CN109078004A - A kind of freeze-drying oral disnitegration tablet and preparation method thereof - Google Patents
A kind of freeze-drying oral disnitegration tablet and preparation method thereof Download PDFInfo
- Publication number
- CN109078004A CN109078004A CN201710440784.3A CN201710440784A CN109078004A CN 109078004 A CN109078004 A CN 109078004A CN 201710440784 A CN201710440784 A CN 201710440784A CN 109078004 A CN109078004 A CN 109078004A
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- Prior art keywords
- freeze
- gelatin
- oral disnitegration
- disnitegration tablet
- drying
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 229960001862 atracurium Drugs 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 229950011405 deramciclane Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- ASXBYYWOLISCLQ-HZYVHMACSA-N dihydrostreptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O ASXBYYWOLISCLQ-HZYVHMACSA-N 0.000 description 1
- 229960002222 dihydrostreptomycin Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- YMMXHEYLRHNXAB-RMKNXTFCSA-N milameline Chemical compound CO\N=C\C1=CCCN(C)C1 YMMXHEYLRHNXAB-RMKNXTFCSA-N 0.000 description 1
- 229950004373 milameline Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- QOBGWWQAMAPULA-RLLQIKCJSA-N n,n-dimethyl-2-[[(1r,3s,4r)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine Chemical compound C1([C@@]2([C@]3(C)CC[C@@H](C3(C)C)C2)OCCN(C)C)=CC=CC=C1 QOBGWWQAMAPULA-RLLQIKCJSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 150000003571 thiolactams Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- 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
- 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
-
- 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
- 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 present invention relates to a kind of freeze-drying oral disnitegration tablet and using the prescription and technique of freeze-drying preparation freeze-drying oral disnitegration tablet, it include to acidity or the active constituent 1mg~50mg unstable to alkalinity in unit dose, skeletal support agent 1mg~40mg digests gelatin 1mg~40mg.Preparation method simple process of the present invention is easy, and in good taste, disintegration time is short.Freeze-drying oral disnitegration tablet obtained by the present invention is under high temperature, high humidity, illumination condition, and after setting-out in 21 days, total impurities are lower than 0.34%, and each impurity is without departing from limit of impurities requirement, and each impurity growth rate is slower.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of to be lyophilized to acidity or to the unstable active constituent of alkalinity
Orally disintegrating tablet preparation and preparation method thereof.
Background technique
Oral disnitegration tablet refers to that the preparation that can be disintegrated or dissolve rapidly in oral cavity, such preparation encounter in the oral cavity
Saliva can be disintegrated rapidly and largely dissolve.Patient is to take drug after drug becomes liquid.Oral disnitegration tablet comes across
Later period the 1970s, Gregory etc. have manufactured the pharmaceutical carrier of high porosity using Freeze Drying Technique, and the carrier is in mouth
It is dissolved rapidly after encountering saliva in chamber.Oral disnitegration tablet is increasingly liked by patient with its unique superiority, swallows tired
Difficulty is the common adverse effect of antipsychotics, therefore for mental patient, and ordinary tablet is not easy the shortcomings that swallowing and will lead to disease
People's poor compliance, required nursing investment is more, or even the possibility for the threat to life such as cough is choked or choke is eaten occurs.Although drug administration by injection
It is rapid-action, but price is higher, and patient compliance is also poor.
Gelatin is degraded by the collagenous portion in the connective tissues such as animal skin, bone, preparation process generally include alkaline process,
Acid system and enzyme process.The method of preparation of gelatin with enzyme can be divided into two kinds: the first is to handle ossein or collagen with enzyme solutions,
It stirs in an acidic solution, first obtains collagen solution, then pass through the principle acquisition precipitating fiber of isoelectric precipitation, precipitation and separation,
Heating obtains gelatin；Second is to be handled to replace liming process with enzyme solutions, through a period of time processing bone or cladding, reheats and takes out
Mention acquisition gelatin.Enzyme for enzyme process glue can be divided by its source: animal protease, plant rennet and microprotein
Three kinds of enzyme.Common animal protease has trypsase (trypsin), pepsin (pepsin) and chymotrypsin
(chymotrypsin) etc..Plant rennet has papain (papain), bromelain (bromelin) and fig
Protease (ficin) etc..It is micro- that microbial protease arises primarily at bacillus subtilis, bacillus licheniformis, streptomycete etc.
The compound protease of bio secretion.
However, it is found by the inventors that contain partial impurities in the gelatin being prepared under acid condition or alkaline condition,
Influenced by this impurity, the later period production oral disnitegration tablet technical process in easily make the active constituent in preparation be oxidized or
It is hydrolyzed to generate the impurity such as lactams, thio lactam, nitrogen oxides, and exception is easy to appear during medical fluid deposit.
A kind of olanzapine orally-disintegrating tablet preparation is disclosed in CN101904824B, although selection microcrystalline cellulose is dry adhesives
Disintegration time is improved, but due to containing microcrystalline cellulose in prescription, residual is had on lingual surface, grittiness sense, people in oral cavity
Body compliance is poor, and piece mouldability is poor.
A kind of Olanzapine freeze-drying oral disnitegration tablet is disclosed in CN104706603A, selects gelatin and gelatin hydrolysate 3-4:1
The mixed system of composition is adhesive, but gelatin, after hydrolysis, peptide bond fracture becomes polypeptide, molecular weight is down to 2000-
10000, on the one hand its disintegrating property reduce, another aspect gelatin hydrolysis become gelatin hydrolysate after may bring more impurity at
Point, it equally will cause the degradation of active constituent.
Summary of the invention
The present invention solves each impurity in the freeze-drying orally disintegrating tablet preparation containing gelatin and easily exceeds limit of impurities requirement
Defect provides that a kind of drugloading rate is high, oral absorption speed is fast, impurity content is low containing unstable to acidity or to alkalinity
Oral disnitegration tablet is lyophilized in active constituent.
This invention also solves the freeze-drying oral disnitegration tablet preparation process herb liquid exceptions containing gelatin, especially with stirring
The extension of time, medical fluid is more and more sticky, samples difficult defect.
Therefore, one aspect of the present invention provides a kind of freeze-drying oral disnitegration tablet, the freeze-drying oral disnitegration tablet unit dose
Include in amount: to acidity or the active constituent 1mg~50mg, preferably 5mg~10mg unstable to alkalinity；Skeletal support agent 1mg
~40mg, preferably 4mg~8mg；Adhesive 1mg~40mg, preferably 4mg~8mg, the adhesive is enzymatic hydrolysis gelatin, described
Enzymatic hydrolysis gelatin molecular weight be 30000-300000.
Preferably, the enzymatic hydrolysis gelatin is enzymatic hydrolysis Swine bone gelatin, enzymatic hydrolysis pigskin gelatin or digests ox bone gelatin, more preferably
, the enzymatic hydrolysis gelatin is enzymatic hydrolysis ox bone gelatin.
Enzymatic hydrolysis gelatin of the present invention can pass through trypsase, pepsin, cathepsin, chymotrypsin, wood
Melon protease, bromelain, ficin either derive from bacillus subtilis, bacillus licheniformis, streptomycete
The collagen tissue of the compound protease enzymatic hydrolysis animal of equal microorganism secretions obtains.For example, can using patent CN102329843A,
CN101107974、CN104419742A、CN1473901A、CN101107974A。
Skeletal support agent of the present invention includes carbohydrate: mannitol, sorbierite, maltitol, xylitol, lactitol,
Antierythrite, hydroxyl isomaltulose, Semen gossypii sugar, maltose, glucose sugar, galactolipin, trehalose, dextrin or hydroxypropyl cyclodextrin:
Inorganic salts: sodium phosphate, sodium chloride or alumina silicate；Amino acid containing 2 to 12 carbon atoms: glycine, alanine, asparagus fern ammonia
Acid, glutamic acid, hydroxyl proline, isoleucine, leucine or phenylalanine, preferably mannitol.
Corrigent 0.1mg~10mg can also be contained in freeze-drying oral disnitegration tablet unit dose of the present invention, preferably
0.5mg~2mg.
The corrigent includes that Aspartame, acesulfame potassium, Sucralose, aspartame, sucrose etc. naturally or manually close
At one or more of sweetener, preferred Aspartame.
Preservative can also be contained in freeze-drying oral disnitegration tablet unit dose of the present invention, the preservative can be with
For one or both of oxybenzene formicester sodium, oxybenzene the third rouge sodium, contain oxybenzene in the freeze-drying oral disnitegration tablet unit dose
Formicester sodium is 0.01mg~2mg, preferably 0.1mg~1mg, contains the third rouge of oxybenzene in the freeze-drying oral disnitegration tablet unit dose
Sodium unit dose is 0.01mg~2mg, preferably 0.02mg~1mg.
The active constituent unstable to alkalinity of the present invention refers to during processing and/or storage in alkaline condition
The medicinal chemicals of lower degradation.Active constituent of the present invention to acid instability, which refers to, is processing and/or is storing process
In the medicinal chemicals degraded in acid condition.
Specifically to the example of the unstable drug of alkalinity include but is not limited to testosterone, oxybutynin, morphine, fentanyl,
Aspirin, Omeprazole, Pantoprazole, Rabeprazole, naltrexone, benzocainum, penicillin, is gone on first kidney Lansoprazole
Parathyrine, isoprel, thiamine, asenapine, Lamotrigine, Risperidone, Olanzapine, atracurium, beta carotene,
Cephalosporin, chloramphenicol, first miaow replace fourth, Cisapride, Cladribine, chlordiazepoxide, Deramciclane, Didanosine, digitalose
Glycosides, dihydrostreptomycin, erythromycin, Etoposide, famotidine, Milameline, ovobiocin, pancreatin, penicillin salt, more Acarasiales
Element, Pravastatin, quinapril.
It is furthermore preferred that described to acidity or be asenapine, Lamotrigine, Li Pei to the unstable active constituent of alkalinity
The combination of one or more of ketone, Olanzapine.
In the specific embodiment of the present invention, the freeze-drying oral disnitegration tablet, unit dose is by Olanzapine 1mg
~50mg, skeletal support agent 1mg~40mg, adhesive 1mg~40mg composition.
In the specific embodiment of the present invention, the freeze-drying oral disnitegration tablet, unit dose is by asenapine
1mg~50mg, skeletal support agent 1mg~40mg, adhesive 1mg~40mg composition.
In the specific embodiment of the present invention, the freeze-drying oral disnitegration tablet, unit dose is by asenapine
1mg~50mg, skeletal support agent 1mg~40mg, adhesive 1mg~40mg, corrigent 0.1mg~10mg, preservative composition
0.01mg~2mg.
In the specific embodiment of the present invention, the freeze-drying oral disnitegration tablet, unit dose is by Olanzapine 1mg
~50mg, skeletal support agent 1mg~40mg, adhesive 1mg~40mg, corrigent 0.1mg~10mg, preservative form 0.01mg
~2mg.
The present invention provides a kind of preparation methods that oral disnitegration tablet is lyophilized, and this method comprises the following steps:
Gelatin will be digested, after to acidity or to the unstable active constituent of alkalinity and the dissolution of remaining solid adjuvant material
It is added in the enzymatic hydrolysis gelatin of dissolution, stirs and evenly mixs, after being de-gassed, inject in mold, under conditions of -40 DEG C~-170 DEG C
It after 1~60min of pre-freeze, is transferred in freeze dryer, is freezed under conditions of 0.01mbar~10mbar pressure, -30 DEG C~30 DEG C dry
Dry 1~10h to get.
Preferably, a kind of preparation method of freeze-drying oral disnitegration tablet includes the following steps:
Gelatin is weighed, water is added, in 45-100 DEG C, such as 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 of heating water bath dissolutions；Weigh to acidity or to the unstable activity of alkalinity at
Point and remaining solid adjuvant material, be placed in container, it is dry-mixed uniformly after plus a small amount of water, stirring；It will be to acidity or to alkaline unstable
It is added in the enzymatic hydrolysis gelatin of dissolution, stirs and evenly mixs after active constituent and the dissolution of remaining solid adjuvant material, after being de-gassed, injection
In mold, under conditions of -40 DEG C~-170 DEG C after 1~60min of pre-freeze, preferred pre-freeze under conditions of -40 DEG C~-80 DEG C
After 30min, the pre-freeze 5min more preferably in -60 DEG C of refrigerators is transferred in freeze dryer, and the condenser temperature of the freeze dryer is -40 DEG C
~-70 DEG C, in 0.01mbar~10mbar pressure, the preferably 30 μ bar of μ bar~250, being freeze-dried temperature is -70 DEG C~50 DEG C,
Preferably freeze drying temperature rises to 0 DEG C~15 DEG C for -40 DEG C~-10 DEG C, 10~50min；0 DEG C~15 DEG C of maintenance, 30min~
5h；18 DEG C~40 DEG C are risen to by 0 DEG C~15 DEG C, 5min~45min；18 DEG C~40 DEG C are maintained, 30min~5h is to get the jelly
Dry oral disnitegration tablet.
Preparation method simple process of the present invention is easy, and in good taste, disintegration time is short, Olanzapine obtained by the present invention
Oral disnitegration tablet is lyophilized under high temperature, high humidity, illumination condition, after setting-out in 21 days, total impurities are less than or equal to 0.34%, respectively
Impurity is without departing from limit of impurities requirement, and each impurity growth rate is slower.
Specific embodiment
Embodiment 1
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 2
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) asenapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 3
Olanzapine 8mg
Mannitol 7mg
Digest ox bone gelatin 10mg
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 4
Asenapine 9mg
Mannitol 6mg
Digest ox bone gelatin 10mg
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) asenapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 5
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 6
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 7
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 8
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 9
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 250 μ bar of vacuum degree in -25 DEG C, keeps 30min, is risen to by -25 DEG C
10 DEG C, 35min；10 DEG C are maintained, 3h；25 DEG C are risen to by 10 DEG C, 15min；25 DEG C are maintained, 2h.
7) aluminium plastic bag is sealed.
Embodiment 10
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 11
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
Embodiment 12
Preparation process is as follows:
1) gelatin is weighed, water is added, is made it completely dissolved in 60 DEG C of heating water baths.
2) Olanzapine and remaining solid adjuvant material are weighed, is placed in container, dry-mixed uniformly rear plus a small amount of water, stirring.
3) 1) products obtained therefrom is added in 2) products obtained therefrom, is stirred evenly.
4) 3) products obtained therefrom is deaerated.
5) 4) products obtained therefrom is sub-packed in mold, is placed in pre-freeze 5min in -60 DEG C of refrigerators.
6) 5) products obtained therefrom is placed in freeze dryer, 100 μ bar of vacuum degree in -40 DEG C, keeps 50min, is risen to by -40 DEG C
4 DEG C, 50min；4 DEG C are maintained, 1h；35 DEG C are risen to by 4 DEG C, 25min；35 DEG C are maintained, 5h.
7) aluminium plastic bag is sealed.
The test of 13 Olanzapine defects inspecting of embodiment
Test group: the freeze-drying oral disintegrated preparation that embodiment 10,11 and 12 is prepared
Test method: according to 34 editions Olanzapine bulk pharmaceutical chemicals related substances detection methods of United States Pharmacopeia.Buffer solution be
13g lauryl sodium sulfate is dissolved in 2000ml beaker in 1500ml pure water, adjusts pH to 2.5, mistake with sodium hydroxide solution
Filter degassing is spare.Mobile phase A is the mixed liquor of buffer solution and acetonitrile 52:48 (v/v), and Mobile phase B is buffer solution and acetonitrile
The mixed liquor of 30:70 (v/v) detects, the L7 column of 4.6mm*25cm, 5um, flow rate of mobile phase 1.5ml/ at 220nm wavelength
Min, 35 DEG C of detections, sample feeding volume are 20ul.
Test result:
10 defects inspecting test data of embodiment is as follows:
Note: RRT refers to one of relative retention time, liquid chromatogram parameter.
11 defects inspecting test data of embodiment is as follows:
Note: RRT refers to one of relative retention time, liquid chromatogram parameter.
12 defects inspecting test data of embodiment is as follows:
Note: RRT refers to one of relative retention time, liquid chromatogram parameter.
Conclusion (of pressure testing): confirming through research, under high temperature, high humidity, illumination condition, samples after placing same time, compared to
Oral disnitegration tablet is lyophilized using the Olanzapine that Acid hydrolysis ox bone gelatin, alkali process hydrolysis ox bone gelatin are prepared as adhesive, with enzymatic hydrolysis
Ox bone gelatin is that oral disnitegration tablet total impurities are lyophilized lower than 1.0% in the Olanzapine of adhesive preparation, and each impurity is without departing from " gift
Carry out import drugs registered standard " in the limit of impurities requirement, each impurity growth rate is slower, and does not occur prolonging with mixing time
Long, medical fluid is more and more sticky, samples difficult phenomenon.
Claims (10)
1. a kind of freeze-drying oral disnitegration tablet, include in the freeze-drying oral disnitegration tablet unit dose: not to acidity or to alkalinity
Stable active constituent 1mg~50mg, skeletal support agent 1mg~40mg, adhesive 1mg~40mg, the adhesive are enzyme
Gelatin is solved, the molecular weight of the enzymatic hydrolysis gelatin is 30000-300000.
2. a kind of freeze-drying oral disnitegration tablet according to claim 1, the skeleton supporting agent is selected from mannitol, sorb
Alcohol, maltitol, xylitol, lactitol, antierythrite, hydroxyl isomaltulose, Semen gossypii sugar, maltose, glucose sugar, galactolipin,
Trehalose, dextrin or hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride or alumina silicate, glycine, alanine, aspartic acid, paddy ammonia
The one or more of acid, hydroxyl proline, isoleucine, leucine or phenylalanine.
3. a kind of freeze-drying oral disnitegration tablet according to claim 1, it is characterised in that: the enzymatic hydrolysis gelatin is enzymatic hydrolysis pig
One or more of bone gelatin, enzymatic hydrolysis ox bone gelatin or enzymatic hydrolysis pigskin gelatin.
4. a kind of freeze-drying oral disnitegration tablet according to claim 1, it is characterised in that: it is described to acidity or to alkalinity not
Stable active constituent is the combination of one or more of asenapine, Lamotrigine, Risperidone, Olanzapine.
5. a kind of freeze-drying oral disnitegration tablet according to claim 4, it is characterised in that: also contain in the freeze-drying oral disintegrating tablet
There is corrigent, the corrigent is selected from Aspartame, one of acesulfame potassium, Sucralose, aspartame, sucrose or several
Kind.
6. a kind of freeze-drying oral disnitegration tablet described in -5 any one according to claim 1, it is characterised in that: the freeze-drying mouth
Cavity disintegrating tablet also contains preservative.
7. a kind of freeze-drying oral disnitegration tablet according to claim 6, the preservative is oxybenzene formicester sodium, the third rouge of oxybenzene
One or both of sodium.
8. a kind of freeze-drying oral disnitegration tablet according to claim 6, the interior packet of the freeze-drying oral disnitegration tablet unit dose
Sodium 0.01mg~the 2mg of formicester containing oxybenzene, oxybenzene the third rouge sodium 0.01mg~2mg.
9. it is according to claim 1 it is a kind of be lyophilized oral disnitegration tablet preparation method, the method include: will digest it is bright
Peptization solution, will be to acidity or to the enzymatic hydrolysis for being added to dissolution after the unstable active constituent of alkalinity and the dissolution of remaining solid adjuvant material
It in gelatin, stirs and evenly mixs, after being de-gassed, injects in mold, under conditions of -40 DEG C~-170 DEG C after 1~60min of pre-freeze,
Be transferred in freeze dryer, under conditions of 0.01mbar~10mbar pressure, -70 DEG C~50 DEG C be freeze-dried 1~10h to get.
10. a kind of preparation method that oral disnitegration tablet is lyophilized according to claim 9, the method include:
Enzymatic hydrolysis gelatin is weighed, water is added, is dissolved in 45~100 DEG C of heating water baths；It weighs to acidity or the work unstable to alkalinity
Property ingredient and remaining solid adjuvant material, be placed in container, it is dry-mixed uniformly after plus a small amount of water, stirring；It will be to acidity or to alkaline unstable
It is added in the enzymatic hydrolysis gelatin of dissolution, stirs and evenly mixs after fixed active constituent and the dissolution of remaining solid adjuvant material, after being de-gassed,
It injects in mold, under conditions of -40 DEG C~-80 DEG C after pre-freeze 30min, is transferred in freeze dryer, in 0.01mbar~10mbar
Pressure, under conditions of -70 DEG C~50 DEG C 1~10h of freeze-drying to get.
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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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| CN110151718A (en) * | 2019-06-13 | 2019-08-23 | 厦门医学院 | A kind of Olanzapine oral disnitegration tablet and preparation method thereof |
| 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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| CN113081982B (en) | 2022-04-29 |
| CN113081982A (en) | 2021-07-09 |
| CN109078004B (en) | 2021-05-04 |
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