CN109078004B - Freeze-dried orally disintegrating tablet and preparation method thereof - Google Patents
Freeze-dried orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN109078004B CN109078004B CN201710440784.3A CN201710440784A CN109078004B CN 109078004 B CN109078004 B CN 109078004B CN 201710440784 A CN201710440784 A CN 201710440784A CN 109078004 B CN109078004 B CN 109078004B
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- orally disintegrating
- disintegrating tablet
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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
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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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
- 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
Abstract
The invention relates to a freeze-dried orally disintegrating tablet and a prescription and a process for preparing the freeze-dried orally disintegrating tablet by adopting a freeze-drying method, wherein the unit dose comprises 1 mg-50 mg of active ingredients unstable to acidity or alkalinity, 1 mg-40 mg of skeleton propping agent and 1 mg-40 mg of enzymolysis gelatin. The preparation method has the advantages of simple and easy process, good taste and short disintegration time. After 21 days of lofting, the total amount of impurities of the freeze-dried orally disintegrating tablet prepared by the invention is lower than 0.34 percent under the conditions of high temperature, high humidity and illumination, all the impurities do not exceed the limit requirements of the impurities, and the growth speed of all the impurities is slower.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an active ingredient freeze-dried orally disintegrating tablet preparation unstable to acidity or alkalinity and a preparation method thereof.
Background
Orally disintegrating tablets refer to preparations which disintegrate or dissolve rapidly in the oral cavity, and such preparations disintegrate rapidly and dissolve mostly in the oral cavity when exposed to saliva. The patient takes the medicine after the medicine becomes liquid. Orally disintegrating tablets have emerged in the late 70 s of the 20 th century, and Gregory et al employed freeze-drying technology to produce highly porous pharmaceutical carriers that rapidly dissolve in the oral cavity upon encountering saliva. The orally disintegrating tablet is more and more favored by patients with unique superiority, the swallowing difficulty is a common side effect of the antipsychotic, so for mental patients, the disadvantage that the common tablet is not easy to swallow can cause poor compliance of the patients, more nursing investment is needed, and even the possibility of life threatening such as cough or dysphagia occurs. The injection administration has quick effect, but has higher price and poor patient compliance.
Gelatin is degraded from collagen in connective tissues such as animal skin and bone, and is generally prepared by an alkaline method, an acid method, and an enzymatic method. The first method is to treat ossein or collagen skin with enzyme solution, stir in acid solution to obtain collagen solution, precipitate fiber via isoelectric point precipitation, separate precipitate, and heat to obtain gelatin; the second method is to use enzyme solution to replace the liming process, treat the bone or skin material for a period of time, and then heat and extract to obtain the gelatin. The enzyme used for preparing the glue by the enzyme method can be divided into three types, namely animal protease, plant protease and microbial protease according to the sources. Commonly used animal proteases are trypsin (trypsin), pepsin (pepsin), chymotrypsin (chymotrypsin), etc. The plant protease includes papain (papain), bromelin (broomelin), ficin (ficin), etc. The microbial protease is mainly a compound protease secreted by microorganisms such as bacillus subtilis, bacillus licheniformis, streptomyces and the like.
However, the inventors have found that gelatin produced under acidic or basic conditions contains some impurities, and that, due to the impurities, the active ingredient in the preparation is easily oxidized or hydrolyzed to form impurities such as lactam, thiolactam, and nitroxide during the later production process of the orally disintegrating tablet, and that abnormalities are likely to occur during the storage of the drug solution.
CN101904824B discloses an olanzapine orally disintegrating tablet preparation, which uses microcrystalline cellulose as dry adhesive to improve disintegration time, but because the prescription contains microcrystalline cellulose, there is residue on tongue surface, gritty feeling in oral cavity, poor compliance of human body and poor tablet formability.
CN104706603A discloses an olanzapine freeze-dried orally disintegrating tablet, which is prepared from gelatin and hydrolyzed gelatin 3-4: 1 is a binding agent, but after gelatin is hydrolyzed, peptide bonds are broken and become polypeptide, the molecular weight is reduced to 2000-10000, on one hand, the disintegration performance is reduced, on the other hand, more impurity components are possibly brought after the gelatin is hydrolyzed into hydrolyzed gelatin, and the degradation of active ingredients is also caused.
Disclosure of Invention
The invention solves the defect that each impurity in a freeze-dried orally disintegrating tablet preparation containing gelatin easily exceeds the requirement of the limit of the impurity, and provides the freeze-dried orally disintegrating tablet containing the active ingredient which is unstable to acidity or alkalinity, and has high drug loading, high oral absorption speed and low impurity content.
The invention also solves the defects that the liquid medicine is abnormal in the preparation process of the freeze-dried orally disintegrating tablet containing the gelatin, and particularly, the liquid medicine is more viscous and more viscous along with the extension of the stirring time and the sampling is difficult.
Accordingly, in one aspect, the present invention provides a lyophilized orally disintegrating tablet comprising, in a unit dose: 1mg to 50mg, preferably 5mg to 10mg, of an acid-or alkaline-labile active ingredient; 1 mg-40 mg of skeleton propping agent, preferably 4 mg-8 mg; 1 mg-40 mg of adhesive, preferably 4 mg-8 mg of adhesive, wherein the adhesive is enzymolysis gelatin, and the molecular weight of the enzymolysis gelatin is 30000-300000.
Preferably, the enzymatic hydrolyzed gelatin is enzymatic hydrolyzed pig bone gelatin, enzymatic hydrolyzed pig skin gelatin or enzymatic hydrolyzed ox bone gelatin, and more preferably, the enzymatic hydrolyzed gelatin is enzymatic hydrolyzed ox bone gelatin.
The enzymolysis gelatin can be obtained by enzymolysis of collagen tissues of animals by trypsin, pepsin, cathepsin, chymotrypsin, papain, bromelin, ficin or compound protease secreted by microorganisms such as bacillus subtilis, bacillus licheniformis, streptomyces and the like. For example, patents CN102329843A, CN101107974, CN104419742A, CN1473901A, CN101107974A may be employed.
The skeletal propping agent comprises the following saccharides: mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, raffinose, maltose, glucose, galactose, trehalose, dextrin or hydroxypropyl cyclodextrin: inorganic salts: sodium phosphate, sodium chloride or aluminum silicate; amino acids containing 2 to 12 carbon atoms: glycine, alanine, aspartic acid, glutamic acid, hydroxyproline, isoleucine, leucine or phenylalanine, preferably mannitol.
The unit dose of the freeze-dried orally disintegrating tablet can also contain 0.1 mg-10 mg of flavoring agent, preferably 0.5 mg-2 mg.
The flavoring agent comprises one or more of aspartame, acesulfame potassium, sucralose, aspartame, sucrose and other natural or artificial sweeteners, preferably aspartame.
The unit dose of the freeze-dried orally disintegrating tablet can also contain a preservative, the preservative can be one or two of sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate, the unit dose of the freeze-dried orally disintegrating tablet contains 0.01-2 mg of sodium methyl hydroxybenzoate, preferably 0.1-1 mg, and the unit dose of the freeze-dried orally disintegrating tablet contains 0.01-2 mg of sodium hydroxy phenylpropionate, preferably 0.02-1 mg.
The alkaline labile active ingredient of the present invention refers to a chemical drug substance that degrades under alkaline conditions during processing and/or storage. The active ingredient unstable to acidity in the present invention refers to a chemical drug substance that degrades under acidic conditions during processing and/or storage.
Examples of specific alkaline labile drugs include, but are not limited to, testosterone, oxybutynin, morphine, fentanyl, aspirin, lansoprazole, omeprazole, pantoprazole, rabeprazole, naltrexone, benzocaine, penicillin, norepinephrine, isoproterenol, thiamine, asenapine, lamotrigine, risperidone, olanzapine, atracurium, beta-carotene, cephalosporin, chloramphenicol, cimetidine, cisapride, cladribine, chlordiazepoxide, deramciclane, didanosine, digitoxin, dihydrostreptomycin, erythromycin, etoposide, famotidine, melameryline, novobiocin, pancreatin, penicillin salts, polymyxin, pravastatin, quinapril.
More preferably, the active ingredient unstable to acidity or alkalinity is one or the combination of more than two of asenapine, lamotrigine, risperidone and olanzapine.
In a specific embodiment of the invention, the unit dosage of the freeze-dried orally disintegrating tablet is composed of 1 mg-50 mg of olanzapine, 1 mg-40 mg of skeleton supporting agent and 1 mg-40 mg of adhesive.
In a specific embodiment of the invention, the freeze-dried orally disintegrating tablet comprises 1 mg-50 mg of asenapine, 1 mg-40 mg of skeleton supporting agent and 1 mg-40 mg of adhesive in unit dose.
In a specific embodiment of the invention, the unit dose of the freeze-dried orally disintegrating tablet is composed of 1 mg-50 mg of asenapine, 1 mg-40 mg of a skeleton supporting agent, 1 mg-40 mg of an adhesive, 0.1 mg-10 mg of a flavoring agent and 0.01 mg-2 mg of a preservative.
In a specific embodiment of the invention, the unit dose of the freeze-dried orally disintegrating tablet is composed of 1 mg-50 mg of olanzapine, 1 mg-40 mg of a skeleton supporting agent, 1 mg-40 mg of a binding agent, 0.1 mg-10 mg of a flavoring agent and 0.01 mg-2 mg of a preservative.
The invention provides a preparation method of a freeze-dried orally disintegrating tablet, which comprises the following steps:
dissolving the enzymatic hydrolysis gelatin, dissolving an acidic or alkaline unstable active ingredient and other solid auxiliary materials, adding the dissolved enzymatic hydrolysis gelatin into the dissolved enzymatic hydrolysis gelatin, uniformly stirring, degassing, injecting into a mold, pre-freezing for 1-60 min at-40 to-170 ℃, transferring into a freeze dryer, and freeze-drying for 1-10 h under the conditions of 0.01-10 mbar pressure and-30 to 30 ℃ to obtain the final product.
Preferably, the preparation method of the freeze-dried orally disintegrating tablet comprises the following steps:
weighing gelatin, adding water, and heating and dissolving in 45-100 deg.C water bath at 45 deg.C, 50 deg.C, 55 deg.C, 60 deg.C, 65 deg.C, 70 deg.C, 75 deg.C, 80 deg.C, 85 deg.C, 90 deg.C, 95 deg.C, 100 deg.C, preferably 60 deg.C; weighing an active ingredient unstable to acidity or alkalinity and other solid auxiliary materials, putting the active ingredient unstable to acidity or alkalinity and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring; dissolving an acidic or alkaline unstable active ingredient and other solid auxiliary materials, adding the dissolved active ingredient and other solid auxiliary materials into dissolved enzymatic hydrolysis gelatin, uniformly stirring, degassing, injecting into a mold, prefreezing for 1-60 min at-40 to-170 ℃, preferably for 30min at-40 to-80 ℃, more preferably for 5min in a refrigerator at-60 ℃, transferring into a freeze dryer, wherein the temperature of a cold trap of the freeze dryer is-40 to-70 ℃, the pressure of 0.01mbar to 10mbar, preferably for 30 mu bar to 250 mu bar, the freeze drying temperature is-70 to 50 ℃, and the freeze drying temperature is preferably raised to 0 ℃ to 15 ℃ at-40 to-10 ℃, and is 10-50 min; maintaining the temperature at 0-15 ℃ for 30 min-5 h; raising the temperature from 0-15 ℃ to 18-40 ℃ for 5-45 min; maintaining the temperature at 18-40 ℃ for 30 min-5 h to obtain the freeze-dried orally disintegrating tablet.
The preparation method has the advantages of simple and easy process, good mouthfeel and short disintegration time, and after 21 days of lofting, the total amount of impurities is less than or equal to 0.34 percent under the conditions of high temperature, high humidity and illumination, all the impurities do not exceed the limit requirement of the impurities, and the growth speed of all the impurities is relatively low.
Detailed Description
Example 1
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 2
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing asenapine and the rest solid auxiliary materials, putting into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 3
Olanzapine 8mg
Mannitol 7mg
Enzymolysis ox bone gelatin 10mg
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 4
Asenapine 9mg
Mannitol 6mg
Enzymolysis ox bone gelatin 10mg
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing asenapine and the rest solid auxiliary materials, putting into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 5
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 6
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 7
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 8
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 9
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-25 deg.C, maintaining the vacuum degree of 250 μ bar for 30min, heating to 10 deg.C from-25 deg.C, and 35 min; maintaining the temperature at 10 ℃ for 3 h; heating from 10 deg.C to 25 deg.C for 15 min; the temperature is maintained at 25 ℃ for 2 h.
7) And sealing and storing the aluminum-plastic bag.
Example 10
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 11
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 12
The preparation process comprises the following steps:
1) gelatin is weighed, added with water and heated in a water bath at 60 ℃ to be completely dissolved.
2) Weighing olanzapine and the rest solid auxiliary materials, placing the olanzapine and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring.
3) Adding the product obtained in the step 1) into the product obtained in the step 2), and uniformly stirring.
4) Degassing the product obtained in 3).
5) And (4) subpackaging the product obtained in the step (4) into a mold, and pre-freezing for 5min in a refrigerator at the temperature of-60 ℃.
6) Placing the product obtained in step 5) in a freeze dryer at-40 deg.C, maintaining the vacuum degree of 100 μ bar for 50min, heating to 4 deg.C from-40 deg.C, and 50 min; maintaining the temperature at 4 ℃ for 1 h; heating from 4 deg.C to 35 deg.C for 25 min; the temperature is maintained at 35 ℃ for 5 h.
7) And sealing and storing the aluminum-plastic bag.
Example 13 olanzapine impurity detection assay
And (3) test groups: lyophilized orally disintegrating formulations prepared in examples 10, 11 and 12
The test method comprises the following steps: according to the detection method of related substances of olanzapine raw material medicine in the 34 th edition of the United states pharmacopoeia. The buffer solution was prepared by dissolving 13g of sodium lauryl sulfate in 1500ml of purified water in a 2000ml beaker, adjusting the pH to 2.5 with sodium hydroxide solution, and filtering and degassing for use. Mobile phase a was buffer solution and acetonitrile 52: 48(v/v), mobile phase B is a buffer solution and acetonitrile 30: 70(v/v), detected at a wavelength of 220nm, 4.6mm 25cm, 5um L7 column, mobile phase flow rate of 1.5ml/min, detection at 35 ℃ and sample injection volume of 20 ul.
And (3) test results:
example 10 impurity detection test data are as follows:
note: RRT refers to one of the relative retention times, liquid chromatography parameters.
Example 11 impurity detection test data are as follows:
note: RRT refers to one of the relative retention times, liquid chromatography parameters.
Example 12 impurity detection test data are as follows:
note: RRT refers to one of the relative retention times, liquid chromatography parameters.
And (4) test conclusion: research proves that the olanzapine freeze-dried orally disintegrating tablet prepared by taking the enzymolysis ox bone gelatin as the adhesive has less than 1.0 percent of total impurities, has no impurity limit requirement in the 'present imported drug registration standard', has slow growth speed of each impurity, and does not have the phenomena of more viscous liquid medicine and difficult sampling along with the extension of stirring time in the prior art, compared with the olanzapine freeze-dried orally disintegrating tablet prepared by taking acid hydrolysis ox bone gelatin and alkali hydrolysis ox bone gelatin as the adhesive.
Claims (9)
1. A lyophilized orally disintegrating tablet comprising within a unit dose thereof: 5-10 mg of active ingredients which are unstable to acidity or alkalinity, 4-8 mg of framework propping agent and 4-8 mg of adhesive, wherein the adhesive is enzymolysis gelatin, and the molecular weight of the enzymolysis gelatin is 30000-300000;
the active ingredient which is unstable to acidity or alkalinity is olanzapine.
2. The lyophilized orally disintegrating tablet of claim 1, wherein said matrix supporting agent is selected from one or more of mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomaltitol, raffinose, maltose, glucose, galactose, trehalose, dextrin or hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride or aluminum silicate, glycine, alanine, aspartic acid, glutamic acid, hydroxyproline, isoleucine, leucine or phenylalanine.
3. The lyophilized orally disintegrating tablet of claim 1, wherein: the enzymolysis gelatin is one or more of enzymolysis pig bone gelatin, enzymolysis ox bone gelatin or enzymolysis pig skin gelatin.
4. The lyophilized orally disintegrating tablet of claim 1, wherein: the freeze-dried orally disintegrating tablet also contains a flavoring agent, wherein the flavoring agent is selected from one or more of aspartame, acesulfame potassium, sucralose, aspartame and sucrose.
5. A lyophilized orally disintegrating tablet according to any one of claims 1 to 4, wherein: the freeze-dried orally disintegrating tablet also contains a preservative.
6. The lyophilized orally disintegrating tablet of claim 5, wherein said preservative is one or both of sodium methylparaben and sodium propylparaben.
7. The freeze-dried orally disintegrating tablet of claim 5, wherein the unit dose of the freeze-dried orally disintegrating tablet comprises 0.01-2 mg of sodium oxybenzoate and 0.01-2 mg of sodium oxybenzoate.
8. A process for the preparation of a lyophilized orally disintegrating tablet according to claim 1, said process comprising: dissolving the enzymatic hydrolysis gelatin, dissolving an acidic or alkaline unstable active ingredient and other solid auxiliary materials, adding the dissolved enzymatic hydrolysis gelatin into the dissolved enzymatic hydrolysis gelatin, uniformly stirring, degassing, injecting into a mold, pre-freezing for 1-60 min at-40 to-170 ℃, transferring into a freeze dryer, and freeze-drying for 1-10 h under the conditions of 0.01-10 mbar pressure and-70 to 50 ℃ to obtain the final product.
9. The process for preparing a lyophilized orally disintegrating tablet according to claim 8, said process comprising:
weighing enzymolysis gelatin, adding water, and heating in a water bath at 45-100 ℃ for dissolving; weighing an active ingredient unstable to acidity or alkalinity and other solid auxiliary materials, putting the active ingredient unstable to acidity or alkalinity and the rest solid auxiliary materials into a container, adding a small amount of water after dry mixing uniformly, and stirring; dissolving an acidic or alkaline unstable active ingredient and other solid auxiliary materials, adding the dissolved active ingredient and the rest solid auxiliary materials into dissolved enzymolysis gelatin, stirring and uniformly mixing, degassing, injecting into a mold, pre-freezing for 30min at-40 to-80 ℃, transferring into a freeze dryer, and freeze-drying for 1 to 10 hours under the conditions of 0.01mbar to 10mbar pressure and-70 to 50 ℃ to obtain the gelatin.
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| CN202110376762.1A CN113081982B (en) | 2017-06-13 | 2017-06-13 | Freeze-dried orally disintegrating tablet and preparation method thereof |
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| CN112107551A (en) * | 2019-06-19 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Edoxaban freeze-dried orally disintegrating tablet and preparation method thereof |
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| CN102188448A (en) * | 2010-03-19 | 2011-09-21 | 董玲 | Pilose antler freeze-dried excipient with smooth appearance and production method thereof |
| CN104367558A (en) * | 2013-08-15 | 2015-02-25 | 北京星昊医药股份有限公司 | Oseltamivir lyophilized orally-disintegrating tablets and preparation method thereof |
| CN104706603A (en) * | 2013-12-13 | 2015-06-17 | 北京星昊医药股份有限公司 | Olanzapine freeze-drying orally disintegrating tablet and preparation method thereof |
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| EP2044929A1 (en) * | 2007-10-04 | 2009-04-08 | Laboratorios del Dr. Esteve S.A. | Oral fast distintegrating tablets |
| CN102614138A (en) * | 2011-01-26 | 2012-08-01 | 量子高科（北京）研究院有限公司 | Oral disintegrating tablet and preparation method thereof |
| WO2013123623A1 (en) * | 2012-02-24 | 2013-08-29 | 量子高科（北京）研究院有限公司 | Oroally disintegrating tablet and preparation method therefor |
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| CN102188448A (en) * | 2010-03-19 | 2011-09-21 | 董玲 | Pilose antler freeze-dried excipient with smooth appearance and production method thereof |
| CN104367558A (en) * | 2013-08-15 | 2015-02-25 | 北京星昊医药股份有限公司 | Oseltamivir lyophilized orally-disintegrating tablets and preparation method thereof |
| CN104706603A (en) * | 2013-12-13 | 2015-06-17 | 北京星昊医药股份有限公司 | Olanzapine freeze-drying orally disintegrating tablet and preparation method thereof |
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| CN109078004A (en) | 2018-12-25 |
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