhydrate (C)27H29N5O6S) 16g |
| Hydrolyzed gelatin | 16 | |
| Xylitol, its preparation method and use | 2 |
The preparation steps of the freeze-dried orally disintegrating tablet are as follows:
dissolving: adding hydrolyzed gelatin into 100ml water, mixing and heating, and continuously mixing until completely dissolving; adding the uniformly mixed mixture of xylitol and bosentan, stirring uniformly, adding water to a constant volume of the mixed solution to 125ml, and stirring and mixing uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.5ml per tablet;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 deg.C;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and keeping the temperature for 2 hours when the vacuum degree reaches 10-20 Pa;
raising the temperature of the shelf to 0 to-10 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 2 hours;
and (3) product packaging: laminating, cutting and printing batch numbers and production dates under the condition of strictly controlling humidity.
The lyophilized oral disintegrating tablet contains bosentan 64 mg.
EXAMPLE five
The preparation steps of the freeze-dried orally disintegrating tablet are as follows:
dissolving: adding hydrolyzed gelatin into 150ml water, mixing and heating, and continuously mixing until completely dissolving; adding bosentan, stirring uniformly, adding water to a constant volume of the mixed solution to 200ml, and stirring and mixing uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.4 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 deg.C;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and keeping the temperature for 2 hours when the vacuum degree reaches 10-20 Pa;
raising the temperature of the shelf to 0-minus 10 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 2 hours;
and (3) product packaging: and (3) laminating, shearing and printing the batch number and the production date under the condition of strictly controlling the humidity.
The lyophilized oral disintegrating tablet contains 32mg of bosentan.
EXAMPLE six
The dissolution curves of 32mg specification of commercially available bosentan dispersible tablets (commercially available tablets) and the home-made bosentan lyophilized orally disintegrating tablets (self-tabletting) in example one were compared. The dissolution method was paddle method, 75 rpm. Four media (pH1.2 hydrochloric acid solution, pH4.5 acetate buffer, pH6.8 phosphate buffer, water) were selected for comparison of dissolution curves. Referring to the bosentan pH-solubility curve, except for pH6.8 medium, bosentan solubility in all three other media was lower. Therefore, 0.1% SDS was added to all three media except the medium at pH 6.8. The dissolution curves are shown in FIGS. 1, 2, 3 and 4. The self-prepared bosentan freeze-dried orally disintegrating tablet can be quickly disintegrated and dissolved, and the dissolving rate is higher than that of a commercially available bosentan dispersible tablet.
EXAMPLE seven
Accelerated stability test, investigation conditions: 40 ℃ C. + -. 2 ℃ C., 75%. + -. 5% RH.
Example one home-made lyophilized oral tablets of bosentan showed by accelerated 3 month test results: the appearance, content and dissolution rate of the sample are not significantly changed compared with the initial values. The other single impurities and unknown total impurities of related substances are slightly increased, and the impurity B is unchanged. The results of 3 months accelerated at present show that the bosentan oral disintegrating tablet has stable quality.
Table 1: accelerated stability test data sheet
The foregoing is illustrative of the preferred embodiments of this invention, and it is to be understood that the invention is not limited to the precise form disclosed herein and that various other combinations, modifications, and environments may be resorted to, falling within the scope of the concept as disclosed herein, either as described above or as apparent to those skilled in the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A lyophilized oral disintegrating tablet of bosentan comprises main drug bosentan and auxiliary materials, and is characterized in that the auxiliary materials of the lyophilized oral disintegrating tablet contain adhesive.
2. The lyophilized orally disintegrating tablet of claim 1,
each freeze-dried orally disintegrating tablet contains bosentan anhydrous compound: 8 parts by weight;
each freeze-dried orally disintegrating tablet contains a binder: 1 to 10 parts by weight.
3. The lyophilized orally disintegrating tablet of claim 2, wherein the binder is one or more of gelatin, hydrolyzed gelatin, pullulan, polyvinyl alcohol, dextran.
4. The lyophilized orally disintegrating tablet according to claim 2, wherein the lyophilized orally disintegrating tablet further comprises a bulking agent.
5. The lyophilized orally disintegrating tablet according to claim 4, wherein the filler is 0 to 10 parts by weight.
6. The lyophilized orally disintegrating tablet of claim 5, wherein the bulking agent is one or more of mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, xylose, galactose, trehalose, dextrin, glycine.
7. The freeze-dried orally disintegrating tablet according to any one of claims 2 to 6, wherein the auxiliary material of the freeze-dried orally disintegrating tablet further comprises 0 to 5 parts by weight of a flavoring agent.
8. The lyophilized orally disintegrating tablet of claim 7, wherein the flavoring agent is: one or more of sucralose, aspartame, milk flavor, chocolate flavor, orange flavor and strawberry flavor.
9. A method for preparing the lyophilized orally disintegrating tablet according to any one of claims 1 to 8, wherein the lyophilized orally disintegrating tablet is prepared by a method of freeze-drying under reduced pressure.
10. The method of claim 9, further comprising the steps of:
dissolving: adding the adhesive into water, mixing and heating to 40 ℃, and continuously mixing until the adhesive is completely dissolved; adding the uniformly mixed filler and the mixture of other auxiliary materials and bosentan, and stirring uniformly;
injection molding: sucking the liquid medicine and injecting the liquid medicine into the mold according to the dosage;
quick-freezing: rapidly freezing the liquid medicine into solid at-60 to-90 ℃;
freeze-drying: cooling the freeze dryer to-20 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing, and preserving heat for 1-2 hours when the vacuum degree is below 10-20 Pa;
raising the temperature of the shelf to 0 to-10 ℃, and keeping the temperature for 3 to 4 hours;
raising the temperature of the shelf to 10-0 ℃ and keeping the temperature for 3-4 hours;
raising the temperature of the shelf to 30-20 ℃, and preserving the heat for 1-2 hours;
and (3) product packaging: laminating, cutting and printing batch numbers and production dates under the condition of strictly controlling humidity.
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