CN113768890A - Lurasidone freeze-dried orally disintegrating tablet and preparation method and application thereof - Google Patents
Lurasidone freeze-dried orally disintegrating tablet and preparation method and application thereof Download PDFInfo
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- CN113768890A CN113768890A CN202111180979.1A CN202111180979A CN113768890A CN 113768890 A CN113768890 A CN 113768890A CN 202111180979 A CN202111180979 A CN 202111180979A CN 113768890 A CN113768890 A CN 113768890A
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- Prior art keywords
- lurasidone
- orally disintegrating
- disintegrating tablet
- essence
- freeze
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Links
- 229960001432 lurasidone Drugs 0.000 title claims abstract description 51
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 title claims abstract description 51
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 25
- 229960002863 lurasidone hydrochloride Drugs 0.000 claims abstract description 24
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 239000000796 flavoring agent Substances 0.000 claims abstract description 18
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 17
- 239000000853 adhesive Substances 0.000 claims abstract description 16
- 230000001070 adhesive effect Effects 0.000 claims abstract description 16
- 235000019640 taste Nutrition 0.000 claims abstract description 6
- 239000011159 matrix material Substances 0.000 claims abstract description 5
- 239000000686 essence Substances 0.000 claims description 36
- 239000007788 liquid Substances 0.000 claims description 25
- 229920000159 gelatin Polymers 0.000 claims description 17
- 108010010803 Gelatin Proteins 0.000 claims description 16
- 239000008273 gelatin Substances 0.000 claims description 16
- 235000019322 gelatine Nutrition 0.000 claims description 16
- 235000011852 gelatine desserts Nutrition 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 14
- 238000007710 freezing Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- 201000000980 schizophrenia Diseases 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 7
- 108010011485 Aspartame Proteins 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000605 aspartame Substances 0.000 claims description 6
- 235000010357 aspartame Nutrition 0.000 claims description 6
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 6
- 229960003438 aspartame Drugs 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 230000008014 freezing Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000001746 injection moulding Methods 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000811 xylitol Substances 0.000 claims description 6
- 235000010447 xylitol Nutrition 0.000 claims description 6
- 229960002675 xylitol Drugs 0.000 claims description 6
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 235000003599 food sweetener Nutrition 0.000 claims description 4
- 239000008267 milk Substances 0.000 claims description 4
- 210000004080 milk Anatomy 0.000 claims description 4
- 235000013336 milk Nutrition 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000003765 sweetening agent Substances 0.000 claims description 4
- 229940085605 saccharin sodium Drugs 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 claims description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 claims description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 235000019219 chocolate Nutrition 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 229960003082 galactose Drugs 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 239000012528 membrane Substances 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 4
- 239000003693 atypical antipsychotic agent Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000003340 mental effect Effects 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940127236 atypical antipsychotics Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007968 orange flavor Substances 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 208000017194 Affective disease Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 206010041235 Snoring Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 230000009747 swallowing Effects 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
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Molecular Biology (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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Abstract
The invention discloses a lurasidone freeze-dried orally disintegrating tablet and a preparation method and application thereof. The lurasidone orally disintegrating tablet is a freeze-dried orally disintegrating tablet, and the single dose of the matrix comprises the following components: 2-20 mg of adhesive, 10-100 mg of framework propping agent, 0-10 mg of flavoring agent and 0-10 mg of essence; lurasidone hydrochloride is 10 mg-50 mg; the dosage of the flavoring agent and the essence is not 0. The invention has the advantages of few auxiliary materials, convenient preparation process, high medicine content, high disintegration speed, good absorption of a permeable membrane, good in-vitro dissolution and good taste, and can provide a preparation containing lurasidone or salt thereof with convenient taking, quick absorption and high bioavailability for patients.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, and in particular relates to a lurasidone freeze-dried orally disintegrating tablet and a preparation method and application thereof.
Background
Schizophrenia (schizophrenia) is a common mental disease whose etiology is not completely clarified, and the disease mostly occurs in young and old years, and is often disordered in aspects of perception, thinking, emotion, behavior and the like, and is generally disordered in unconsciousness and intelligence. The disease course is prolonged, the disease attacks are repeated, partial patients suffer from mental activity decline and social function defects of different degrees, the mental activity decline accounts for more than half of patients in the psychiatric department, about half of patients finally suffer from mental disabilities, and serious burden is brought to the society, patients and family members.
Lurasidone (Lurasidone) is a novel atypical anti-schizophrenia drug approved by the Food and Drug Administration (FDA) in 28 u.s.u.s.a.in 2010 for sale under the trade name Latudao. Lurasidone is an atypical antipsychotic whose exact mechanism for treating schizophrenia remains unclear, like other atypical antipsychotics, and may be associated with antagonism of dopamine D2 and 5-hydroxytryptamine 2A (5-HT2A) receptors. It is used for treating schizophrenia, and research reports that lurasi snore can improve cognitive function.
The lurasidone common tablet has the following defects that the lurasidone common tablet needs to be swallowed by water, the disintegration speed is slow, and the onset time is longer. However, patients with schizophrenia have difficulty in swallowing, have poor compliance, and cannot achieve the effect of drug therapy, so that a novel tablet which can be disintegrated without water in the oral cavity or swallowed and can be absorbed well through a film under the tongue needs to be developed.
Disclosure of Invention
The invention aims to provide a lurasidone freeze-dried orally disintegrating tablet and a preparation method and application thereof.
The invention aims to provide a lurasidone freeze-dried orally disintegrating tablet convenient for oral administration, which is prepared by adopting a freeze-drying technology, is simple and convenient to take, is quickly disintegrated, is instantly dissolved in the mouth, is directly swallowed without water, is quickly absorbed, and is convenient for patients with mental diseases to take.
Lurasidone hydrochloride is an atypical antipsychotic drug which is insoluble in water, is used for treating depressive episode and schizophrenia related to bipolar affective disorder, and is suitable for preparing lurasidone freeze-dried orally disintegrating tablets.
The invention provides a lurasidone freeze-dried orally disintegrating tablet and a preparation method thereof. The lurasidone freeze-dried orally disintegrating tablet is prepared from a matrix and lurasidone hydrochloride, wherein the lurasidone orally disintegrating tablet is a freeze-dried orally disintegrating tablet, and single dose of the matrix comprises the following components: 2-20 mg of adhesive, 10-100 mg of framework propping agent, 0-10 mg of flavoring agent and 0-10 mg of essence;
lurasidone hydrochloride is 10 mg-50 mg;
the dosage of the flavoring agent and the essence is not 0.
In the lurasidone orally disintegrating tablet, the binder is at least one selected from gelatin, hydrolyzed gelatin, partially hydrolyzed gelatin and polyvinyl alcohol;
the skeleton propping agent is selected from at least one of mannitol, xylitol, sorbitol, maltitol, lactitol, galactose, glucan and amino acid;
the flavoring agent is a sweetening agent and/or essences with different tastes;
the sweetener is at least one selected from sucrose, aspartame and saccharin sodium;
the essence is at least one of milk essence, chocolate essence, mint essence, orange essence and strawberry essence.
The lurasidone orally disintegrating tablet is a product prepared by the method of claim 5.
The lurasidone orally disintegrating tablet is any one of the following lurasidone orally disintegrating tablets a-d:
the lurasidone orally disintegrating tablet a comprises the following components: 40mg of lurasidone hydrochloride; 10mg of adhesive, 19mg of framework propping agent, 0.5mg of flavoring agent and 0.5mg of essence;
the lurasidone orally disintegrating tablet b comprises the following components: 20mg of lurasidone hydrochloride; 20mg of adhesive, 28mg of framework propping agent, 1.5mg of flavoring agent and 0.5mg of essence;
the lurasidone orally disintegrating tablet c comprises the following components: 50mg of lurasidone hydrochloride; 20mg of adhesive, 40mg of framework propping agent, 2mg of flavoring agent and 1mg of essence;
the lurasidone orally disintegrating tablet d comprises the following components: 40mg of lurasidone hydrochloride; 10mg of adhesive, 50mg of framework propping agent, 1mg of flavoring agent and 0.2mg of essence.
The lurasidone orally disintegrating tablet provided by the invention is applied to the preparation of medicines for treating diseases caused by bipolar disorder and schizophrenia.
The method for preparing the lurasidone orally disintegrating tablet provided by the invention comprises the following steps:
1) dissolving: adding the adhesive into water, mixing and heating to 50 ℃, and continuously mixing until the adhesive is completely dissolved; adding the uniformly mixed mixture of the framework propping agent and the lurasidone hydrochloride, and stirring the mixture until the mixture is uniform; continuously adding the correctant and the essence, stirring and mixing uniformly, adding water to a constant volume (such as 500ml) to obtain a medicinal liquid;
2) injection molding: sucking the liquid medicine according to dosage (such as 0.2, 0.5-1 ml/tablet) and injecting into a mold;
3) quick-freezing: rapidly freezing the liquid medicine to be solid under the environment of-60 ℃ to-120 ℃ (such as-80 ℃);
4) freeze-drying: cooling the freeze dryer to-45 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing after half an hour, and preserving heat for 2 hours when the vacuum degree reaches below 10-30 Pa (such as 20 Pa);
raising the temperature of the shelf to-10-5 ℃ (such as 0 ℃) and keeping for 5 hours;
raising the temperature of the shelf to 5-15 ℃ (such as 10 ℃) and keeping for 4 hours;
and raising the temperature of the shelf to 20-35 ℃ (such as 25 ℃) and keeping for 2 hours to obtain the lurasidone orally disintegrating tablet.
The invention provides a freeze-dried orally disintegrating tablet/sublingual tablet solid preparation which has good taste and convenient administration, can meet the requirement of dissolution rate and takes effect quickly.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified. The gelatin and hydrolyzed gelatin used in the following examples were obtained from Lusirocco (Guangdong) gelatin Co.
Example 1
[ prescription ]
| Components | Dosage g |
| Lurasidone hydrochloride | 40 |
| Hydrolyzed gelatin | 10 |
| Mannitol | 19 |
| Mint-flavored essence | 0.5 |
| Aspartame | 0.5 |
[ PREPARATION METHOD ]
Dissolving: adding gelatin (binder) into 400ml water, mixing and heating to 50 deg.C, and continuously dissolving completely; adding the mixture of mannitol (skeleton agent) and lurasidone hydrochloride which are uniformly mixed, and stirring until the mixture is uniform; continuously adding aspartame (correctant) and peppermint essence, stirring and mixing uniformly, adding water to constant volume to 500 ml;
injection molding: sucking the liquid medicine and injecting the liquid medicine into a mould according to 0.5 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-80 deg.C;
freeze-drying: cooling the freeze dryer to-45 deg.C, placing the mold filled with the medicinal liquid into the freeze dryer, vacuumizing after half an hour, and keeping the temperature for 2 hours when the vacuum degree is below 20 Pa;
the shelf temperature was raised to 0 ℃ and held for 5 hours;
the shelf temperature was raised to 10 ℃ and held for 4 hours;
the shelf temperature was raised to 25 ℃ for 2 hours;
and after the freeze drying is finished, the obtained product is taken out of a freeze dryer for packaging to obtain the lurasidone orally disintegrating tablet.
Example 2
[ prescription ]
| Components | Dosage g |
| Lurasidone hydrochloride | 20 |
| Hydrolyzed gelatin | 20 |
| Xylitol, its preparation method and use | 28 |
| Orange flavour essence | 0.5 |
| Sucrose | 1.5 |
[ PREPARATION METHOD ]
Dissolving: adding hydrolyzed gelatin (binder) into 400ml water, mixing and heating to 50 deg.C, and continuously dissolving completely; adding a mixture of xylitol (skeleton agent) and lurasidone hydrochloride which are uniformly mixed, and stirring the mixture until the mixture is uniform; continuously adding sucrose (correctant) and orange flavor essence, stirring and mixing, adding water to a constant volume of 500 ml;
injection molding: sucking the liquid medicine and injecting the liquid medicine into the mold according to 1 ml/piece;
quick-freezing: rapidly freezing the liquid medicine into solid at-80 deg.C;
freeze-drying: cooling the freeze dryer to-45 deg.C, placing the mold filled with the medicinal liquid into the freeze dryer, vacuumizing after half an hour, and keeping the temperature for 2 hours when the vacuum degree is below 20 Pa;
the shelf temperature was raised to 0 ℃ and held for 5 hours;
the shelf temperature was raised to 10 ℃ and held for 4 hours;
the shelf temperature was raised to 25 ℃ for 2 hours;
and after the freeze drying is finished, the obtained product is taken out of a freeze dryer for packaging to obtain the lurasidone orally disintegrating tablet.
Example 3
[ prescription ]
| Components | Dosage g |
| Lurasidone hydrochloride | 50 |
| Gelatin | 20 |
| Mannitol | 40 |
| Milk flavor essence | 1 |
| Aspartame | 2 |
[ PREPARATION METHOD ]
Dissolving: adding gelatin (binder) into 150ml water, mixing and heating to 50 deg.C, and continuously dissolving completely; adding the mixture of mannitol (skeleton agent) and lurasidone hydrochloride which are uniformly mixed, and stirring until the mixture is uniform; adding aspartame (correctant) and milk essence, stirring, mixing, adding water to desired volume of 250 ml;
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-80 deg.C;
freeze-drying: cooling the freeze dryer to-45 deg.C, placing the mold filled with the medicinal liquid into the freeze dryer, vacuumizing after half an hour, and keeping the temperature for 2 hours when the vacuum degree is below 20 Pa;
the shelf temperature was raised to 0 ℃ and held for 5 hours;
the shelf temperature was raised to 10 ℃ and held for 4 hours;
the shelf temperature was raised to 25 ℃ for 2 hours;
and after the freeze drying is finished, the obtained product is taken out of a freeze dryer for packaging to obtain the lurasidone orally disintegrating tablet.
Example 4
[ prescription ]
| Components | Dosage g |
| Lurasidone hydrochloride | 40 |
| Gelatin | 10 |
| Xylitol, its preparation method and use | 50 |
| Saccharin sodium salt | 1 |
| Essence | 0.2 |
[ PREPARATION METHOD ]
Dissolving: adding gelatin (binder) into 150ml water, mixing and heating to 50 deg.C, and continuously dissolving completely; adding a mixture of xylitol (skeleton agent) and lurasidone hydrochloride which are uniformly mixed, and stirring the mixture until the mixture is uniform; continuously adding saccharin sodium (correctant) and essence, stirring and mixing, adding water to constant volume of 200 ml;
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-80 deg.C;
freeze-drying: cooling the freeze dryer to-45 deg.C, placing the mold filled with the medicinal liquid into the freeze dryer, vacuumizing after half an hour, and keeping the temperature for 2 hours when the vacuum degree is below 20 Pa;
the shelf temperature was raised to 0 ℃ and held for 5 hours;
the shelf temperature was raised to 10 ℃ and held for 4 hours;
the shelf temperature was raised to 25 ℃ for 2 hours;
and after the freeze drying is finished, the obtained product is taken out of a freeze dryer for packaging to obtain the lurasidone orally disintegrating tablet.
The evaluation of mouth feel and the detection method of the oral mucosa irritation and dissolution rate of the lurasidone orally disintegrating tablets in the above embodiments 1 to 4 of the invention are as follows:
the mouth feel test was conducted on 4 tablets of each of the lyophilized orally disintegrating tablets of example 1 to example 4, which were randomly selected from 20 volunteer subjects aged between 20 and 25 years and randomly divided into 5 groups of 4 persons.
TABLE 1 taste test
Disintegration time limit:
referring to the general rule of the fourth part of the 'Chinese pharmacopoeia' 2015 edition < 0921: the disintegration time limit detection method > determines the disintegration condition of the lurasidone freeze-dried orally disintegrating tablet:
TABLE 2 disintegration time results
| Group of | Disintegration time (S) | Phenomenon of disintegration |
| Example 1 | 17 | Rapidly disintegrating |
| Example 2 | 15 | Rapidly disintegrating |
| Example 3 | 12 | Rapidly expanding and disintegrating |
| Example 4 | 10 | Rapidly expanding and disintegrating |
Dissolution rate:
adopts the fourth part of the year 2015 edition of Chinese pharmacopoeia<0931: dissolution ofDegree and release determination>In the second method, 75rpm, at pH1.2, pH3.8 phosphate buffer solution, pH4.0 phosphate buffer solution, and pH6.8 phosphate buffer solution, the samples of comparative examples were measured at 15min (Q)15min) (n-12).
Table 3 dissolution results
The test result shows that: the lurasidone freeze-dried orally disintegrating tablets prepared in the prescription examples 1, 2, 3 and 4 have the same dissolution characteristics with the commercially available tablets, wherein the dissolution behaviors of the prescription examples 2 and 4 are closer to those of the commercially available tablets.
In conclusion, the freeze-dried orally disintegrating tablet disclosed by the invention is small in auxiliary material variety, good in taste, small in stimulation to oral cavity, high in disintegration speed and good in permeable membrane absorption, and can be effectively used for oral/sublingual administration. The lurasidone freeze-dried orally disintegrating tablet provided by the invention has similar dissolution behavior and effective storage period with the commercially available preparation.
Claims (6)
1. A lurasidone orally disintegrating tablet is prepared from a matrix and lurasidone hydrochloride, and is characterized in that: the lurasidone orally disintegrating tablet is a freeze-dried orally disintegrating tablet, and the single dose of the matrix comprises the following components: 2-20 mg of adhesive, 10-100 mg of framework propping agent, 0-10 mg of flavoring agent and 0-10 mg of essence;
lurasidone hydrochloride is 10 mg-50 mg;
the dosage of the flavoring agent and the essence is not 0.
2. The lurasidone orally disintegrating tablet of claim 1, wherein: the adhesive is selected from at least one of gelatin, hydrolyzed gelatin, partially hydrolyzed gelatin and polyvinyl alcohol;
the skeleton propping agent is selected from at least one of mannitol, xylitol, sorbitol, maltitol, lactitol, galactose, glucan and amino acid;
the flavoring agent is a sweetening agent and/or essences with different tastes;
the sweetener is at least one selected from sucrose, aspartame and saccharin sodium;
the essence is at least one of milk essence, chocolate essence, mint essence, orange essence and strawberry essence.
3. The lurasidone orally disintegrating tablet according to any one of claims 1 or 2, wherein: the lurasidone orally disintegrating tablet is a product prepared by the method of claim 5.
4. The lurasidone orally disintegrating tablet according to any one of claims 1 to 3, wherein: the lurasidone orally disintegrating tablet is any one of the following lurasidone orally disintegrating tablets a-d:
the lurasidone orally disintegrating tablet a comprises the following components: 40mg of lurasidone hydrochloride; 10mg of adhesive, 19mg of framework propping agent, 0.5mg of flavoring agent and 0.5mg of essence;
the lurasidone orally disintegrating tablet b comprises the following components: 20mg of lurasidone hydrochloride; 20mg of adhesive, 28mg of framework propping agent, 1.5mg of flavoring agent and 0.5mg of essence;
the lurasidone orally disintegrating tablet c comprises the following components: 50mg of lurasidone hydrochloride; 20mg of adhesive, 40mg of framework propping agent, 2mg of flavoring agent and 1mg of essence;
the lurasidone orally disintegrating tablet d comprises the following components: 40mg of lurasidone hydrochloride; 10mg of adhesive, 50mg of framework propping agent, 1mg of flavoring agent and 0.2mg of essence.
5. Use of the lurasidone orally disintegrating tablet as described in any one of claims 1 to 4 for the preparation of a medicament for the treatment of bipolar disorder, schizophrenia induced diseases.
6. A method of preparing the lurasidone orally disintegrating tablet of any one of claims 1 to 4, comprising:
1) dissolving: adding the adhesive into water, mixing and heating to 50 ℃, and continuously mixing until the adhesive is completely dissolved; adding the uniformly mixed mixture of the framework propping agent and the lurasidone hydrochloride, and stirring the mixture until the mixture is uniform; continuously adding the flavoring agent and the essence, stirring and mixing uniformly, adding water to a constant volume to obtain a liquid medicine;
2) injection molding: sucking the liquid medicine according to the dosage and injecting the liquid medicine into a mould;
3) quick-freezing: rapidly freezing the liquid medicine into solid at-60 ℃ to-120 ℃;
4) freeze-drying: cooling the freeze dryer to-45 ℃, putting the mould filled with the liquid medicine into the freeze dryer, vacuumizing after half an hour, and preserving heat for 2 hours when the vacuum degree reaches below 10-30 Pa;
raising the temperature of the shelf to-10-5 ℃ and keeping the temperature for 5 hours;
raising the temperature of the shelf to 5-15 ℃ and keeping the temperature for 4 hours;
and (3) raising the temperature of the shelf to 20-35 ℃, and keeping for 2 hours to obtain the lurasidone orally disintegrating tablet.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054824A (en) * | 2012-12-21 | 2013-04-24 | 北京万全德众医药生物技术有限公司 | Lurasidone hydrochloride orally-disintegrating tablet preparation 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 |
| CN107007565A (en) * | 2017-03-17 | 2017-08-04 | 万全万特制药江苏有限公司 | A kind of Lurasidone HCl oral disintegrating tablet and preparation method thereof |
| CN110652500A (en) * | 2019-11-04 | 2020-01-07 | 杭州百诚医药科技股份有限公司 | Lornoxicam freeze-dried orally disintegrating tablet and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054824A (en) * | 2012-12-21 | 2013-04-24 | 北京万全德众医药生物技术有限公司 | Lurasidone hydrochloride orally-disintegrating tablet preparation 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 |
| CN107007565A (en) * | 2017-03-17 | 2017-08-04 | 万全万特制药江苏有限公司 | A kind of Lurasidone HCl oral disintegrating tablet and preparation method thereof |
| CN110652500A (en) * | 2019-11-04 | 2020-01-07 | 杭州百诚医药科技股份有限公司 | Lornoxicam freeze-dried orally disintegrating tablet and preparation method thereof |
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