CN108066305B - Method for improving hardness and disintegration of orally disintegrating tablet and location release orally disintegrating tablet - Google Patents

Method for improving hardness and disintegration of orally disintegrating tablet and location release orally disintegrating tablet Download PDF

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CN108066305B
CN108066305B CN201611031006.0A CN201611031006A CN108066305B CN 108066305 B CN108066305 B CN 108066305B CN 201611031006 A CN201611031006 A CN 201611031006A CN 108066305 B CN108066305 B CN 108066305B
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tablet
orally disintegrating
coating
release
disintegrating tablet
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CN108066305A (en
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马俊
刘晓燕
唐振钦
高学琴
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SHENZHEN WANHE PHARMACEUTICAL CO Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides

Abstract

The present invention relates to a method for improving the hardness and disintegration of orally disintegrating tablets and a site-directed release orally disintegrating tablet. In particular to an orally disintegrating tablet which is a tablet formed by compressing through a tabletting process; the tablet includes a tablet matrix composed of a plurality of excipients, and a plurality of coated pellets substantially uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing an active ingredient and at least one layer of coating covering the surface of the pellet core. Also relates to a preparation method and related application of the orally disintegrating tablet. The method of the invention has the excellent effects as described in the specification.

Description

Method for improving hardness and disintegration of orally disintegrating tablet and location release orally disintegrating tablet
Technical Field
The invention belongs to the technical field of pharmacy, and relates to a method for improving the hardness and disintegration of orally disintegrating tablets. The invention also relates to an orally disintegrating tablet and a preparation method thereof, in particular to the orally disintegrating tablet embedded with drug-containing coated pellets in a tablet matrix, wherein the drug-containing coated pellets can provide the active ingredients in the orally disintegrating tablet with positioning release, delayed release and/or controlled release in the whole process from the oral cavity to the gastrointestinal tract.
Background
In order to improve the convenience of medicine use and solve the problem of drug compliance of specific indications and special patient groups, the pharmaceutical industry develops a tablet which can be disintegrated into fine particles only by being placed on the tongue surface and reach the intestines and stomach along with saliva, and the tablet is generally called as an orally disintegrating tablet or an orally disintegrating tablet. The orally disintegrating tablet can be taken without chewing, swallowing or water. This mode of administration is beneficial for pediatric patients, geriatric patients, dysphagia patients, and patients with poor compliance (e.g., psychiatric patients).
The preparation technology of the orally disintegrating tablet products on the market at present mainly comprises a freeze-drying method and a compression method. The product prepared by the freeze-drying method has high disintegration speed, but the tablet has almost no hardness and extremely strong hygroscopicity, and is not beneficial to the production, transportation and taking of patients; meanwhile, the freeze-drying method needs special equipment, increases the production cost and is not beneficial to the wide popularization of the technology. The preparation process of the compression method is similar to that of a common tablet, special equipment is not needed, meanwhile, the product has certain hardness, but the disintegration time of the product is prolonged along with the increase of the hardness, in order to obtain shorter disintegration time, the orally disintegrating tablets produced by the compression method on the market at present are all low-hardness tablets (the hardness is about 1-2 kg), and the product is easy to damage or break due to low hardness of the tablets, so that the production, the transportation and the patient taking of the product are not facilitated. In addition, tablets made by compression methods are highly hygroscopic when exposed to air, which can cause a number of problems in production, packaging, storage, transportation, use, and the like.
The hardness (friability may in some cases also reflect the hardness properties of the tablet) and disintegration time of an orally disintegrating tablet is clearly a pair of spears in the tablet industry. In order to maintain the integrity of the tablets during a series of processes such as preparation, packaging, storage, transportation, use, etc., a higher hardness (e.g., hardness ≥ 3kg, even ≥ 4kg, even ≥ 5kg) is necessary for an orally disintegrating tablet. It is also necessary to have a sufficiently fast disintegration time (e.g. a disintegration time of less than 2min, such as less than 1min, such as less than 45 seconds, such as less than 30 seconds) for the orally disintegrating tablet. However, as the hardness of the tablet increases, the disintegration time is significantly prolonged.
In addition, since the orally disintegrating tablet disintegrates in the oral cavity, there is a possibility that a problem of taking medicine discomfort may be caused due to the bad taste of the medicine. The problem of taste discomfort present in such orally disintegrating tablets can sometimes be addressed by coating the drug for taste masking purposes.
Furthermore, in some cases, localized or controlled release of the drug may be desirable, for example, certain acid-labile drugs may be enteric coated to achieve localized release in the intestine; some drugs requiring controlled release profiles are coated with sustained release coatings to achieve controlled release of the drug. With these requirements for localized or controlled release, great challenges are faced in preparing orally disintegrating formulations.
Therefore, there are many attempts to prepare the drug into pellets (in order to achieve the purposes of taste masking and/or localized release and/or controlled release of the active drug), and then mix the pellets with other excipients, especially with good solubility, and compress them together into tablets to achieve the performance of orally disintegrating tablets. For example, tamsulosin hydrochloride orally disintegrating sustained release tablets which are currently sold clinically are an example, and are characterized in that the targeted release and the controlled release of the drug are realized.
Tamsulosin (Tamsulosin Hydrochloride), also known as Tamsulosin, is clinically solubilized as its Hydrochloride salt with the chemical name: 5- [ (2R) -2- [ [2- (2-ethoxyphenoxy) ethyl group]Amino group]Propyl radical]-2-methoxybenzenesulphonamide hydrochloride with the chemical name in english: 5- [ (2R) -2- [ [2- (2-ethoxyphenyloxy) ethyl]amino]propyl]-2-methoxybenzzene-sulfonimide hydrochloride, CAS number: 106463-17-6; the molecular formula of tamsulosin hydrochloride: c 20 H 28 N 2 O 5 S · HCl, molecular weight: 444.97; tamsulosin hydrochloride has 1 chiral carbon atom in the molecular structure, and clinically used medicines are in the R configuration. Tamsulosin hydrochloride is a novel long-acting alpha-1 adrenoceptor antagonist. The medicine has the characteristics of good selectivity, quick curative effect and less side effect, and is widely used for treating benign prostatic hyperplasia and relevant symptoms thereof clinically.
Tamsulosin hydrochloride preparations were first marketed in the mountain of japan (hereinafter, anstela), and were first sustained-release capsules in which sustained-release granules were filled in the capsule shell. The sustained release capsule is still sold in the U.S. market at present under the trade name
Figure BDA0001154543080000021
However, since tamsulosin hydrochloride is used for the treatment of benign prostatic hyperplasia and its associated symptoms, patients are more likely to sufferFor the elderly, capsules are inconvenient for such people in terms of swallowing. For this purpose, the original developer ansetta modified it to an orally disintegrating sustained release tablet of tamsulosin hydrochloride which can be disintegrated directly in the mouth without the aid of water and swallowed with saliva, under the trade name tamsulosin hydrochloride
Figure BDA0001154543080000022
Japanese name of ハルナール D Tab, 0.1mg or 0.2mg per plate, and the like
Figure BDA0001154543080000023
Have been marketed in Japan and the drug specifications thereof are well known
Figure BDA0001154543080000024
The pharmaceutical instruction of (1) is described
Figure BDA0001154543080000025
The drug release curve of the tamsulosin hydrochloride orally disintegrating sustained release tablet is completely matched with that of the previously sold sustained release capsules. Such as
Figure BDA0001154543080000026
The process for preparing tamsulosin hydrochloride orally disintegrating sustained release tablets is described, for example, in CN1473035B (chinese patent application No. 02802886.4), for example, in example 1 therein. The tamsulosin hydrochloride orally disintegrating sustained release tablet is basically prepared by the following steps: 1) coating tamsulosin hydrochloride on the surface of the microcrystalline cellulose blank pellet core; 2) coating the pill with ethyl cellulose controlled release film; 3) coating the controlled release pellets with an enteric coating material; 4) wet preparing granule with water soluble sugar alcohol such as mannitol, binder solution or suspension, and enteric pellet; 5) mixing the granules with a lubricant and tabletting by a conventional method; 6) (when a highly formable saccharide is used as a binder, for example, maltose, etc.) the temperature and humidity equilibrium treatment is carried out under predetermined temperature and humidity conditions (for example, humidification treatment at 25 ℃ and 75% relative humidity for about 20 hours, and heat treatment at 30 ℃ and 40% relative humidity for about 3 hours). In the above method, the step (1) requires the use of a large amount of an organic solventSuch as methanol, which is not environmentally friendly. In addition, the hardness requirement of the tablet obtained in the step (5) is very low, and then the temperature and humidity balance treatment is carried out through the step (6) to improve the hardness of the tablet, but the temperature and humidity balance treatment needs to take nearly one day, so that the production efficiency is greatly reduced. In addition, in the step 4), when a water-soluble high molecular substance such as polyvinylpyrrolidone or the like is used as a binder or when a low-melting sugar such as sucrose or the like is used as a binder, the tablet is subjected to a high temperature treatment of, for example, 90 to 150 ℃ for 10 to 20 minutes and then cooled to return to a room temperature environment in the step 6) instead of the temperature-humidity equilibrium treatment, thereby increasing the hardness of the tablet. Since extremely accurate temperature and humidity regulation is required for the warm-humid equilibration process for tablets, the use of very high temperatures for the high-temperature treatment of tablets greatly increases the process inoperability, and it is unpredictable whether other problems are thereby caused to the tablets by such warm-humid equilibration or high-temperature treatment processes. Therefore, there is still a need in the art for a new method for preparing orally disintegrating tablets having excellent pharmaceutical properties.
Similar to tamsulosin hydrochloride described above, there are also other drug requirements for localized release, delayed release and/or controlled release, and it would be beneficial to prepare orally disintegrating tablets while satisfying one or more of these requirements. Such as Memantine Hydrochloride, the chemical name 1-Amino-3, 5-dimethyl-amantadine Hydrochloride, the name British 1-Amino-3, 5-dimethyl-amantane Hydrochloride, the formula C 12 H 21 N · HCl, molecular weight Mr 215.77, memantine hydrochloride dissolved in water. Memantine hydrochloride belongs to NMDA receptor regulation medicine. Unlike the conventional cerebral circulation improver and cholinergic enhancer, the product can effectively regulate and control excitatory transmitter, reduce the over-stimulation of nerve cells and further slow down the nerve degeneration process. Clinical tests show that the cognitive ability and the living ability of patients treated by the product are obviously improved. The effective rate is 2 to 3 times higher than that of a placebo group. After the product is used, the dependence on nursing is obviously reduced, so that the burden of the family economy and time personnel of a patient can be greatly reduced.
Other drugs are also available for preparing orally disintegrating tablets and there is a need for localized, delayed and/or controlled release. For example, drugs for mental disorders, nervous system, such as olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, and the like; drugs such as those used for digestive tract diseases, e.g., lansoprazole, famotidine, domperidone, racecadotril; other types of drugs such as loratadine, nisoldipine, salbutamol sulfate, glipizide, glimepiride, granisetron, ondansetron, and the like. Still other drugs such as hypnotic sedative, sleep inducer, anxiolytic agent, antiepileptic agent, antidepressant, anti-Parkinson's disease agent, psychoneurotic agent, central nervous system agent, local anesthetic, skeletal muscle relaxant, autonomic nerve agent, antipyretic, analgesic and anti-inflammatory agent, antispasmodic agent, antihalation agent, cardiotonic agent, antiarrhythmic agent, diuretic agent, hypotensive agent, vasoconstrictor, vasodilator, circulatory organ agent, hyperlipemia agent, respiratory promoter, antitussive agent, expectorant, antitussive, expectorant, bronchodilator, antidiarrheal agent, intestinal tract agent, peptic ulcer agent, stomachic and digestive agent, acid inhibitor, laxative, choleretic agent, digestive organ agent, adrenal hormone, hormone agent, urinary organ agent, vitamin agent, hemostatic agent, liver disease agent, gout therapeutic agent, diabetes therapeutic agent, antihistamine, antihistaminic agent, and pharmaceutical, Antibiotics, antibacterial agents, anti-malignant tumor agents, chemotherapy agents, comprehensive cold agents, nourishing and strengthening health care drugs, osteoporosis drugs and the like, which have the requirements of preparing orally disintegrating tablets, and have the requirements of positioning release, delayed release and/or controlled release, so that the drugs are wrapped in drug-containing micro-pills, and then the drug-containing micro-pills are mixed into orally disintegrating tablets to prepare the orally disintegrating tablets by a compression method, and the process is beneficial to the purposes of realizing the positioning release, the delayed release and/or the controlled release of the drugs. There is therefore a need in the art for a combination of these agents.
Disclosure of Invention
It is a general object of the present invention to provide a method for improving the hardness and disintegration of orally disintegrating tablets. More specifically, the present invention aims to provide a novel process for preparing orally disintegrating tablets having excellent pharmaceutical properties. Such methods are expected to exhibit one or more beneficial effects, such as the ability of the resulting orally disintegrating tablets to achieve one or more of taste masking and/or localized release, delayed release and/or controlled release of the active agent, good tablet hardness and disintegration properties, high manufacturing efficiency, and greater process operability.
To this end, the present invention provides, in a first aspect, an orally disintegrating tablet which is a tablet compressed by a tableting process; the tablet comprises a tablet matrix composed of a plurality of excipients, and a plurality of coated pellets substantially uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing an active ingredient and at least one layer of coating covering the surface of the pellet core.
In the present invention, the term "pellet" may also be referred to as a microparticle.
As is well known, orally disintegrating tablets, otherwise known as orally disintegrating tablets, have an appearance that is itself in the form of a conventional tablet. The tablet of the present invention has a plurality of pellets dispersed and embedded therein, and therefore, it is to be understood that the term "tablet base" of the present invention refers to the portion of the tablet other than the pellets. The material forming the "tablet matrix" portion, refers to all materials except the pellets, which are rendered into tablet form without disrupting pellet structure during the tableting process.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the weight of said coated pellets is 5-50%, such as 5-40%, such as 5-30%, such as 5-25% of the total weight of the orally disintegrating tablet. In examples 1-6 and examples 11-16 below of the present invention, the ratio of coated pellets to sugar/sugar alcohol is properly changed to make the amount of coated pellets in the range of 5-25% of the total weight of the orally disintegrating tablet, such as about 5%, about 10%, about 15%, about 20%, about 25%, so that the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, stability of the finally obtained orally disintegrating tablet are close to those of the examples, and no obvious difference exists.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the weight of said active ingredient is 1-40%, such as 2-30%, such as 3-25%, such as 5-20% of the total weight of the coated pellet. In examples 1-6 and examples 11-16 below of the present invention, when pellet cores with different contents are prepared by appropriately changing the ratio of the active ingredient to the microcrystalline cellulose (or sucrose, etc.) and making the weight of the active ingredient in the range of 2-30%, for example, 3-25%, for example, about 3%, about 5%, about 10%, about 15%, about 20%, about 25% of the total weight of the coated pellet obtained later, the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablet finally obtained are close to those of these examples, and no significant difference exists.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said coated pellets have an average particle size of 50 to 350 μm, such as 50 to 300 μm, such as 100 to 250 μm. In examples 1-6 and examples 11-16 below of the present invention, the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablets finally obtained were similar to those of these examples without significant difference, when the pellet core size was appropriately changed to obtain coated pellets having an average particle size ranging from 50 to 300 μm, for example, an average particle size of about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is substantially uniformly coated on the surface of said pellet core or said active ingredient is substantially uniformly dispersed in said pellet core.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is selected from the group consisting of: hypnotic/sedative agent, sleep inducer, anxiolytic agent, antiepileptic agent, antidepressant, anti-Parkinson's disease agent, psychogenic agent, central nervous system agent, local anesthetic agent, skeletal muscle relaxant, autonomic nerve agent, antipyretic, analgesic and anti-inflammatory agent, antispasmodic agent, antihalation agent, cardiotonic agent, antiarrhythmic agent, diuretic agent, hypotensive agent, vasoconstrictor, vasodilator, circulatory organ agent, hyperlipemia agent, respiratory promoter, antitussive agent, expectorant, antitussive, expectorant, bronchodilator, antidiarrheal agent, intestinal agent, peptic ulcer agent, digestive and digestive agent, antacid, cathartic, choleretic agent, digestive organ agent, adrenal hormone, urinary organ agent, vitamin, hemostatic agent, liver disease agent, gout therapeutic agent, diabetes agent, antihistamine, antibiotic, antibacterial agent, antidiarrheal agent, analgesic, and analgesic, Anti-malignant tumor agent, chemotherapy agent, influenza agent, tonic health drug, osteoporosis drug, such as indomethacin, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, metronidazole, aspirin, ethenzamide, acetaminophen (paracetamol), aminopyrine, phenacetin, hyoscine, scopolamine butylbromide, morphine, etodoline, antalgin, fenoprofen calcium, naproxen, Celecoxib, Valdecoxib, tramadol, antipyretic, antispasmodic or analgesic drugs, etodol, antihypoxic drugs such as isoniazid, ethambutol hydrochloride, antitubercular drugs such as isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indonololol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, nitrate ethidium nitrate, ethidium hydrochloride, hydralazuride, hydralazuril hydrochloride, meclozine hydrochloride, meclol, ethidium hydrochloride, ethiprolide hydrochloride, and the like, Circulating organ drugs such as reserpine, sulfamolol hydrochloride, lisinopril, metoprolol, pilocarpine, paroxetine, chlorpromazine hydrochloride, amitriptyline hydrochloride, nemorubine, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, alprazolam, methylphenidate, milnacipran, risperidone, sodium valproate, and other anti-psychotropic drugs, metoclopramide hydrochloride, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, and azasetron hydrochloride, and other anti-emetics, chlorphenamine maleate, and diphenhydramine hydrochloride, thiamine nitrate, vitamin E acetate, thiocoramine, pyridoxal phosphate, cobalamine, ascorbic acid, and nicotinamide and other vitamins, allopurinol, colchicine, and propathion, levodopa, and other Parkinson's disease drugs, and priapigenin, Hypnotic sedatives such as bromoisoflurane, midazolam, chloral hydrate, etc., anti-malignant tumor drugs such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc., anti-allergic drugs such as pseudoephedrine, terfenadine, etc., decongestants such as phenylpropanolamine, ephedrine, etc., diabetes drugs such as acehexol, insulin, tolbutamide, desmopressin, glipizide, etc., diuretics such as hydrochlorothiazide, poishiazide, triamterene, etc., bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc., antitussives such as codeine phosphate, narcotine, dimemorfan phosphate, dextromethorphan, etc., antiarrhythmics such as quinidine nitrate, digitaloxacin, propafenone hydrochloride, procainamide, etc., surface anesthetics such as ethyl aminobenzoate, lidocaine, cinchocaine hydrochloride, etc., antibiotics such as phenytoin, ethosuximide, antiepilone, etc., hydrocortisone, etc., anti-drugs such as hydrocortisone, etc., and the like, Synthetic adrenocortical steroids such as prednisolone, triamcinolone and betamethasone, digestive system drugs such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenoxate, 5-aminosalicylic acid, sulfasalazine, omeprazole and lansoprazole, central nervous system drugs such as indolozine, idebenone, sulpiride, dimesnam and calcium pantothenate, hyperlipidemia therapeutic agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin and atorvastatin, antibiotics such as phthalazinol hydrochloride, cefotetan and josamycin, BPH therapeutic agents such as tamsulosin, doxazosin and terazosin, antiasthmatic agents such as pranlukast, zafirlukast, salbutamol, ambroxol, budesonide and levosalbutamol, peripheral circulation improving agents such as prostaglandin I derivatives such as bebestatin sodium, Antithrombotic agent, antihypertensive agent, therapeutic agent for heart failure, therapeutic agent for diabetic complications, therapeutic agent for peptic ulcer, therapeutic agent for skin ulcer, therapeutic agent for hyperlipidemia, and anti-asthma agent. The drug may be any of an episome and a pharmaceutically acceptable salt.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is selected from the group consisting of: tamsulosin, memantine, olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, lansoprazole, famotidine, domperidone, racecadotril, loratadine, nisodipine, salbutamol sulfate, glipizide, glimepiride, granisetron, ondansetron, and pharmaceutically acceptable salts, isomers, and the like thereof.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the core material of said coated pellets is selected from the group consisting of cellulose or derivatives thereof (e.g. microcrystalline cellulose) or spheres thereof, sucrose or sucrose spheres, starch or starch spheres, lactose or lactose spheres.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the cores of said coated pellets are microcrystalline cellulose cores or sucrose spheres. It has been found that the selection of the pellet core material does not affect the practice of the present invention, for example, in examples 1 to 6 and examples 11 to 16 of the present invention below, when the microcrystalline cellulose as the pellet core is changed to sucrose spheres or sucrose in the initial step, the resulting orally disintegrating tablets have no difference in physical and chemical properties from the tablets of examples 1 to 6 and examples 11 to 16.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet core, the active ingredient being substantially uniformly coated on the surface of the pellet core.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet core, and the active ingredient is substantially uniformly coated on the surface of the pellet core after being compounded into a solution or suspension with a binder. In one embodiment, the solvent in which the solution or suspension is formulated does not include an organic solvent. In one embodiment, the solvent in which the solution or suspension is formulated is water. It has been surprisingly found that when water is used as the solvent for formulating the adhesive solution or suspension in the above process, the resulting drug-containing pellet core has significantly better content uniformity of the active ingredient than when using the organic solvent methanol or methanol-water mixture as the solvent.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the pellet core of said coated pellets is a microcrystalline cellulose pellet core, said active ingredient being substantially homogeneously distributed inside said pellet core.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the core of said coated pellets is a microcrystalline cellulose core pellet, said active ingredient being substantially homogeneously distributed within said core pellet; uniformly mixing the active ingredients and microcrystalline cellulose, adding a solution or suspension containing a binding agent, and preparing the active ingredients and the microcrystalline cellulose into a pill core by a stirring granulation method or a fluidized bed granulation method; alternatively, a solution or suspension containing the active ingredient and a binder is added to the microcrystalline cellulose to prepare a pellet core by a stirring granulation method or a fluidized bed granulation method. In one embodiment, the solvent in which the solution or suspension is formulated does not include an organic solvent. In one embodiment, the solvent in which the solution or suspension is formulated is water. It has been surprisingly found that when water is used as the solvent for formulating the adhesive solution or suspension in the above process, the resulting drug-containing pellet core has significantly better content uniformity of the active ingredient than when using the organic solvent methanol or methanol-water mixture as the solvent.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said binder used for preparing said pellet cores is a polymeric substance, for example a water soluble polymeric substance, for example selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone or polyvinyl alcohol, and combinations thereof. Of course, the polymer may be used as a binder in other steps. As is well known, the amount of such binder can be readily adjusted based on experience and textbook teaching by those skilled in the art, for example, the binder can be 1-10% by weight of the pellet core, for example, the binder can be 1-7.5% by weight of the pellet core, for example, the binder can be 1-5% by weight of the pellet core.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the at least one coating on the surface of said coated pellets is selected from: film coatings, enteric coatings, gastric coatings, sustained release coatings, controlled release coatings, and combinations thereof. When multiple coatings are used, the sequence of coating layers may be determined for different purposes. For example, when it is desired that the drug is not dissolved in the stomach but is slowly released from the intestinal fluid, the drug-containing pellet core may be coated with a sustained-release coating layer, and then the sustained-release coating layer may be coated with an enteric coating layer. For another example, when the requirement of covering the unpleasant taste of the drug and slowly releasing the drug in gastrointestinal fluids is required, the drug-containing pellet core can be coated with a sustained-release coating layer, so as to achieve the purpose.
Film coatings are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
Enteric coatings are well known to those skilled in the art. Exemplary enteric coating film forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit model L, S.
Gastric coatings are well known to those skilled in the art. Exemplary gastric-coating film-forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit type E.
Sustained release coatings and controlled release coatings are well known to those skilled in the art. Exemplary sustained release coatings and controlled release coating film forming materials are most typically ethyl cellulose.
The addition of certain additives to the coating material to suit specific coating requirements can be readily determined empirically by those skilled in the art. For example, a plasticizer, a coloring agent, a masking agent, and the like may be added to the coating liquid.
When the surface of the coated pellet is coated, the solvent in the coating liquid can be organic solution or water or the mixed solution of the organic solution and the water. In one embodiment, the solvent in the coating solution does not include an organic solvent. In one embodiment, the solvent in the coating solution is water.
The preparation of cores and their coatings to obtain coated pellets according to the present invention is well known in the art and is typically a granulation, coating process using the fluid bed principle, e.g. the preparation of sustained release microparticles as already described in CN 1473035B. As is well known, the amount of coating layer to be applied to the surface of the pellet core can be readily adjusted according to the experience of those skilled in the art and the teaching of textbooks, for example, the weight of the coating layer can be 1 to 20% of the weight of the pellet core, for example, the weight of the coating layer can be 1 to 15% of the weight of the pellet core, and for example, the weight of the coating layer can be 1 to 10% of the weight of the pellet core.
The orally disintegrating tablet according to any one of the embodiments of the first aspect of the present invention, wherein only water and not an organic solvent is used as a solvent for formulating the binder solution or the coating solution in preparing said coated pellet. Although CN1473035B teaches the use of a mixed solvent of methanol and a small amount of water, the present invention finds better process performance using water rather than an organic solvent.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the excipients forming the tablet base comprise excipients selected from the group consisting of the following (sugars and/or sugar alcohols): mannitol, lactose, sucrose, maltose, trehalose, sorbitol, maltitol, xylitol, erythritol, glucose, and combinations thereof. In particular, such an excipient preferably uses a combination of one or more of the above sugars and/or sugar alcohols. It is well known that too small a tablet can increase tableting difficulty; however, if the amount of saliva is small, the disintegration effect and the taste are impaired when the tablet is too large. Generally, it is preferable to control the weight of the orally disintegrating tablet to 60 to 600mg, particularly 75 to 500mg, and particularly 100 to 500mg per tablet of 30mg or less of the active ingredient. Therefore, in one embodiment of the present invention, the orally disintegrating tablet of the present invention has a tablet weight of 60 to 600mg, particularly 75 to 500mg, particularly 100 to 500 mg. Since the main material in the orally disintegrating tablet is an excipient, the amount of the excipient in the orally disintegrating tablet may be added as an amount of the equilibrium tablet weight, for example, in a manner similar to "an amount added to the tablet weight", "an appropriate amount, to the entire weight of the tablet", "an appropriate amount to make the tablet weight … mg", and the like, or other similar expressions, which means the same as "an amount added as the equilibrium tablet weight (up to … mg)".
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the excipients forming the tablet base comprise a binder. In one embodiment, the binder may be the same as used in the preparation of the coated pellets. In one embodiment, the binder may be the same as the sugar or sugar alcohol described above as the excipient. In particular, when tablets are prepared, a solution of a part or all of one or more of sugar or sugar alcohol as an excipient is prepared with water as a binder, and then the coated pellets are mixed with the excipient and wet-granulated with the binder solution. The amount of binder added during the preparation process to form the tablet matrix can be easily adjusted according to experience and textbook teaching of the skilled person, e.g. the weight of the binder can be 1-20% of the weight of the orally disintegrating tablet, e.g. the weight of the binder can be 2-15% of the weight of the orally disintegrating tablet, e.g. the weight of the binder can be 3-12% of the weight of the orally disintegrating tablet. In examples 1 to 6 and examples 11 to 16 of the present invention below, when hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sorbitol, or xylitol, or the like, was used as a binder for forming the matrix of the tablet, and the amount of the binder added was in the range of 3 to 12% by weight of the orally disintegrating tablet, the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablet obtained were similar to those of the examples, and no significant difference was observed.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the binder forming the tablet matrix is one or more selected from the group consisting of: maltose, trehalose, sorbitol, maltitol, glucose, xylitol, erythritol, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, or polyvinyl alcohol. It has been found that the addition of an appropriate amount of salt to the matrix of an orally disintegrating tablet using the method of the present invention, regardless of which binder is used, can be directly compressed into tablets of desired hardness and has excellent disintegration properties without the need for compression at low pressure and subsequent humidification-drying or high temperature-cooling as in the prior art.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the auxiliary material forming the tablet base may further comprise a disintegrant. Typical disintegrants are for example, but not limited to: corn starch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethylcellulose, crospovidone, low-substitution hydroxypropylcellulose, and the like. The amount of disintegrant added during the preparation process to form the tablet matrix can be readily adjusted according to the experience of the skilled person and the teaching of the textbook, e.g. the weight of the disintegrant can be 1 to 20% of the weight of the orally disintegrating tablet, e.g. the weight of the disintegrant can be 1 to 15% of the weight of the orally disintegrating tablet, e.g. the weight of the disintegrant can be 2 to 10% of the weight of the orally disintegrating tablet. In examples 1-6 and examples 11-16 below of the present invention, when the above-mentioned disintegrating agent corn starch, carboxymethylcellulose calcium, crospovidone, or sodium starch glycolate, which is 2-10% of the weight of the orally disintegrating tablet, is properly added, the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablet produced are all close to those of the examples, and no significant difference is observed.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein the auxiliary materials forming the tablet base may further comprise additives such as sweeteners, colorants and the like. The amount of the sweetener, colorant, etc. additives added during the preparation process to form the tablet base may be readily adjusted according to the experience of the skilled person and the teaching of the textbook, for example, the weight of the sweetener, colorant, etc. additives may each independently be 0.1 to 5% of the weight of the orally disintegrating tablet, for example, the weight of the sweetener, colorant, etc. additives may each independently be 0.2 to 2.5% of the weight of the orally disintegrating tablet, for example, the weight of the sweetener, colorant, etc. additives may each independently be 0.5 to 2% of the weight of the orally disintegrating tablet.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the excipients forming the tablet base further comprise salts selected from the group consisting of: sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof. The present inventors have surprisingly found that not only can tablets having excellent hardness and friability indexes be directly obtained by a wet granulation tableting method without long-term temperature and humidity equilibration treatment or extremely high temperature treatment, but also such hardness and friability indexes have excellent stability, and more expensively, the tablets of the present invention have excellent disintegration properties on the premise of having excellent hardness and friability indexes, when an appropriate amount of the above-mentioned salts is added to the tablet matrix. The invention determines the dosage of the salt added in the preparation process of forming the tablet matrix, in particular, the weight of the salt can be 1-15% of the weight of the orally disintegrating tablet, for example, the weight of the salt can be 2-10% of the weight of the orally disintegrating tablet, for example, the weight of the salt can be 2.5-10% of the weight of the orally disintegrating tablet. In examples 1 to 6 and examples 11 to 16, which are described below, of the present invention, when the above salts are added and the weight is adjusted to be in the range of 2 to 10% by weight of the orally disintegrating tablet, the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablet produced are similar to those of the examples, and there is no significant difference. In discovering the effects of the above salts in the tablets of the invention, the present inventors tried to change to other salts (e.g. organic salts such as sodium citrate, e.g. calcium salts such as calcium sulfate, calcium carbonate and calcium hydrogen phosphate) and found that none of them could achieve the effect of improving the tablet strength without affecting the disintegration as mentioned above for the salts of the invention.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein the excipients forming the tablet base may further comprise a lubricant. The inclusion of conventional amounts of lubricant is beneficial for tablet appearance and to prevent sticking. Lubricants which may be used are selected from: magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid, and the like, and combinations thereof. The amount of lubricant added during the preparation process to form the tablet matrix can be readily adjusted according to experience and textbook teachings of those skilled in the art, for example the weight of the lubricant can be 0.5-10% of the weight of orally disintegrating tablets, for example the weight of the lubricant can be 0.5-5% of the weight of orally disintegrating tablets, for example the weight of the lubricant can be 0.5-2% of the weight of orally disintegrating tablets. In examples 1-6 and examples 11-16 below, the above lubricants were added in an amount of 0.5-2% by weight of the orally disintegrating tablet, and the hardness, content uniformity, friability, moisture absorption rate, disintegration time, dissolution rate, and stability of the orally disintegrating tablet were similar to those of the examples, and no significant difference was observed.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein the excipients forming the tablet base comprise: excipient, binder, salt and lubricant.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, which is prepared by a process comprising the steps of: mixing the coated pellets with excipients, spraying a binder solution into the mixture using a fluid bed granulation process to form wet granules and drying (as is well known to those skilled in the art of pharmaceutical manufacturing, drying generally results in a material having a moisture content of less than 5%, particularly less than 4%, particularly less than 3%), adding a lubricant to the resulting dry granules, mixing well, and tabletting. In one embodiment, when present, the salts may be added by mixing with the coated pellets together with excipients. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salt is added in powder form at the stage of lubricant addition.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, which is prepared by a process comprising the steps of: spraying binder solution into excipient by fluidized bed granulation process to make wet granule, drying (generally, drying to make water content of less than 5%, especially less than 4%, especially less than 3%), adding coated pellet and lubricant into the obtained dry granule, mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with excipients and preparing granules. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salt is added in powder form at the stage of lubricant addition.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention, which is repeatedly measured for 6 tablets of disintegration time, 6 tablets all disintegrating in 60 seconds and passing through a sieve, according to the regulation under the item "0921 disintegration time limit inspection method" and "orally disintegrating tablet" in the general rules of the four parts of the chinese pharmacopoeia 2015 edition; in particular 6 tablets all disintegrated within 45 seconds and passed through the screen; in particular 6 tablets all disintegrated within 30 seconds and passed through the sieve.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention has a friability of the tablet, measured according to the method under the item "0923 tablet friability test" of the fourth general rule of chinese pharmacopoeia 2015, no fractures, cracks and crushed tablets, and a weight loss reduction of less than 3%, such as less than 2%, such as less than 1.5%, such as less than 1%. The "weight loss" may also be generally referred to as "abrasion".
The orally disintegrating TABLET according to any of the embodiments of the first aspect of the invention has a hardness of the TABLET measured according to the method of USP35-NF30 edition "< 1217> TABLET BREAKING FORCE", which value is in the range of 3 to 6kg, for example in the range of 4 to 6 kg.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, which has a moisture absorption rate of less than 20% (e.g. less than 15%, e.g. less than 12.5%, e.g. less than 10%) as measured by the following method: taking tablets with the total weight of 5.0-5.5 g, and precisely weighing; exposing the mixture to 25 ℃ and 75% relative humidity for 24 hours, and precisely weighing the mixture; the moisture absorption was calculated as follows:
the moisture absorption rate is [ (weight of sheet after moisture absorption treatment-weight of sheet before moisture absorption treatment) ÷ weight of sheet before moisture absorption treatment ] × 100%.
Since the taste of a portion of the active agents contemplated by the present invention, such as memantine hydrochloride, is very bitter, it is often desirable to try to mask the undesirable bitter taste when preparing oral formulations. The orally disintegrating tablets of the present invention can easily achieve taste masking by pellet surface coating (the kind of coating film is not generally limited, HPMC-based, polyethylene glycol-based, Eudragit-based, ethylcellulose-based, etc.). To achieve this taste masking, it is generally considered satisfactory to require that the drug dissolution rate be less than 20% within 15 minutes of residence in the mouth of the medicament. Therefore, whether slow release or delayed release is required, the drug dissolution rate of the drug-containing coated micro-pill orally disintegrating tablet with poor mouthfeel is less than 20 percent in 15 minutes in water, which meets the design requirement of the medicament. In addition, if it is desired to impart a release profile to the active agent with sustained release properties, this can be achieved by simply coating the coated pellets with a sustained release coating which also has the function of masking bitter taste. Thus, for the orally disintegrating tablets of the invention comprising coated pellets of the active drug, any type of coating layer may achieve taste masking purposes, while sustained release purposes are only one of its options when needed.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention has a dissolution rate of less than 20%, such as less than 15%, within 15 minutes at a rotation speed of 50 rpm in a water volume of 250ml as a dissolution medium according to the third method of 0931 dissolution and release determination method of the general rule of the four parts of the pharmacopoeia 2015 edition of China.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention, wherein the coated pellets before contact with the material of the tablet base (i.e. the state of the coated pellets after completion of coating of each layer and before proceeding to the subsequent non-coating process) show a drug dissolution rate of 50%, the absolute value of the difference between the dissolution rate of the coated pellets and the dissolution rate of the orally disintegrating tablet is in the range of 0 to 15%, particularly in the range of 0 to 12.5%. The difference in dissolution rates between the coated pellets and the orally disintegrating tablets at the above time points may be referred to as a 50% dissolution difference in the present invention. The dissolution difference can be used for reflecting the dissolution behavior difference between the coated pellet and the final tablet thereof and reflecting the influence of the subsequent process treatment process of the coated pellet on the dissolution behavior of the pellet.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, prepared substantially according to a process comprising the steps of:
i) coating the active ingredient on the surface of the pellet core or dispersing the active ingredient in the pellet core, and coating the pellet core to obtain coated pellet;
ii) mixing said coated pellets with said salts and excipients forming said tablet matrix and tabletting. [ in one example, the excipients forming the tablet base include excipients, salts, binders, lubricants, and the like ]
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein step ii) is performed as follows:
iia) mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to make wet granules and drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salts may be added by mixing with excipients and with the coated pellets, or the salts may be added by adding to the binder solution, or the salts are added in powder form at the stage of adding the lubricant.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein step ii) is performed as follows:
iib) spraying a binder solution into the excipient by using a fluidized bed granulation process to make wet granules and dry, adding the coated pellets and the lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salt can be added in a manner of preparing granules after mixing with an excipient, or the salt can be added in a manner of adding into a binder solution, or the salt is added in a form of powder at the stage of adding a lubricant.
The above iia) and iib) are mixed with excipients, and the inventors have respectively verified that the two mixing methods produce orally disintegrating tablets with no difference in properties, especially in properties of imparting excellent physical strength and rapid disintegration effect to the tablets. In addition, the present inventors have demonstrated the performance of tablets obtained by incorporating salts into granules containing excipients by a granulation process; furthermore, the inventors have also verified in supplementary tests that the salt is added at the final stage before tabletting, i.e. in powder form at the stage of adding the lubricant, and have found that this addition does not differ from the above-described addition of salt to the granules in terms of the properties of the tablets obtained.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention, which is a tablet measured according to the method under the "second method (baking method)" of the general rule "0832 moisture determination" on the national pharmacopoeia 2015 edition of china, the tablet having a water content of less than 10%, such as less than 7.5%, such as less than 5%, such as in the range of 2 to 5%. The invention hereinafter relates to various tablets prepared by the method of the invention, which have a water content in the range of 2-5% when prepared, within 24 hours after preparation and after 5 months of stability test.
The orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, e.g. tamsulosin hydrochloride. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is a slow release coating layer. In one embodiment, said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and said coating is an enteric coating layer. In one embodiment, said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and said coating comprises two layers, a sustained release coating layer and an enteric coating layer from the inside to the outside. The invention has outstanding contribution to the prior art and is found that the physical strength and the disintegration property of the tablet can be obviously improved by adding a proper amount of salt into the orally disintegrating tablet with embedded pellets. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained-release effect of the release profile of tamsulosin or a pharmaceutically acceptable salt thereof, for example, a sustained-release or controlled-release effect to release substantially in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, it is possible to achieve by adjusting the thickness of the sustained-release coating layer or the like, which is easily accomplished in the field of pharmaceutical preparations.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein said active ingredient is memantine or a pharmaceutically acceptable salt thereof, e.g. memantine hydrochloride. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a film coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a slow release coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is an enteric coating layer. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside out. The invention has outstanding contribution to the prior art and the discovery that the addition of a proper amount of salt to the orally disintegrating tablet of the embedded pellets can obviously improve the physical strength and the disintegration performance of the tablet. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained release effect of memantine hydrochloride release profile, for example, a sustained release or controlled release effect which is substantially released in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, if necessary, can be achieved by means of adjusting the thickness of the sustained release coating layer or the like, which is easily achieved in the field of pharmaceutical agents.
An orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is an antipsychotic agent such as olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, aclidinam, alprazolam, methylphenidate, milnacipran, sodium valproate, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention, wherein said active ingredient is an antiemetic such as ramosetron, granisetron, ondansetron, azasetron or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
An orally disintegrating tablet according to any embodiment of the first aspect of the invention, wherein said active ingredient is chlorpheniramine, loratadine or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The orally disintegrating tablet according to any embodiment of the first aspect of the present invention, wherein the active ingredient is an agent for cardiovascular administration such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, nisoldipine, glipizide, glimepiride, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
An orally disintegrating tablet according to any of the embodiments of the first aspect of the invention, wherein said active ingredient is famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praanoltol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, domperidone, racecadotril or like digestive system drug or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
The orally disintegrating tablet according to any of the embodiments of the first aspect of the present invention, wherein the active ingredient is a hyperlipemia therapeutic agent such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
The orally disintegrating tablet according to any embodiment of the first aspect of the present invention, wherein said active ingredient is a BPH therapeutic agent such as tamsulosin, doxazosin, terazosin or the like, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
Further, the second aspect of the present invention provides a method for preparing an orally disintegrating tablet, which comprises compressing the orally disintegrating tablet by a tabletting process; the tablet comprises a tablet matrix composed of a plurality of excipients, and a plurality of coated pellets substantially uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing an active ingredient and at least one coating layer covering the surface of the pellet core.
A method according to any embodiment of the second aspect of the invention, comprising the steps of:
i) coating the active ingredient on the surface of the pellet core or dispersing the active ingredient in the pellet core, and coating the pellet core to obtain coated pellet;
ii) mixing said coated pellets with excipients forming said tablet matrix and tabletting.
The method according to any embodiment of the second aspect of the present invention, wherein step ii) is performed as follows:
iia) mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to make wet granules and drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting; or
iib) spraying a binder solution into the excipient by using a fluidized bed granulation process to perform wet granulation and drying, adding the coated pellets and the lubricant into the obtained dry granules, uniformly mixing, and tabletting.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the excipients forming the tablet matrix further comprise a salt selected from the group consisting of: sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof. In one embodiment, in step iia), the salts may be added by mixing with excipients and with the coated pellets, or the salts may be added by adding to the binder solution, or the salts are added in powder form at the stage of adding the lubricant. In one embodiment, in step iib), the salts may be added by mixing with excipients to prepare granules, or the salts may be added by adding to a binder solution, or the salts are added in the form of powder at the stage of adding the lubricant.
The process according to any embodiment of the second aspect of the present invention, wherein the weight of said coated pellets is 5 to 50%, such as 5 to 40%, such as 5 to 30%, such as 5 to 25% of the total weight of the orally disintegrating tablet.
The process according to any of the embodiments of the second aspect of the present invention, wherein the weight of the active ingredient is 1 to 40%, such as 2 to 30%, such as 3 to 25%, such as 5 to 20% of the total weight of the coated pellet.
The process according to any embodiment of the second aspect of the invention, wherein the coated pellets have an average particle size of 50 to 350 μm, such as 50 to 300 μm, such as 100 to 250 μm.
According to the method of any embodiment of the second aspect of the present invention, the active ingredient is substantially uniformly coated on the surface of the pellet core or the active ingredient is substantially uniformly dispersed in the pellet core.
The method according to any embodiment of the second aspect of the present invention, wherein the active ingredient is selected from the group consisting of: hypnotic/sedative agent, sleep inducer, anxiolytic agent, antiepileptic agent, antidepressant, anti-Parkinson's disease agent, psychogenic agent, central nervous system agent, local anesthetic agent, skeletal muscle relaxant, autonomic nerve agent, antipyretic, analgesic and anti-inflammatory agent, antispasmodic agent, antihalation agent, cardiotonic agent, antiarrhythmic agent, diuretic agent, hypotensive agent, vasoconstrictor, vasodilator, circulatory organ agent, hyperlipemia agent, respiratory promoter, antitussive agent, expectorant, antitussive, expectorant, bronchodilator, antidiarrheal agent, intestinal agent, peptic ulcer agent, digestive and digestive agent, antacid, cathartic, choleretic agent, digestive organ agent, adrenal hormone, urinary organ agent, vitamin, hemostatic agent, liver disease agent, gout therapeutic agent, diabetes agent, antihistamine, antibiotic, antibacterial agent, antidiarrheal agent, analgesic, and analgesic, Anti-malignant tumor agent, chemotherapy agent, influenza agent, tonic health drug, osteoporosis drug, such as indomethacin, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, metronidazole, aspirin, ethenzamide, acetaminophen (paracetamol), aminopyrine, phenacetin, hyoscine, scopolamine butylbromide, morphine, etodoline, antalgin, fenoprofen calcium, naproxen, Celecoxib, Valdecoxib, tramadol, antipyretic, antispasmodic or analgesic drugs, etodol, antihypoxic drugs such as isoniazid, ethambutol hydrochloride, antitubercular drugs such as isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indonololol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, nitrate ethidium nitrate, ethidium hydrochloride, hydralazuride, hydralazuril hydrochloride, meclozine hydrochloride, meclol, ethidium hydrochloride, ethiprolide hydrochloride, and the like, Circulating organ drugs such as reserpine, sulfamolol hydrochloride, lisinopril, metoprolol, pilocarpine, paroxetine, chlorpromazine hydrochloride, amitriptyline hydrochloride, nemorubine, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, alprazolam, methylphenidate, milnacipran, risperidone, sodium valproate, and other anti-psychotropic drugs, metoclopramide hydrochloride, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, and azasetron hydrochloride, and other anti-emetics, chlorphenamine maleate, and diphenhydramine hydrochloride, thiamine nitrate, vitamin E acetate, thiocoramine, pyridoxal phosphate, cobalamine, ascorbic acid, and nicotinamide and other vitamins, allopurinol, colchicine, and propathion, levodopa, and other Parkinson's disease drugs, and priapigenin, Hypnotic sedatives such as bromoisoflurane, midazolam, chloral hydrate, etc., anti-malignant tumor drugs such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc., anti-allergic drugs such as pseudoephedrine, terfenadine, etc., decongestants such as phenylpropanolamine, ephedrine, etc., diabetes drugs such as acehexol, insulin, tolbutamide, desmopressin, glipizide, etc., diuretics such as hydrochlorothiazide, poishiazide, triamterene, etc., bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc., antitussives such as codeine phosphate, narcotine, dimemorfan phosphate, dextromethorphan, etc., antiarrhythmics such as quinidine nitrate, digitaloxacin, propafenone hydrochloride, procainamide, etc., surface anesthetics such as ethyl aminobenzoate, lidocaine, cinchocaine hydrochloride, etc., antibiotics such as phenytoin, ethosuximide, antiepilone, etc., hydrocortisone, etc., anti-drugs such as hydrocortisone, etc., and the like, Synthetic adrenocortical steroids such as prednisolone, triamcinolone and betamethasone, digestive system drugs such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenoxate, 5-aminosalicylic acid, sulfasalazine, omeprazole and lansoprazole, central nervous system drugs such as indolozine, idebenone, sulpiride, dimesnam and calcium pantothenate, hyperlipidemia therapeutic agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin and atorvastatin, antibiotics such as phthalazinol hydrochloride, cefotetan and josamycin, BPH therapeutic agents such as tamsulosin, doxazosin and terazosin, antiasthmatic agents such as pranlukast, zafirlukast, salbutamol, ambroxol, budesonide and levosalbutamol, peripheral circulation improving agents such as prostaglandin I derivatives such as bebestatin sodium, Antithrombotic agent, hypotensive agent, therapeutic agent for heart failure, therapeutic agent for diabetic complications, therapeutic agent for peptic ulcer, therapeutic agent for skin ulcer, therapeutic agent for hyperlipidemia, and antiasthmatic agent. The drug may be any of an episome and a pharmaceutically acceptable salt.
The method according to any one of the embodiments of the second aspect of the invention, wherein the active ingredient is selected from the group consisting of: tamsulosin, memantine, olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, lansoprazole, famotidine, domperidone, racecadotril, loratadine, nisoldipine, salbutamol sulfate, glipizide, glimepiride, granisetron, ondansetron, and pharmaceutically acceptable salts, isomers, and the like thereof.
The process according to any of the embodiments of the second aspect of the present invention, wherein the core material of the coated pellets is selected from the group consisting of cellulose or derivatives thereof (e.g. microcrystalline cellulose) or spheres thereof, sucrose or sucrose spheres, starch or starch spheres, lactose or lactose spheres.
The process according to any embodiment of the second aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet or a sucrose pellet.
The process according to any of the embodiments of the second aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, and the active ingredient is substantially uniformly coated on the surface of the pellet core.
The process according to any embodiment of the second aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet core, and the active ingredient is substantially uniformly coated on the surface of the pellet core after compounding into a solution or suspension with a binder.
The process according to any of the embodiments of the second aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed inside the pellet core.
The process according to any of the embodiments of the second aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed inside the pellet core; after the active ingredients and the microcrystalline cellulose are uniformly mixed, adding a solution or a suspension containing a bonding agent to prepare a pill core by a stirring granulation method or a fluidized bed granulation method; alternatively, a solution or suspension containing the active ingredient and a binder is added to microcrystalline cellulose to prepare a pellet core by a stirring granulation method or a fluidized bed granulation method.
The process according to any embodiment of the second aspect of the present invention, wherein the binder used to prepare the pellet core is a polymeric substance, for example a water soluble polymeric substance, for example selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone or polyvinyl alcohol, and combinations thereof. Of course, the polymer may be used as a binder in other steps.
The process according to any embodiment of the second aspect of the present invention, wherein the at least one coating on the surface of the coated pellets is selected from the group consisting of: film coatings, enteric coatings, gastric coatings, sustained release coatings, controlled release coatings, and combinations thereof. When multiple coatings are used, the sequence of coating layers may be determined for different purposes. For example, when it is desired that the drug is not dissolved in the stomach but is slowly released from the intestinal fluid, the drug-containing pellet core may be coated with a sustained-release coating layer, and then the sustained-release coating layer may be coated with an enteric coating layer. For another example, when the requirement of covering the unpleasant taste of the drug and slowly releasing the drug in gastrointestinal fluids is required, the drug-containing pellet core can be coated with a sustained-release coating layer, so as to achieve the purpose.
Film coatings are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
Enteric coatings are well known to those skilled in the art. Exemplary enteric coating film forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit model L, S.
Gastric coatings are well known to those skilled in the art. Exemplary gastric-coating film-forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit type E.
Sustained release coatings and controlled release coatings are well known to those skilled in the art. Exemplary sustained release coatings and controlled release coating film forming materials are most typically ethyl cellulose.
The addition of certain additives to the coating material to suit specific coating requirements can be readily determined empirically by those skilled in the art. For example, a plasticizer, a coloring agent, a masking agent, and the like may be added to the coating liquid.
The preparation of cores and their coatings to obtain coated pellets according to the present invention is well known in the art and is typically a granulation, coating process using the fluid bed principle, e.g. the preparation of sustained release microparticles as already described in CN 1473035B. As is well known, the amount of coating layer to be applied to the surface of the pellet core can be readily adjusted according to the experience of those skilled in the art and the teaching of textbooks, for example, the weight of the coating layer can be 1 to 20% of the weight of the pellet core, for example, the weight of the coating layer can be 1 to 15% of the weight of the pellet core, and for example, the weight of the coating layer can be 1 to 10% of the weight of the pellet core.
The process according to any of the embodiments of the second aspect of the present invention, wherein only water and not an organic solvent is used as a solvent for formulating the binder solution or the coating solution in preparing the coated pellets. Although CN1473035B teaches the use of a mixed solvent of methanol and a small amount of water, the present invention finds better process performance using water rather than an organic solvent.
The process according to any one of the embodiments of the second aspect of the present invention, wherein the excipients forming the tablet matrix comprise excipients selected from the group consisting of the following (sugars and/or sugar alcohols): mannitol, lactose, sucrose, maltose, trehalose, sorbitol, maltitol, xylitol, erythritol, glucose, and combinations thereof. In particular, such an excipient preferably uses a combination of one or more of the above sugars and/or sugar alcohols.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the excipient forming the base of the tablet comprises a binder. In one embodiment, the binder may be the same as used in the preparation of the coated pellets. In one embodiment, the binder may be the same as the sugar or sugar alcohol described above as the excipient. In particular, a part or all of one or more of sugar or sugar alcohol as an excipient may be prepared into a solution with water as a binder, and then the coated pellets may be mixed with the excipient and then wet-granulated with the binder solution when preparing a tablet.
The process according to any embodiment of the second aspect of the present invention, wherein the binder forming the tablet matrix is one or more selected from the group consisting of: maltose, trehalose, sorbitol, maltitol, glucose, xylitol, erythritol, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, or polyvinyl alcohol. It has been found that the addition of an appropriate amount of salt to the matrix of an orally disintegrating tablet using the method of the present invention, regardless of which binder is used, can be directly compressed into tablets of desired hardness and has excellent disintegration properties without the need for compression at low pressure and subsequent humidification-drying or high temperature-cooling as in the prior art.
The process according to any embodiment of the second aspect of the invention, wherein the auxiliary material forming the matrix of the tablet may further comprise a disintegrant. Typical disintegrants are for example, but not limited to: corn starch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethylcellulose, crospovidone, low-substitution hydroxypropylcellulose, and the like.
The process according to any embodiment of the second aspect of the present invention, wherein the excipients forming the base of the tablet may further comprise additives such as sweeteners, colorants and the like.
The method according to any embodiment of the second aspect of the present invention, wherein the excipients forming the tablet matrix may further comprise a lubricant. The inclusion of conventional amounts of lubricant is beneficial for tablet appearance and to prevent sticking. Lubricants which may be used are selected from: magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid, and the like, and combinations thereof.
The method according to any embodiment of the second aspect of the invention, wherein the excipients forming the tablet matrix comprise: excipient, binder, salt and lubricant.
The process according to any embodiment of the second aspect of the present invention, said orally disintegrating tablet is prepared by a process comprising the steps of: mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to form wet granules, drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with the coated pellets together with excipients. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salt is added in powder form at the stage of lubricant addition.
According to the method of any embodiment of the second aspect of the present invention, the orally disintegrating tablet is prepared by a process comprising the steps of: spraying binder solution into excipient by fluidized bed granulation process to make wet granule, drying, adding coated pellet and lubricant into the obtained dry granule, mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with excipients to make granules. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salt is added in powder form at the stage of lubricant addition.
According to the method of any one of the embodiments of the second aspect of the present invention, the orally disintegrating tablets are repeatedly measured for disintegration time of 6 tablets as specified in the item of "0921 disintegration time limit inspection method" of the general rules of the four parts of the 2015 edition of chinese pharmacopoeia and "orally disintegrating tablets" therein, and 6 tablets all disintegrate in 60 seconds and pass through a screen; in particular 6 tablets all disintegrated within 45 seconds and passed through the screen; in particular 6 tablets all disintegrated within 30 seconds and passed through the sieve.
According to the method of any embodiment of the second aspect of the present invention, the orally disintegrating tablets have a friability of tablets, measured according to the method under the item "0923 tablet friability test" of the four general rules of chinese pharmacopoeia 2015 edition, without breaking, cracking and crushing of the tablets, and a weight loss reduction of less than 3%, such as less than 2%, such as less than 1.5%, such as less than 1%.
According to the method of any embodiment of the second aspect of the invention, the orally disintegrating TABLET has a hardness in the range of 3 to 6kg, for example in the range of 4 to 6kg, measured according to the method of USP35-NF30 edition "< 1217> target BREAKING FORCE".
According to the method of any embodiment of the second aspect of the invention, the orally disintegrating tablet has a moisture absorption rate of less than 20% (e.g. less than 15%, e.g. less than 12.5%, e.g. less than 10%) as measured by the following method: taking tablets with the total weight of 5.0-5.5 g, and precisely weighing; exposing the mixture to 25 ℃ and 75% relative humidity for 24 hours, and precisely weighing; the moisture absorption rate was calculated as follows:
the moisture absorption rate is [ (weight of sheet after moisture absorption treatment-weight of sheet before moisture absorption treatment) ÷ weight of sheet before moisture absorption treatment ] × 100%.
According to the method of any embodiment of the second aspect of the present invention, the orally disintegrating tablets have a dissolution rate of less than 20%, such as less than 15%, within 15 minutes at a rotation speed of 50 rpm with 250ml of water as a dissolution medium according to the third method of 0931 dissolution and release determination method of the general rule of four parts of the pharmacopoeia 2015 edition of China.
According to the method of any embodiment of the second aspect of the present invention, the coated pellets before contact with the material of the tablet matrix (i.e. the state of the coated pellets after completion of coating of each layer and before proceeding to the subsequent non-coating process) show a drug dissolution rate of 50% at each time point, and the absolute value of the difference between the dissolution rate of the coated pellets and the dissolution rate of the orally disintegrating tablet is in the range of 0-15%, particularly in the range of 0-12.5%.
According to the method of any embodiment of the second aspect of the present invention, the orally disintegrating tablet produced by the method is a tablet having a water content of less than 10%, such as less than 7.5%, such as less than 5%, measured according to the method under the "second method (baking method)" of the "0832 moisture determination" general rule in the four parts of the pharmacopoeia 2015 edition of china.
The method according to any of the embodiments of the second aspect of the present invention, wherein said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, e.g. tamsulosin hydrochloride. In one embodiment, said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and said coating is a slow release coating. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is an enteric coating layer. In one embodiment, said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and said coating comprises two layers, a sustained release coating layer and an enteric coating layer from the inside to the outside. The invention has outstanding contribution to the prior art and the discovery that the addition of a proper amount of salt to the orally disintegrating tablet of the embedded pellets can obviously improve the physical strength and the disintegration performance of the tablet. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained-release effect of the release profile of tamsulosin or a pharmaceutically acceptable salt thereof, for example, a sustained-release or controlled-release effect to release substantially in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, it is possible to achieve by adjusting the thickness of the sustained-release coating layer or the like, which is easily accomplished in the field of pharmaceutical preparations.
A method according to any one of the embodiments of the second aspect of the invention, wherein the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, e.g. memantine hydrochloride. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a film coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a slow release coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is an enteric coating layer. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside out. The invention has outstanding contribution to the prior art and is found that the physical strength and the disintegration property of the tablet can be obviously improved by adding a proper amount of salt into the orally disintegrating tablet with embedded pellets. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained release effect of memantine hydrochloride release profile, for example, a sustained release or controlled release effect which is substantially released in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, if necessary, can be achieved by means of adjusting the thickness of the sustained release coating layer or the like, which is easily achieved in the field of pharmaceutical agents.
A method according to any one of the embodiments of the second aspect of the invention, wherein the active ingredient is an antipsychotic agent such as olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, aclidinam, alprazolam, methylphenidate, milnacipran, sodium valproate or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
A method according to any one of the embodiments of the second aspect of the present invention, wherein the active ingredient is an antiemetic agent such as ramosetron, granisetron, ondansetron, azasetron or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
A method according to any one of the embodiments of the second aspect of the invention, wherein the active ingredient is chlorpheniramine, loratadine or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the active ingredient is a cardiovascular agent such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, nisoldipine, glipizide or glimepiride, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
A method according to any one of the embodiments of the second aspect of the invention, wherein the active ingredient is a medicament for the digestive system such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praanoltol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, domperidone, racecadotril or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The method according to any embodiment of the second aspect of the present invention, wherein the active ingredient is a hyperlipemia therapeutic agent such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The method according to any of the embodiments of the second aspect of the present invention, wherein the active ingredient is tamsulosin, doxazosin, terazosin and like BPH therapeutic agents or pharmaceutically acceptable salts thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
Further, the third aspect of the present invention provides a method for improving hardness and improving disintegration property of an orally disintegrating tablet, which comprises compressing the orally disintegrating tablet by a tabletting process; the tablet comprises a tablet matrix composed of a plurality of excipients, and a plurality of coated pellets substantially uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing active ingredients and at least one layer of coating covering the surface of the pellet core, and the auxiliary materials forming the tablet matrix comprise salts.
The method according to any one of the embodiments of the third aspect of the invention, wherein said salt is selected from the group consisting of: sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.
According to the method of any embodiment of the third aspect of the present invention, the method of preparing the orally disintegrating tablet comprises the steps of:
i) coating the active ingredient on the surface of the pellet core or dispersing the active ingredient in the pellet core, and coating the pellet core to obtain coated pellet;
ii) mixing said coated pellets with excipients forming said tablet matrix and tabletting.
The method according to any embodiment of the third aspect of the present invention, wherein step ii) is performed as follows:
iia) mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to make wet granules and drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting; or
iib) spraying a binder solution into the excipient by using a fluidized bed granulation process to form wet granules, drying, adding the coated pellets and the lubricant into the obtained dry granules, uniformly mixing, and tabletting.
The process according to any of the embodiments of the third aspect of the present invention, wherein in step iia), the salts may be added by mixing with excipients with the coated pellets, or the salts may be added by adding to the binder solution, or the salts are added in powder form at the stage of adding the lubricant.
The method according to any embodiment of the third aspect of the present invention, wherein in step iib), the salts may be added by mixing with excipients to prepare granules, or the salts may be added by adding to a binder solution, or the salts are added in the form of powder at the stage of adding a lubricant.
The process according to any embodiment of the third aspect of the present invention, wherein the weight of said coated pellets is 5 to 50%, such as 5 to 40%, such as 5 to 30%, such as 5 to 25% of the total weight of the orally disintegrating tablet.
The process according to any of the embodiments of the third aspect of the present invention, wherein the weight of the active ingredient is 1 to 40%, such as 2 to 30%, such as 3 to 25%, such as 5 to 20% of the total weight of the coated pellet.
The process according to any embodiment of the third aspect of the invention, wherein the coated pellets have an average particle size of 50 to 350 μm, such as 50 to 300 μm, such as 100 to 250 μm.
The process according to any one of the embodiments of the third aspect of the present invention, wherein the active ingredient is substantially uniformly coated on the surface of the pellet core or the active ingredient is substantially uniformly dispersed in the pellet core.
The method according to any embodiment of the third aspect of the present invention, wherein the active ingredient is selected from the group consisting of: hypnotic sedative, sleep inducer, anxiolytic agent, antiepileptic agent, antidepressant, anti-Parkinson's disease agent, psychogenic agent, central nervous system agent, local anesthetic, skeletal muscle relaxant, autonomic nerve agent, antipyretic, analgesic, anti-inflammatory agent, antispasmodic agent, antihalating agent, cardiotonic agent, antiarrhythmic agent, diuretic agent, hypotensive agent, vasoconstrictor, vasodilator, circulating organ agent, hyperlipemia agent, respiratory promoter, antitussive agent, expectorant, antitussive, expectorant, bronchodilator, antidiarrheal agent, intestinal regulating agent, peptic ulcer agent, stomachic and digestive agent, antacid, cathartic, choleretic agent, digestive organ agent, adrenal hormone, urinary organ agent, vitamin, hemostatic agent, liver disease agent, gout therapeutic agent, diabetes agent, antihistamine, antibiotic, antibacterial agent, neuroleptic agent, local anesthetic, bone relaxant, autonomic nerve agent, antipyretic agent, analgesic, bronchodilator, antidiarrheal agent, and so forth, Anti-malignant tumor agent, chemotherapeutic agent, influenza agent, tonic health drug, osteoporosis drug, etc., such as indomethacin, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, metronidazole (mepizol), aspirin, ethenzamide, acetaminophen (paracetamol), aminopyrine, phenacetin, butoscopolamine, morphine, etodoline, antalgin, fenoprofen calcium, naproxen, Celecoxib, Valdecoxib, tramadol, etc., antiinflammatory, antipyretic, antispasmodic or analgesic, etodolac, etc., isoniazide, ethambutol hydrochloride, etc., anti-tubercular drug, isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, furamel nitrate, furamesine nitrate, ethidine hydrochloride, etc, Circulating organ drugs such as reserpine, sulfamolol hydrochloride, lisinopril, metoprolol, pilocarpine, paroxetine, chlorpromazine hydrochloride, amitriptyline hydrochloride, nemorubine, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, alprazolam, methylphenidate, milnacipran, risperidone, sodium valproate, and other anti-psychotropic drugs, metoclopramide hydrochloride, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, and azasetron hydrochloride, and other anti-emetics, chlorphenamine maleate, and diphenhydramine hydrochloride, thiamine nitrate, vitamin E acetate, thiocoramine, pyridoxal phosphate, cobalamine, ascorbic acid, and nicotinamide and other vitamins, allopurinol, colchicine, and propathion, levodopa, and other Parkinson's disease drugs, and priapigenin, Hypnotic sedatives such as bromoisoflurane, midazolam, chloral hydrate, etc., anti-malignant tumor drugs such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc., anti-allergic drugs such as pseudoephedrine, terfenadine, etc., decongestants such as phenylpropanolamine, ephedrine, etc., diabetes drugs such as acehexol, insulin, tolbutamide, desmopressin, glipizide, etc., diuretics such as hydrochlorothiazide, poishiazide, triamterene, etc., bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc., antitussives such as codeine phosphate, narcotine, dimemorfan phosphate, dextromethorphan, etc., antiarrhythmics such as quinidine nitrate, digitaloxacin, propafenone hydrochloride, procainamide, etc., surface anesthetics such as ethyl aminobenzoate, lidocaine, cinchocaine hydrochloride, etc., antibiotics such as phenytoin, ethosuximide, antiepilone, etc., hydrocortisone, etc., anti-drugs such as hydrocortisone, etc., and the like, Synthetic adrenocortical steroids such as prednisolone, triamcinolone and betamethasone, digestive system drugs such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenoxate, 5-aminosalicylic acid, sulfasalazine, omeprazole and lansoprazole, central nervous system drugs such as indolozine, idebenone, sulpiride, dimesnam and calcium pantothenate, hyperlipidemia therapeutic agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin and atorvastatin, antibiotics such as phthalazinol hydrochloride, cefotetan and josamycin, BPH therapeutic agents such as tamsulosin, doxazosin and terazosin, antiasthmatic agents such as pranlukast, zafirlukast, salbutamol, ambroxol, budesonide and levosalbutamol, peripheral circulation improving agents such as prostaglandin I derivatives such as bebestatin sodium, Antithrombotic agent, antihypertensive agent, therapeutic agent for heart failure, therapeutic agent for diabetic complications, therapeutic agent for peptic ulcer, therapeutic agent for skin ulcer, therapeutic agent for hyperlipidemia, and anti-asthma agent. The drug may be any of free form or pharmaceutically acceptable salts.
The method according to any embodiment of the third aspect of the present invention, wherein the active ingredient is selected from the group consisting of: tamsulosin, memantine, olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, lansoprazole, famotidine, domperidone, racecadotril, loratadine, nisoldipine, salbutamol sulfate, glipizide, glimepiride, granisetron, ondansetron, and pharmaceutically acceptable salts, isomers, and the like thereof.
The process according to any of the embodiments of the third aspect of the present invention, wherein the core material of the coated pellets is selected from the group consisting of cellulose or derivatives thereof (e.g. microcrystalline cellulose) or spheres thereof, sucrose or sucrose spheres, starch or starch spheres, lactose or lactose spheres.
The process according to any of the embodiments of the third aspect of the present invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet or a sucrose pellet.
The process according to any of the embodiments of the third aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, and the active ingredient is substantially uniformly coated on the surface of the pellet core.
The process according to any embodiment of the third aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet core, and the active ingredient is substantially uniformly coated on the surface of the pellet core after being compounded into a solution or suspension with the binder.
The process according to any of the embodiments of the third aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed inside the pellet core.
The process according to any embodiment of the third aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed within the pellet core; uniformly mixing the active ingredients and microcrystalline cellulose, adding a solution or suspension containing a binding agent, and preparing the active ingredients and the microcrystalline cellulose into a pill core by a stirring granulation method or a fluidized bed granulation method; alternatively, a solution or suspension containing the active ingredient and a binder is added to the microcrystalline cellulose to prepare a pellet core by a stirring granulation method or a fluidized bed granulation method.
The process according to any embodiment of the third aspect of the present invention, wherein the binder used to prepare the pellet core is a polymeric substance, for example a water soluble polymeric substance, for example selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone or polyvinyl alcohol, and combinations thereof. Of course, the polymer can also be used as a binder in other steps.
The process according to any embodiment of the third aspect of the present invention, wherein the at least one coating on the surface of the coated pellets is selected from the group consisting of: film coatings, enteric coatings, gastric coatings, sustained release coatings, controlled release coatings, and combinations thereof. When multiple coatings are used, the sequence of coating layers may be determined for different purposes. For example, when it is desired that the drug is not dissolved in the stomach but is slowly released from the intestinal fluid, the drug-containing pellet core may be coated with a sustained-release coating layer, and then the sustained-release coating layer may be coated with an enteric coating layer. For another example, when the requirement of covering the unpleasant taste of the drug and slowly releasing the drug in gastrointestinal fluids is required, the drug-containing pellet core can be coated with a sustained-release coating layer, so as to achieve the purpose.
Film coatings are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
Enteric coatings are well known to those skilled in the art. Exemplary enteric coating film forming materials are for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit model L, S.
Gastric coatings are well known to those skilled in the art. Exemplary gastric-coating film-forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit type E.
Sustained release coatings and controlled release coatings are well known to those skilled in the art. Exemplary sustained release coatings and controlled release coating-forming materials are most typically ethylcellulose.
The addition of certain additives to the coating material to suit specific coating requirements can be readily determined empirically by those skilled in the art. For example, a plasticizer, a coloring agent, a masking agent, and the like may be added to the coating liquid.
The preparation of cores and their coatings to obtain coated pellets according to the present invention is well known in the art and is typically a granulation, coating process using the fluid bed principle, e.g. the preparation of sustained release microparticles as already described in CN 1473035B. As is well known, the amount of coating layer to be applied to the surface of the pellet core can be readily adjusted according to the experience of those skilled in the art and the teaching of textbooks, for example, the weight of the coating layer can be 1 to 20% of the weight of the pellet core, for example, the weight of the coating layer can be 1 to 15% of the weight of the pellet core, and for example, the weight of the coating layer can be 1 to 10% of the weight of the pellet core.
The process according to any of the embodiments of the third aspect of the present invention, wherein only water and not an organic solvent is used as a solvent for formulating the binder solution or the coating solution in preparing the coated pellets. Although CN1473035B teaches the use of a mixed solvent of methanol and a small amount of water, the present invention finds better process performance using water rather than an organic solvent.
The process according to any of the embodiments of the third aspect of the present invention, wherein the excipients forming the tablet matrix comprise excipients selected from the group consisting of the following (sugars and/or sugar alcohols): mannitol, lactose, sucrose, maltose, trehalose, sorbitol, maltitol, xylitol, erythritol, glucose, and combinations thereof. In particular, such an excipient preferably uses a combination of one or more of the above sugars and/or sugar alcohols.
The process according to any embodiment of the third aspect of the invention, wherein the excipient forming the tablet matrix comprises a binder. In one embodiment, the binder may be the same as used in the preparation of the coated pellets. In one embodiment, the binder may be the same as the sugar or sugar alcohol described above as the excipient. In particular, a part or all of one or more of sugar or sugar alcohol as an excipient may be prepared into a solution with water as a binder, and then the coated pellets may be mixed with the excipient and then wet-granulated with the binder solution when preparing a tablet.
The process according to any embodiment of the third aspect of the present invention, wherein the binder forming the tablet matrix is one or more selected from the group consisting of: maltose, trehalose, sorbitol, maltitol, glucose, xylitol, erythritol, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, or polyvinyl alcohol. It has been found that the addition of an appropriate amount of salt to the matrix of an orally disintegrating tablet using the method of the present invention, regardless of which binder is used, can be directly compressed into tablets of desired hardness and has excellent disintegration properties without the need for compression at low pressure and subsequent humidification-drying or high temperature-cooling as in the prior art.
The process according to any embodiment of the third aspect of the present invention, wherein the auxiliary material forming the tablet base may further comprise a disintegrant. Typical disintegrants are for example, but not limited to: corn starch, carboxymethyl cellulose calcium, pregelatinized starch, cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose cross-linked povidone, low-substituted hydroxypropyl cellulose, and the like.
The process according to any embodiment of the third aspect of the present invention, wherein the excipients forming the tablet base may further comprise additives such as sweeteners, colorants and the like.
The process according to any embodiment of the third aspect of the present invention, wherein the excipients forming the tablet matrix may further comprise a lubricant. The inclusion of conventional amounts of lubricant is beneficial for tablet appearance and to prevent sticking. Lubricants which may be used are selected from: magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid, and the like, and combinations thereof.
The process according to any embodiment of the third aspect of the invention, wherein the excipients forming the tablet matrix comprise: excipient, binder, salt and lubricant.
According to the process of any embodiment of the third aspect of the present invention, the orally disintegrating tablet is prepared by a process comprising the steps of: mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to form wet granules, drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with the coated pellets together with excipients. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salts are added in powder form at the stage of lubricant addition.
According to the process of any embodiment of the third aspect of the present invention, the orally disintegrating tablet is prepared by a process comprising the steps of: spraying binder solution into excipient by fluidized bed granulation process to make wet granule, drying, adding coated pellet and lubricant into the obtained dry granule, mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with excipients and preparing granules. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salt is added in powder form at the stage of lubricant addition.
According to the method of any embodiment of the third aspect of the present invention, the orally disintegrating tablets are repeatedly measured for disintegration time of 6 tablets as specified in the item "0921 disintegration time limit inspection method" of the general rules of the four parts of the chinese pharmacopoeia 2015 edition and "orally disintegrating tablets" therein, 6 tablets all disintegrate within 60 seconds and pass through a screen; in particular 6 tablets all disintegrated within 45 seconds and passed through the screen; in particular 6 tablets all disintegrated within 30 seconds and passed through the sieve.
According to the method of any embodiment of the third aspect of the present invention, the orally disintegrating tablets have a friability of tablets, measured according to the method under the item "0923 tablet friability test" of the four general rules of chinese pharmacopoeia 2015 edition, without breaking, cracking and crushing the tablets, and the weight loss reduction is less than 3%, such as less than 2%, such as less than 1.5%, such as less than 1%.
According to the method of any of the embodiments of the third aspect of the present invention, the orally disintegrating TABLET has a hardness in the range of 3 to 6kg, for example in the range of 4 to 6kg, measured according to the method of USP35-NF30 edition "< 1217> TABLET BREAKING FORCE".
According to the method of any embodiment of the third aspect of the invention, the orally disintegrating tablet has a moisture absorption rate of less than 20% (e.g. less than 15%, e.g. less than 12.5%, e.g. less than 10%) as measured by the following method: taking tablets with the total weight of 5.0-5.5 g, and precisely weighing; exposing the mixture to 25 ℃ and 75% relative humidity for 24 hours, and precisely weighing the mixture; the moisture absorption rate was calculated as follows:
the moisture absorption rate is [ (weight of sheet after moisture absorption treatment-weight of sheet before moisture absorption treatment) ÷ weight of sheet before moisture absorption treatment ] × 100%.
According to the method of any embodiment of the third aspect of the present invention, the orally disintegrating tablets have a dissolution rate of less than 20%, such as less than 15%, within 15 minutes at a rotation speed of 50 rpm with 250ml of water as a dissolution medium according to the third method of 0931 dissolution and release determination method of the general rule of four parts of the pharmacopoeia 2015 edition of China.
According to the method of any embodiment of the third aspect of the present invention, the coated pellets before contact with the material of the tablet base (i.e. the state of the coated pellets after completion of coating of each layer and before proceeding to the subsequent non-coating process) show a drug dissolution of 50% at each time point, and the absolute value of the difference between the dissolution rate of the coated pellets and the dissolution rate of the orally disintegrating tablet is in the range of 0-15%, particularly in the range of 0-12.5%.
According to the method of any embodiment of the third aspect of the present invention, the orally disintegrating tablet produced by the method is a tablet having a water content of less than 10%, for example less than 7.5%, for example less than 5%, measured according to the method under the "second method (baking method)" of "0832 moisture determination" on the general rule of the four parts of the pharmacopoeia 2015 edition of china.
The method according to any of the embodiments of the third aspect of the present invention, wherein said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, such as tamsulosin hydrochloride. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is a slow release coating layer. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is an enteric coating layer. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating comprises two layers, a sustained release coating layer and an enteric coating layer from the inside out, respectively. The invention has outstanding contribution to the prior art and the discovery that the addition of a proper amount of salt to the orally disintegrating tablet of the embedded pellets can obviously improve the physical strength and the disintegration performance of the tablet. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained-release effect of the release profile of tamsulosin or a pharmaceutically acceptable salt thereof, for example, a sustained-release or controlled-release effect to release substantially in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, it is possible to achieve by adjusting the thickness of the sustained-release coating layer or the like, which is easily accomplished in the field of pharmaceutical preparations.
The method according to any embodiment of the third aspect of the invention, wherein the active ingredient is memantine or a pharmaceutically acceptable salt thereof, e.g. memantine hydrochloride. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a film coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a slow release coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is an enteric coating layer. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside out. The invention has outstanding contribution to the prior art and is found that the physical strength and the disintegration property of the tablet can be obviously improved by adding a proper amount of salt into the orally disintegrating tablet with embedded pellets. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained release effect of memantine hydrochloride release profile, for example, a sustained release or controlled release effect which is substantially released in the first order equation or the zero order equation within 6 hours, 12 hours or 18 hours, if necessary, can be achieved by means of adjusting the thickness of the sustained release coating layer or the like, which is easily achieved in the field of pharmaceutical agents.
The method according to any of the embodiments of the third aspect of the present invention, wherein the active ingredient is an antipsychotic agent such as olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, aclidinium, alprazolam, methylphenidate, milnacipran, sodium valproate, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
A process according to any one of the embodiments of the third aspect of the invention wherein the active ingredient is an antiemetic agent such as ramosetron, granisetron, ondansetron, azasetron or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
A method according to any one of the embodiments of the third aspect of the invention, wherein the active ingredient is chlorpheniramine, loratadine or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a desired sustained release effect of a drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical agents.
The method according to any embodiment of the third aspect of the present invention, wherein the active ingredient is a cardiovascular agent such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, nisoldipine, glipizide, glimepiride, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
A method according to any of the embodiments of the third aspect of the present invention, wherein the active ingredient is a digestive system drug such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenotol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, domperidone, racecadotril, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The method according to any one of the embodiments of the third aspect of the present invention, wherein the active ingredient is a hyperlipemia therapeutic agent such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The method according to any of the embodiments of the third aspect of the present invention, wherein the active ingredient is tamsulosin, doxazosin, terazosin and like BPH therapeutic agents or pharmaceutically acceptable salts thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
Further, the present invention provides, in a fourth aspect, the use of a salt for the preparation of an orally disintegrating tablet having high hardness and rapid disintegration properties, which is compressed by a tabletting process; the orally disintegrating tablet comprises a tablet matrix consisting of a plurality of auxiliary materials and a plurality of coated pellets which are basically and uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing an active ingredient and at least one layer of coating covering the surface of the pellet core; the salts are added to the tablet matrix as an adjuvant.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the salt is selected from the group consisting of: sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.
For use according to any of the embodiments of the fourth aspect of the invention, the process for preparing said orally disintegrating tablet comprises the steps of:
i) coating the active ingredient on the surface of the pellet core or dispersing the active ingredient in the pellet core, and coating the pellet core to obtain coated pellet;
ii) mixing said coated pellets with said salt and excipients forming said tablet matrix and tabletting.
Use according to any of the embodiments of the fourth aspect of the present invention, wherein step ii) is performed according to the following operations:
iia) mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to make wet granules and drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salts may be added by mixing with excipients and with the coated pellets, or the salts may be added by adding to the binder solution, or the salts are added in powder form at the stage of adding the lubricant.
Use according to any of the embodiments of the fourth aspect of the present invention, wherein step ii) is performed as follows:
iib) spraying a binder solution into the excipient by using a fluidized bed granulation process to make wet granules and dry, adding the coated pellets and the lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salt may be added by mixing with an excipient to prepare a granule, or the salt may be added by adding to a binder solution, or the salt may be added in the form of a powder at the stage of adding a lubricant.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the weight of said coated pellets is 5 to 50%, such as 5 to 40%, such as 5 to 30%, such as 5 to 25% of the total weight of the orally disintegrating tablet.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the weight of the active ingredient is 1 to 40%, such as 2 to 30%, such as 3 to 25%, such as 5 to 20% of the total weight of the coated pellet.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the coated pellets have an average particle size of 50 to 350 μm, such as 50 to 300 μm, such as 100 to 250 μm.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is substantially uniformly coated on the surface of the pellet core or the active ingredient is substantially uniformly dispersed in the pellet core.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the active ingredient is selected from the group consisting of: hypnotic/sedative agent, sleep inducer, anxiolytic agent, antiepileptic agent, antidepressant, anti-Parkinson's disease agent, psychogenic agent, central nervous system agent, local anesthetic agent, skeletal muscle relaxant, autonomic nerve agent, antipyretic, analgesic and anti-inflammatory agent, antispasmodic agent, antihalation agent, cardiotonic agent, antiarrhythmic agent, diuretic agent, hypotensive agent, vasoconstrictor, vasodilator, circulatory organ agent, hyperlipemia agent, respiratory promoter, antitussive agent, expectorant, antitussive, expectorant, bronchodilator, antidiarrheal agent, intestinal agent, peptic ulcer agent, digestive and digestive agent, antacid, cathartic, choleretic agent, digestive organ agent, adrenal hormone, urinary organ agent, vitamin, hemostatic agent, liver disease agent, gout therapeutic agent, diabetes agent, antihistamine, antibiotic, antibacterial agent, antidiarrheal agent, analgesic, and analgesic, Anti-malignant tumor agent, chemotherapeutic agent, influenza agent, tonic health drug, osteoporosis drug, etc., such as indomethacin, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, metronidazole (mepizol), aspirin, ethenzamide, acetaminophen (paracetamol), aminopyrine, phenacetin, butoscopolamine, morphine, etodoline, antalgin, fenoprofen calcium, naproxen, Celecoxib, Valdecoxib, tramadol, etc., antiinflammatory, antipyretic, antispasmodic or analgesic, etodolac, etc., isoniazide, ethambutol hydrochloride, etc., anti-tubercular drug, isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, furamel nitrate, furamesine nitrate, ethidine hydrochloride, etc, Circulating organ drugs such as reserpine, sulfamolol hydrochloride, lisinopril, metoprolol, pilocarpine, paroxetine, chlorpromazine hydrochloride, amitriptyline hydrochloride, nemorubine, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, alprazolam, methylphenidate, milnacipran, risperidone, sodium valproate, and other anti-psychotropic drugs, metoclopramide hydrochloride, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, and azasetron hydrochloride, and other anti-emetics, chlorphenamine maleate, and diphenhydramine hydrochloride, thiamine nitrate, vitamin E acetate, thiocoramine, pyridoxal phosphate, cobalamine, ascorbic acid, and nicotinamide and other vitamins, allopurinol, colchicine, and propathion, levodopa, and other Parkinson's disease drugs, and priapigenin, Hypnotic sedatives such as bromoisoflurane, midazolam, chloral hydrate, etc., anti-malignant tumor drugs such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc., anti-allergic drugs such as pseudoephedrine, terfenadine, etc., decongestants such as phenylpropanolamine, ephedrine, etc., diabetes drugs such as acehexol, insulin, tolbutamide, desmopressin, glipizide, etc., diuretics such as hydrochlorothiazide, poishiazide, triamterene, etc., bronchodilators such as aminophylline, formoterol fumarate, theophylline, etc., antitussives such as codeine phosphate, narcotine, dimemorfan phosphate, dextromethorphan, etc., antiarrhythmics such as quinidine nitrate, digitaloxacin, propafenone hydrochloride, procainamide, etc., surface anesthetics such as ethyl aminobenzoate, lidocaine, cinchocaine hydrochloride, etc., antibiotics such as phenytoin, ethosuximide, antiepilone, etc., hydrocortisone, etc., anti-drugs such as hydrocortisone, etc., and the like, Adrenocortical steroids such as prednisolone, triamcinolone, betamethasone, etc., drugs for digestive systems such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenoxate, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, etc., drugs for central nervous systems such as indelozine, idebenone, tiapride, dimepram, calcium pantothenate, etc., antihyperlipidemic agents such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin, etc., antibiotics such as phthalein hydrochloride, cefotetan, josamycin, etc., BPH therapeutic agents such as tamsulosin, doxazosin, terazosin, etc., anti-asthmatics such as pranlukast, zafirlukast, salbutamol, ambroxol, budesonide, levosalbutamol, etc., peripheral circulation improvers such as prostaglandin I derivatives such as berbeilin sodium, etc., peripheral circulation improvers, Antithrombotic agent, antihypertensive agent, therapeutic agent for heart failure, therapeutic agent for diabetic complications, therapeutic agent for peptic ulcer, therapeutic agent for skin ulcer, therapeutic agent for hyperlipidemia, and anti-asthma agent. The drug may be any of an episome and a pharmaceutically acceptable salt.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the active ingredient is selected from the group consisting of: tamsulosin, memantine, olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, lansoprazole, famotidine, domperidone, racecadotril, loratadine, nisoldipine, salbutamol sulfate, glipizide, glimepiride, granisetron, ondansetron, and pharmaceutically acceptable salts, isomers, and the like thereof.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the core material of the coated pellets is selected from the group consisting of cellulose or a derivative thereof (e.g. microcrystalline cellulose) or spheres thereof, sucrose or sucrose spheres, starch or starch spheres, lactose or lactose spheres.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet or a sucrose pellet.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially uniformly coated on the surface of the pellet core.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet, and the active ingredient is substantially uniformly coated on the surface of the pellet core after being compounded into a solution or suspension with a binder.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the pellet core of the coated pellets is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed within the pellet core.
Use according to any of the embodiments of the fourth aspect of the present invention, wherein the pellet core of the coated pellet is a microcrystalline cellulose pellet core, the active ingredient being substantially homogeneously distributed inside the pellet core; uniformly mixing the active ingredients and microcrystalline cellulose, adding a solution or suspension containing a binding agent, and preparing the active ingredients and the microcrystalline cellulose into a pill core by a stirring granulation method or a fluidized bed granulation method; alternatively, a solution or suspension containing the active ingredient and a binder is added to the microcrystalline cellulose to prepare a pellet core by a stirring granulation method or a fluidized bed granulation method.
Use according to any one of the embodiments of the fourth aspect of the invention, wherein the binder used to prepare the pellet core is a polymeric substance, for example a water soluble polymeric substance, for example selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone or polyvinyl alcohol, and combinations thereof. Of course, the polymer can also be used as a binder in other steps.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the at least one coating on the surface of the coated pellets is selected from the group consisting of: film coatings, enteric coatings, gastric coatings, sustained release coatings, controlled release coatings, and combinations thereof. When multiple coatings are used, the sequence of coating layers may be determined for different purposes. For example, when it is desired that the drug is not dissolved in the stomach but is slowly released from the intestinal fluid, the drug-containing pellet core may be coated with a sustained-release coating layer, and then the sustained-release coating layer may be coated with an enteric coating layer. For another example, when the requirement of covering the unpleasant taste of the drug and slowly releasing the drug in gastrointestinal fluids is required, the drug-containing pellet core can be coated with a sustained-release coating layer, so as to achieve the purpose.
Film coatings are well known to those skilled in the art. Exemplary film coating materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, and the like.
Enteric coatings are well known to those skilled in the art. Exemplary enteric coating film forming materials are for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit model L, S.
Gastric coatings are well known to those skilled in the art. Exemplary gastric-coating film-forming materials are, for example, but not limited to, acrylic and methacrylic ester copolymers, particularly Eudragit type E.
Sustained release coatings and controlled release coatings are well known to those skilled in the art. Exemplary sustained release coatings and controlled release coating film forming materials are most typically ethyl cellulose.
Certain additives are added to the coating material to suit particular coating requirements, as can be readily determined empirically by those skilled in the art. For example, a plasticizer, a coloring agent, a masking agent, and the like may be added to the coating liquid.
The preparation of the cores and their coatings to obtain the coated pellets of the present invention is well known in the art and is typically a granulation, coating process using the fluid bed principle, such as the preparation of sustained release microparticles already described in CN 1473035B. As is well known, the amount of coating layer to be applied to the surface of the pellet core can be readily adjusted according to the experience of those skilled in the art and the teaching of textbooks, for example, the weight of the coating layer can be 1 to 20% of the weight of the pellet core, for example, the weight of the coating layer can be 1 to 15% of the weight of the pellet core, and for example, the weight of the coating layer can be 1 to 10% of the weight of the pellet core.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein only water and not an organic solvent is used as a solvent for formulating the binder solution or the coating solution in the preparation of said coated pellets. Although CN1473035B teaches the use of a mixed solvent of methanol and a small amount of water, the present invention finds better process performance using water instead of an organic solvent.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the excipients forming the tablet matrix comprise excipients selected from the group consisting of the following (sugars and/or sugar alcohols): mannitol, lactose, sucrose, maltose, trehalose, sorbitol, maltitol, xylitol, erythritol, glucose, and combinations thereof. In particular, such an excipient preferably uses a combination of one or more of the above sugars and/or sugar alcohols.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the auxiliary material forming the tablet base comprises a binder. In one embodiment, the binder may be the same as used in the preparation of the coated pellets. In one embodiment, the binder may be the same as the sugar or sugar alcohol described above as the excipient. In particular, a part or all of one or more of sugar or sugar alcohol as an excipient may be prepared into a solution with water as a binder, and then the coated pellets may be mixed with the excipient and then wet-granulated with the binder solution when preparing a tablet.
The process according to any one of the embodiments of the third aspect of the present invention, wherein the binder forming the tablet matrix is one or more selected from the group consisting of: maltose, trehalose, sorbitol, maltitol, glucose, xylitol, erythritol, mannitol, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, or polyvinyl alcohol. It has been found that the addition of an appropriate amount of salt to the matrix of an orally disintegrating tablet using the method of the present invention, regardless of which binder is used, can be directly compressed into tablets of desired hardness and has excellent disintegration properties without the need for compression at low pressure and then moisture-drying or high temperature-cooling as in the prior art.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the auxiliary material forming the matrix of the tablet may further comprise a disintegrant. Typical disintegrants are for example, but not limited to: corn starch, carboxymethylcellulose calcium, pregelatinized starch, crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethylcellulose, crospovidone, low-substitution hydroxypropylcellulose, and the like.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the auxiliary material forming the base of the tablet may further comprise additives such as sweeteners, colorants and the like.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the auxiliary material forming the tablet base may further comprise a lubricant. The inclusion of conventional amounts of lubricant is beneficial for tablet appearance and to prevent sticking. Lubricants which may be used are selected from: magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid, and the like, and combinations thereof.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the auxiliary material forming the tablet base comprises: excipient, binder, salt and lubricant.
The use according to any of the embodiments of the fourth aspect of the present invention, the orally disintegrating tablet is prepared by a process comprising the steps of: mixing the coated pellets with an excipient, spraying a binder solution into the mixture by using a fluidized bed granulation process to form wet granules, drying, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with the coated pellets together with excipients. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salts are added in powder form at the stage of lubricant addition.
The use according to any of the embodiments of the fourth aspect of the invention, said orally disintegrating tablet is prepared by a process comprising the steps of: spraying binder solution into excipient by fluidized bed granulation process to make wet granule, drying, adding coated pellet and lubricant into the obtained dry granule, mixing, and tabletting. In one embodiment, when present, the salts may be added by mixing with excipients to make granules. In one embodiment, when present, the salts may be added by way of addition to the binder solution. In one embodiment, when present, the salts are added in powder form at the stage of lubricant addition.
According to the use of any one of the embodiments of the fourth aspect of the present invention, the orally disintegrating tablet is repeatedly measured for 6 tablets according to the specification of "0921 disintegration time limit inspection method" on the fourth general rule of chinese pharmacopoeia 2015 year edition and "orally disintegrating tablet" therein, and each of the 6 tablets is completely disintegrated within 60 seconds and passes through a screen; in particular 6 tablets all disintegrated within 45 seconds and passed through the screen; in particular 6 tablets all disintegrated within 30 seconds and passed through the sieve.
According to the use of any of the embodiments of the fourth aspect of the present invention, the orally disintegrating tablet has a friability of the tablet, measured according to the method under the item "0923 tablet friability test" on the fourth general guideline of the chinese pharmacopoeia 2015 version, with no fractures, cracks and crushed tablets, and a weight loss reduction of less than 3%, such as less than 2%, such as less than 1.5%, such as less than 1%.
According to the use according to any of the embodiments of the fourth aspect of the invention, the orally disintegrating TABLET has a hardness in the range of 3 to 6kg, for example in the range of 4 to 6kg, measured according to the method of United states Pharmacopeia USP35-NF30 version "< 1217> TABLET BREAKING FORCE".
For use according to any of the embodiments of the fourth aspect of the invention, the orally disintegrating tablet has a moisture absorption rate of less than 20% (e.g. less than 15%, e.g. less than 12.5%, e.g. less than 10%) as measured by the following method: taking tablets with the total weight of 5.0-5.5 g, and precisely weighing; exposing the mixture to 25 ℃ and 75% relative humidity for 24 hours, and precisely weighing the mixture; the moisture absorption rate was calculated as follows:
the moisture absorption rate is [ (weight of sheet after moisture absorption treatment-weight of sheet before moisture absorption treatment) ÷ weight of sheet before moisture absorption treatment ] × 100%.
According to the use of any embodiment of the fourth aspect of the present invention, the orally disintegrating tablets have a dissolution rate of less than 20%, such as less than 15%, within 15 minutes at a rotation speed of 50 rpm in a third method of 0931 dissolution and release determination method according to the general rule of the four parts of the pharmacopoeia 2015 edition of China, using 250ml of water as a dissolution medium.
According to the use of any of the embodiments of the fourth aspect of the present invention, the coated pellets (i.e. the state of the coated pellets after the completion of the coating of each layer and before the subsequent non-coating process) before being contacted with the material of the tablet matrix show a drug dissolution rate of 50% at each time point, and the absolute value of the difference between the dissolution rate of the coated pellets and the dissolution rate of the orally disintegrating tablet is in the range of 0-15%, particularly in the range of 0-12.5%.
According to the use of any of the embodiments of the fourth aspect of the present invention, the orally disintegrating tablet produced thereby has a water content of less than 10%, such as less than 7.5%, such as less than 5%, as measured in the tablet according to the method under the "second method (baking method)" of the national pharmacopoeia 2015 general rule of the four parts of "0832 moisture assay".
The use according to any of the embodiments of the fourth aspect of the present invention, wherein said active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof, such as tamsulosin hydrochloride. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is a slow release coating layer. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating is an enteric coating layer. In one embodiment, the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof and the coating comprises two layers, a sustained release coating layer and an enteric coating layer from the inside out, respectively. The invention has outstanding contribution to the prior art and is found that the physical strength and the disintegration property of the tablet can be obviously improved by adding a proper amount of salt into the orally disintegrating tablet with embedded pellets. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the present inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets with reference to these examples have only one coating layer (i.e., when these examples refer to two or more coatings, one or more of the coatings are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained-release effect of the release profile of tamsulosin or a pharmaceutically acceptable salt thereof, for example, a sustained-release or controlled-release effect which is substantially released by the first order equation or by the zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained-release coating layer, etc., which is easily accomplished in the field of pharmaceutical agents.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the active ingredient is memantine or a pharmaceutically acceptable salt thereof, e.g. memantine hydrochloride. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a film coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is a slow release coating. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating is an enteric coating layer. In one embodiment, the active ingredient is memantine, or a pharmaceutically acceptable salt thereof, and the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside out. The invention has outstanding contribution to the prior art and is found that the physical strength and the disintegration property of the tablet can be obviously improved by adding a proper amount of salt into the orally disintegrating tablet with embedded pellets. The above technical effects exhibited by orally disintegrating tablets obtained from pellets comprising a sustained-release coating layer and an enteric coating layer as two coating layers are demonstrated in some examples of the invention below. In supplementary experiments, the inventors have also found that orally disintegrating tablets obtained when the pellets used in the preparation of orally disintegrating tablets according to these examples have only one coating layer (i.e. when these examples relate to two or more coatings, one or more of which are omitted and only one coating layer is applied) also exhibit the above-mentioned advantageous technical effects. In addition, in order to obtain a desired sustained-release effect of the release profile of memantine hydrochloride, for example, a sustained-release or controlled-release effect which is substantially released in the first order equation or in the zero order equation within 6 hours, 12 hours or 18 hours, if necessary, can be achieved by means of adjusting the thickness of the sustained-release coat layer, etc., which is easily achieved in the field of pharmaceutical agents.
The use according to any of the embodiments of the fourth aspect of the invention, wherein the active ingredient is an antipsychotic agent such as olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, aclidinam, alprazolam, methylphenidate, milnacipran, sodium valproate, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is an antiemetic agent such as ramosetron, granisetron, ondansetron, azasetron or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
Use according to any of the embodiments of the fourth aspect of the invention, wherein the active ingredient is chlorpheniramine, loratadine or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is an agent for cardiovascular administration such as quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, nisoldipine, glipizide, glimepiride, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is an agent for digestive system administration such as famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praenoxate, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, domperidone, racecadotril, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is a hyperlipemia therapeutic agent such as pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
The use according to any of the embodiments of the fourth aspect of the present invention, wherein the active ingredient is a therapeutic agent for BPH such as tamsulosin, doxazosin, terazosin or the like, or a pharmaceutically acceptable salt thereof. In one embodiment, the coating is a film coating. In one embodiment, the coating is a slow release coating layer. In one embodiment, the coating is an enteric coating layer. In one embodiment, the coating comprises two layers, a sustained release coating layer and an enteric coating layer, from the inside to the outside. In addition, in the case where sustained release is required, in order to obtain a sustained release effect of a desired drug release profile, for example, a sustained release or controlled release effect which is substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours, it can be achieved by means of adjusting the thickness of the sustained release coat layer or the like, which is easily achieved in the field of pharmaceutical preparations.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with any other embodiment of the invention, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in any other embodiment of the invention, provided that they do not contradict.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
It should be noted that the term "a sustained-release coating layer" or "an enteric coating layer" as used herein means only one coating layer, for example, only a sustained-release coating layer or only an enteric coating layer. It is known that in the pharmaceutical coating process, it is usually necessary to coat a coating layer continuously or intermittently, and particularly in the case of intermittent coating, such a coating layer is constituted of a plurality of layers, i.e., after spraying a layer of coating liquid and immediately drying it, then continuing to spray a layer of coating liquid and immediately drying it, and repeating such coating until such a coating layer achieves the desired effect.
In the present invention, by adding salts to the tablet base outside the pellet to prepare an orally disintegrating tablet, the tablet can be directly compressed to a desired hardness without undergoing cumbersome and poorly controlled humidification-drying or heating-cooling processes as in CN1473035B, and the prepared tablet has excellent strength and disintegration properties, and has excellent stability. In fact, the inventors have found in experiments that, when preparing orally disintegrating tablets with reference to CN1473035B examples 1 to 9, the tablets were compressed to a degree of hardness of 5 to 5.5kg directly during tabletting, rather than to a degree of about 1 to 2kg, and the tablets obtained did not satisfy the requirements for tablet friability and/or disintegration properties regardless of whether they were subjected to humidification-drying or heating-cooling treatment, specifically, the tablets thus obtained did not have disintegration time longer than 2.5min without humidification-drying or heating-cooling treatment, whereas after humidification-drying or heating-cooling treatment with reference to CN1473035B, the tablets did not satisfy the requirements for friability, had no broken, cracked or crushed tablets in each lot, and had weight loss in the range of 3.4 to 6.1%. Thus, in any embodiment of any aspect of the invention, when the blend comprising the coated pellets is compressed, the blend granules are compressed into tablets on a tablet press under a pressure that is capable of achieving a hardness of the tablets of 3 to 7kg (e.g. of 3.5 to 6.5kg, e.g. of 4 to 6 kg).
The orally disintegrating tablets of the present invention are prepared below, and the water content of the tablets is less than 5%, particularly in the range of 2 to 5%, measured according to the method under the item of the "second method (drying method)" of the "0832 moisture determination method" of the general rule of the four parts of the pharmacopoeia 2015 edition of China.
According to the invention, by adding a small amount of inorganic salt into the orally disintegrating tablet, the tablet with excellent hardness and friability indexes can be directly obtained by a wet granulation tabletting method without long-time temperature and humidity balance treatment or extremely high temperature treatment, and the hardness and friability indexes have excellent stability, so that the tablet has excellent disintegration performance on the premise of having excellent hardness and friability indexes.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
In the present invention, the content uniformity of the active ingredient in the core containing the drug pellet can be characterized by using the content ratio of the large and small particles. The content ratio of the large and small particles is determined as follows: selecting two standard medicine sieves with meshes, wherein the standard medicine sieves can enable 28-38% of the prepared medicine-containing pill cores to pass through a small-mesh medicine sieve (the part of particles are called small particles), 28-38% of the prepared medicine-containing pill cores cannot pass through a large-mesh medicine sieve (the part of particles are called large particles), 28-38% of the prepared medicine-containing pill cores are trapped between the two medicine sieves (the part of particles are called medium particles), classifying and sieving the medicine-containing pill cores by using the two medicine sieves, respectively measuring the medicine content of a small-particle part (which can be marked as Q1) and the medicine content of a large-particle part (which can be marked as Q2), and calculating the ratio of Q2 to Q1, namely the content ratio of the large-particle and the small-particle. The closer this size particle content ratio is to 1, the better content uniformity of the active ingredient in the drug-containing pellet core is, which is very beneficial for its subsequent processing and helps to ensure that tablets with excellent content uniformity are obtained.
Evaluation method of orally disintegrating tablet:
[ content determination of active ingredient ]:
the content of the active ingredient memantine hydrochloride in each material was determined by GC method. Measured according to the appendix VE of the second part of Chinese pharmacopoeia 2010 edition; chromatographic conditions and system applicability test: a capillary column using polydimethylsiloxane as a stationary liquid, a hydrogen flame ionization detector, a column temperature of 200 ℃ (retaining for 7min), a detector temperature of 250 ℃, a sample inlet temperature of 220 ℃, and a split ratio of 10: 1; the number of theoretical plates is not less than 10000 calculated according to memantine hydrochloride peak; the separation degree of the memantine hydrochloride and the internal standard substance is in accordance with the requirement. Preparation of internal standard solution: preparing naphthalene into a solution containing 0.2mg of chloroform in 1 ml; preparation of control solutions: accurately weighing 12.5mg of memantine hydrochloride reference substance, placing in a 25ml measuring flask, dissolving with water, diluting to scale, and shaking; the determination method comprises the following steps: precisely measuring a reference substance solution 2ml and a test sample (containing memantine hydrochloride 1mg), dividing into 10ml test tubes with plugs, respectively adding 5mol/L sodium hydroxide solution 2ml, shaking, precisely adding an internal standard solution 3ml, vortex-shaking and mixing for 5min, standing for 5min, dividing a chloroform layer, precisely measuring 1 μ L, injecting into a gas chromatograph, and recording a chromatogram; calculating according to the peak area by an internal standard method to obtain the product.
The content of tamsulosin hydrochloride is determined by an HPLC method, and the HPLC conditions are as follows: c18 chromatographic column, column length 250mm, inner diameter 4.6mm, packing particle size 5um, mobile phase: methanol/water 70/30, uv detected at 254nm, and quantified by peak area using external standard method.
For the other active ingredients, appropriate modifications may be made as necessary to be suitable for the additional drug based on the above-mentioned HPLC method for tamsulosin; or they can be measured by a known standard method, for example, famotidine can be measured by a content measuring method under the item of famotidine tablets carried in the second part of the Chinese pharmacopoeia 2010 edition.
And (4) stability treatment:the orally disintegrating tablets are packaged in a sealed package simulating the marketing of the tabletsUnder the condition of being left at 40 ℃ for 5 months (this process may be referred to as stability treatment in the present invention), the relevant parameter at 0 month (the value of 0 month is generally equal to the value measured after the tablet is prepared) and the relevant parameter at 5 months are measured, and the values of 0 month and 5 months of the relevant parameters are compared to evaluate the stability of the orally disintegrating tablet.
Content uniformity:this is a conventional method for determining the content difference of small dose solid pharmaceutical preparations in different pharmaceutical units, and the uniformity of the active ingredient in different tablets is characterized by coefficient of variation CV% in the present invention with reference to the method described in CN 1473035B. Generally, it is satisfactory that the CV% is as small as possible and less than 3.5%, and the CV% is more than 3.5% is considered unacceptable.
Friability:the friability of the tablets was measured according to the method (100 rounds) under the item of "0923 tablet friability test method" of the general rules of four parts of the chinese pharmacopoeia 2015 year edition, and it was generally considered as acceptable when the tablets were free from breakage, cracking and crushing and the weight loss (which may be generally referred to as "attrition") was less than a predetermined value, for example, less than 1%. Generally, orally disintegrating tablets show an increase in weight loss after stable handling (if the opposite occurs, a significant increase in tablet hardness is usually present and the disintegration time is greatly prolonged); the difference between the weight loss at 5 months and the weight loss at 0 months is divided by the weight loss at 0 months, and the weight loss increase percentage is determined as the percentage closer to 0, the better. This percentage increase in weight loss may also quantitatively reflect the change in hardness of the tablet after stability handling.
Hardness:according to United states pharmacopoeia USP35-NF30 edition "<1217>The hardness of the TABLETs was measured by the method of TABLET BREAKING FORCE ", and it is generally considered that TABLETs having superior hardness values have a hardness in the range of 4 to 6kg, as represented by the average value obtained by measuring 6 TABLETs.
Moisture absorption rate:taking tablets with the total weight of 5.0-5.5 g, and precisely weighing; exposing the mixture to 25 ℃ and 75% relative humidity for 24 hours, and precisely weighing; the moisture absorption was calculated as follows: moisture absorption rate [ [ (weight of sheet after moisture absorption treatment-weight of sheet before moisture absorption treatment) ÷ weight of sheet before moisture absorption treatment]×100 percent. The moisture absorption rate of the orally disintegrating tablet is usually very high due to the characteristics of the used auxiliary materials, can reach the degree of less than 20 percent, particularly less than 15 percent, and is very excellent, and the moisture absorption rate of the currently sold orally disintegrating tablets measured by the method can reach more than 20 percent and even more than 30 percent.
Disintegration time:according to the rules of the '0921 disintegration time limit inspection method' of the general rule of the four parts of the national pharmacopoeia 2015 year edition and the 'orally disintegrating tablets' item in the method, the disintegration time of 6 tablets is repeatedly measured, and the average value is calculated as the disintegration time of the tablets in the batch, so that the disintegration time is meaningful on the premise that the 6 tablets are completely disintegrated and pass through a screen.
Dissolution performance:
dissolution rate in 15 minutes:according to the third method of 0931 dissolution and release determination method in accordance with the general rule of the four parts of the 2015 edition of Chinese pharmacopoeia, 250ml of water is used as a dissolution medium, the rotation speed is 50 r/min, and the dissolution within 15 min is determined, wherein the dissolution rate is usually required to be less than 20%, for example less than 15%, which indicates that the coating is effective;
difference in 50% dissolution:according to the dissolution test method, the dissolution rate of the coated pellets before the coated pellets contact with the materials of the tablet matrix (namely, the state of the coated pellets after completing each layer coating and before carrying out the subsequent non-coating operation process) is determined, and the drug dissolution rate is shown as 50% of the time point, and the absolute value of the difference between the dissolution rate of the coated pellets and the dissolution rate of the orally disintegrating tablet prepared by using the coated pellets is calculated as 50% of the dissolution rate difference, which is preferably in the range of 0-15%;
release profile:for the orally disintegrating tablet prepared by the pellets coated with the sustained-release coating, according to the dissolution test method, the dissolution and the corresponding time of the material in the orally disintegrating tablet are continuously and randomly monitored within the time range of extending the dissolution test to 90% and then extending the time for 2 hours, and then according to the method of ' 9013 guidance principles of sustained-release, controlled-release and delayed-release preparations ' 6 of the four-part general rules of the Chinese pharmacopoeia 2015 edition, the fitting of a drug release model ' and the use of a one-level equation or a zero-level equation to the releaseAnd fitting the curve. The preferred orally disintegrating tablets with sustained or controlled release effects of the present invention are substantially released in a first order equation or a zero order equation within 6 hours, 12 hours or 18 hours.
Example 1: preparation of memantine hydrochloride orally disintegrating tablet
(1) Memantine hydrochloride 1000g and hydroxypropylmethylcellulose 200g were dissolved in purified water 4000 g. 3000g of microcrystalline cellulose fine particles (Celphere102, Asahi chemical, average particle size of about 120 μm, particle size of 95% or more in the range of 50-150 μm) were placed in a fluidized bed granulator, and the solution was coated by a side spray method to obtain memantine hydrochloride particles.
The fluid bed granulator in the above and the present invention is a WBF-60 type fluid bed granulator manufactured by Chongqing English granulation and coating technology Co. When the fluidized bed granulator is used for granulating and/or coating, the spraying speed can be generally controlled within the range of 10-120 g/min according to different materials, the spraying air pressure can be generally controlled within the range of 0.5-5 kg/cm2, the product temperature can be generally controlled within the range of 30-50 ℃, the air suction temperature can be generally controlled within the range of 40-85 ℃ and is generally 10-25 ℃ higher than the product temperature; these parameters are usual for the person skilled in the art and can be adjusted empirically by the person skilled in the art for the different materials/equipment etc. which, for example, essentially correspond to those used in CN1473035B, and in the context of the present application, when granulation and/or coating are carried out, the equipment is used and the treatment is carried out with parameters in this range, if not stated otherwise.
(2) Subsequently, 500g of ethylcellulose (ground and sieved with a 200 mesh sieve) and 150g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of memantine hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) Then 4000g of the sustained-release pellets were put into a fluidized bed granulator, and coated with a mixture of 1000g of Aquacoat (U.S. FMC), 2000g of Eudragit L30D55 (trade name, Rohm corporation), 300g of Eudragit NE30D (trade name, Rohm corporation) and 5000g of purified water by a lateral spray method to obtain enteric sustained-release pellets (active ingredient content: 17.6%).
(4) 400g of enteric-coated sustained-release pellets, 1500g of mannitol, 300g of lactose and 200g of sodium chloride are granulated and dried by using a 30% w/w aqueous solution containing 200g of maltose in a fluidized bed granulator (continuous spray drying treatment in the fluidized bed granulator is not needed to carry out the intermittent circulation process of spray-drying like CN 1473035B), and granules are obtained, wherein the moisture content is less than 4%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 22g of calcium stearate to obtain final mixed granules, measuring the content of active ingredients in the final mixed granules to calculate the weight of the tablets when each tablet contains a specified amount of the active ingredients, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into tablets containing 10mg of memantine hydrochloride (the weight of the tablets is about 400mg) to obtain the memantine hydrochloride orally disintegrating tablets. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 1.03;
the average grain diameter of the enteric sustained-release pellet obtained in the step (3) is about 147 mu m, and the grain diameter of more than 95 percent of particles is in the range of 120-180 mu m;
hardness: 5.2 kg;
content uniformity: CV% ═ 1.1%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.37%;
moisture absorption rate: 9.4 percent;
disintegration time: 24 seconds;
dissolution rate: 2.1 percent of dissolution rate within 15 minutes, 4.7 percent of dissolution difference within 50 percent, and a first-order release curve within 18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss reduction increase percentage is only 13.6%.
Example 11: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) Tamsulosin hydrochloride 80g and hydroxypropylmethylcellulose 80g were dissolved in 2000g of purified water. 4000g of microcrystalline cellulose fine particles (Celphere102, Asahi chemical, average particle size of about 120 μm, particle size of 95% or more in the range of 50-150 μm) were placed in a fluidized bed granulator, and the solution was coated by a side spray method to obtain tamsulosin hydrochloride particles.
The fluid bed granulator in the above and the present invention is a WBF-60 type fluid bed granulator manufactured by Chongqing English granulation and coating technology Co. When the fluidized bed granulator is used for granulating and/or coating, the spraying speed can be controlled within the range of 10-120 g/min generally according to different materials, the spraying air pressure can be controlled within the range of 0.5-5 kg/cm2 generally, the product temperature can be controlled within the range of 30-50 ℃, the air suction temperature can be controlled within the range of 40-85 ℃ generally and is 10-25 ℃ higher than the product temperature generally; these parameters are usual for the person skilled in the art and can be adjusted empirically by the person skilled in the art for the different materials/equipment etc. which, for example, essentially correspond to those used in CN1473035B, and in the context of the present application, when granulation and/or coating are carried out, the equipment is used and the treatment is carried out with parameters in this range, if not stated otherwise.
(2) Next, 530g of ethylcellulose (ground and passed through a 200 mesh sieve) and 180g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellet.
(3) Then 4000g of the sustained-release pellets were put in a fluidized bed granulator, and were coated with a mixture of 2000g of Aquacoat (U.S. FMC), 4000g of Eudragit L30D55 (trade name, manufactured by Rohm), 667g of Eudragit NE30D (trade name, manufactured by Rohm), and 6667g of purified water by lateral spray to obtain enteric sustained-release pellets (active ingredient content: 1.135%).
(4) 368g of enteric sustained-release pellets, 2320g of mannitol, 640g of lactose and 240g of sodium chloride were granulated and dried (continuous spray drying treatment in the fluidized bed granulator, without the intermittent circulation process of spray-drying like CN 1473035B) with 40% w/w aqueous solution containing 400g of maltose in the fluidized bed granulator to obtain granules with a moisture content of less than 4%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 32g of calcium stearate to obtain final mixed granules, measuring the content of the active ingredients to calculate the weight of the tablets when each tablet contains a specified amount of the active ingredients, enabling the hardness of the tablets to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets (the weight of the tablets is about 196mg) containing 0.2mg of tamsulosin hydrochloride, thereby obtaining the tamsulosin hydrochloride orally disintegrating tablets. And (4) simulating the packaging form of a commercial product, and hermetically packaging to obtain the tablet.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles to the size particles of the tamsulosin hydrochloride particles obtained in the step (1) is as follows: 1.01;
the average grain diameter of the enteric sustained-release pellet obtained in the step (3) is about 153 μm, and the grain diameter of more than 95 percent of particles is in the range of 120-180 μm;
hardness: 5.4 kg;
content uniformity: CV% ═ 1.3%;
friability: no fracture, crack and crushed piece, and the weight loss is reduced by 0.41 percent;
moisture absorption rate: 8.7 percent;
disintegration time: 17 seconds;
dissolution rate: 4.2 percent of dissolution rate within 15 minutes, 4.6 percent of dissolution difference within 50 percent, and a first-order release curve within 16 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 15.7%.
Comparative example 1:
an orally disintegrating tablet was prepared with reference to the ingredients and recipe of example 1, paragraphs [0130] to [0133] of CN1473035B, with the results:
the content ratio of the active drug particles in the size particles is as follows: 0.89;
the average particle size of the enteric sustained-release pellet is about 147m, and the particle size of more than 95 percent of particles is in the range of 120-180 mu m;
hardness: 5.7 kg;
content uniformity: CV% ═ 1.9%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.86%;
moisture absorption rate: 21.3 percent;
disintegration time: 25 seconds;
after 5 months of stability handling: the disintegration time and the dissolution rate are not obviously changed, the hardness and the friability are obviously changed, the hardness is reduced to 3.6kg, and the weight loss increase percentage is 126.1%.
Comparative example 1 a:referring to the above comparative example 1, except that the active ingredient therein was changed to memantine hydrochloride or tamsulosin hydrochloride, the results were substantially the same as those of comparative example 1, and particularly, the content ratio of the large and small particles, the moisture absorption rate, the change in the stability handling, and the like were substantially the same as those of comparative example 1.
Comparative example 2:
the orally disintegrating tablet is prepared by referring to the ingredients and the preparation method of example 2, i.e., [0153] paragraph of CN1473035B, the orally disintegrating tablet is prepared by referring to the ingredients and the preparation method of the above-mentioned document example 5, the orally disintegrating tablet is prepared by referring to the ingredients and the preparation method of the above-mentioned document example 7, the orally disintegrating tablet is prepared by referring to the ingredients and the preparation method of the above-mentioned document example 8, and the orally disintegrating tablet is prepared by referring to the ingredients and the preparation method of the above-mentioned document example 9, respectively.
As a result: the content ratio of the large and small particles of each medicine-containing pellet core particle is 0.85-0.91;
the average particle size of the coated pellets before mixing with the water-soluble sugar or sugar alcohol is within the range of 142-185 μm, and the particle size of more than 95% of particles is within the range of 100-300 μm;
the hardness of each orally disintegrating tablet is within the range of 4.5-6.1 kg;
the content uniformity CV% of each orally disintegrating tablet is within the range of 1.9-3.2%;
in the friability measurement of each orally disintegrating tablet, no fracture, crack or crushed tablet exists, and the weight loss is within the range of 0.68-0.95%;
the moisture absorption rate of each orally disintegrating tablet is within the range of 22.3-31.6%;
the disintegration time of each orally disintegrating tablet is within the range of 20-40 seconds;
after 5 months of stability handling: the disintegration time and the dissolution rate of various tablets are not obviously changed, but the hardness and the friability are obviously changed, the respective reduction value of the hardness reaches 1.3-2.1 kg, and the weight loss increase percentage is within the range of 115-184%.
Comparative example 2 a:referring to the above comparative example 2, except that the active ingredient therein was changed to memantine hydrochloride or tamsulosin hydrochloride, the results were that each tablet was substantially the same as the corresponding tablet of comparative example 2, and in particular, the tablets were substantially the same as comparative example 2 in terms of the content ratio of the large and small particles, the moisture absorption rate, the stability handling change, and the like.
As can be seen from comparative examples 1, 1a, 2 and 2a, the content of active ingredients in the microparticles with different sizes of the drug-containing core particles is obviously different when the orally disintegrating tablet is prepared according to the prior art; although these tablets are manufactured by pre-pressing a low hardness tablet and then a tablet having a desired hardness is obtained by a long-term humidification-drying process or an ultra-high temperature treatment-cooling process, the hardness of such a tablet and the friability stability associated therewith are not ideal.
Comparative example 3:
referring to the formulation and preparation methods of examples 1 to 8 and examples 11 to 18 of the present invention, except that in the first step of preparing drug-containing cores (e.g., memantine hydrochloride particles obtained in step (1) of example 1), 80% of water was replaced with 1.5 times the weight of methanol thereof to prepare a drug-binder solution using a methanol-water mixed solvent (i.e., for example, 4000g of water was replaced with 800g of water and 4800g of methanol in step (1) of example 1), followed by preparing orally disintegrating tablets according to the method.
As a result: the content ratio of the memantine hydrochloride particles or tamsulosin hydrochloride particles obtained in the step (1) is within the range of 0.84-0.91 or 0.87-0.92, and the time for mixing the orally disintegrating tablets with the content uniformity CV% of less than 4% is required to be prolonged when the orally disintegrating tablets are finally mixed with the lubricant (the mixing time is usually 2.5-3.5 times that of examples 1-8 or 2-2.5 times that of examples 11-18); on the premise of mixing for a long time to obtain satisfactory content uniformity, the prepared tablets have no obvious difference from the tablets of examples 1-8 or examples 11-18 in the aspects of hardness, friability, moisture absorption rate, disintegration time, dissolution rate, stability handling and other performances; however, such mixing for a long time can present challenges to process requirements such as moisture protection (avoiding moisture absorption).
Comparative example 4:
with reference to the ingredients and processes of examples 1 to 8 or examples 11 to 18 of the present invention, except that no salt is added when mixing coated pellets with sugar and/or sugar alcohol for granulation or mixing coated pellets with granulated sugar and/or sugar alcohol granules, and during tabletting, as in these examples, tablets are made to a hardness of 5.0 to 5.5kg at a certain pressure on a rotary tablet press, and these final mixed granules are directly (instead of being pre-pressurized with a small pressure and then humidified or heat-treated as in CN 1473035B) compressed into orally disintegrating tablets.
As a result:
the hardness of the tablets is within the range of 4.3-6 kg;
the content uniformity CV percent is within the range of 1-2.5 percent;
friability: the weight loss of the sheet with fracture, cracking and crushing is within the range of 1.83-3.2%;
the moisture absorption rate is within the range of 24.2-34.4%;
the disintegration time is less than 60 seconds;
the dissolution rate and the dissolution rate stability are not obviously different from those of the orally disintegrating tablets obtained in examples 1 to 8 or examples 11 to 18; after the treatment of stability, the weight loss is reduced and the weight is increased by 200-280%. These results show that without the addition of salts and without the pre-application of a small pressure and subsequent humidification or heat treatment as in CN1473035B, the strength of the resulting tablets is very poor and completely unacceptable.
Comparative example 5(# 391): 120g of ambroxol hydrochloride, menthol, sodium chloride, polacrilin potassium, superfine silica powder, xylitol, sucralose and magnesium stearate are weighed according to the weight ratio of 20:8:4:5:3:40:5:2, and 1000 tablets of the ambroxol hydrochloride pharmaceutical composition orally disintegrating tablets are prepared. The specific technical parameters are as follows: 1) the granularity requirement of raw materials and auxiliary materials is as follows: ambroxol hydrochloride, sodium chloride, superfine silica gel powder, menthol, sucralose and magnesium stearate with the granularity of less than 180 micrometers; potassium polacrilin, xylitol particle size less than 250 microns. 2) Adding the ambroxol hydrochloride, the sodium chloride, the superfine silica gel powder, the menthol, the sucralose, the magnesium stearate, the polacrilin potassium and the xylitol into a three-dimensional motion mixer according to the prescription amount, and mixing for 15-30 minutes to obtain the total mixture. The fluidity of the total mixture was 35.2 ° at an angle of repose. 3) Directly tabletting the total mixture to obtain the final product. The hardness of the tablet obtained by direct compression was measured immediately above and was 5.3 kg; the friability shows broken, cracked and crushed pieces, and the weight loss is reduced by 2.3%; the moisture absorption rate is 27.3%; disintegration time 35 seconds. The tablets are immediately sealed and packaged after being pressed, after being placed in a room-temperature dry place for 7 days, the hardness is 2.8kg, the friability shows that the tablets have fracture, crack and crushing, the weight loss is 4.6 percent, and the moisture absorption rate is 29.1 percent; disintegration time 38 seconds. This indicates that the hardness of such tablets does not meet the conventional requirements and that the friability is unacceptable, and that tablets in this state are also a disadvantage which is often present in the target commercial tablets produced by compression.
Example 2: preparation of memantine hydrochloride orally disintegrating tablet
(1) Memantine hydrochloride 200g and hydroxypropylmethylcellulose 80g were dissolved in purified water 2000 g. 4000g of microcrystalline cellulose granules (Celphere102, Asahi Kasei Co., Ltd., average particle size of about 160 μm, particle size of 95% or more in the range of 100-250 μm) were placed in a fluidized bed granulator, and the solution was coated by a side spray method to obtain memantine hydrochloride particles.
(2) Then, 4000g of the memantine hydrochloride granules were put into a fluidized bed granulator, and coated with a mixture of 2000g of Aquacoat (U.S. FMC), 1000g of Eudragit NE30D (trade name, manufactured by Rohm corporation) and 5000g of purified water by a side spray method to obtain enteric pellets.
(3) 360g of the enteric-coated pellets, 2400g of mannitol, 640g of lactose and 250g of potassium chloride were granulated and dried (continuous spray drying procedure) in a fluidized bed granulator using a 30% w/w aqueous solution containing 350g of polyvinylpyrrolidone to obtain granules having a moisture content of less than 3%.
(4) And (3) uniformly mixing the granules obtained in the step (3) with 30g of calcium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets containing a specified amount of the active ingredients in each tablet, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 2mg of memantine hydrochloride in each tablet to obtain the memantine hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 0.99;
the average particle size of the enteric-coated pellet obtained in the step (2) is about 242 μm, and the particle size of more than 95 percent of particles is in the range of 150-350 μm;
hardness: 5.4 kg;
content uniformity: CV% ═ 1.8%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.44%;
moisture absorption rate: 9.6 percent;
disintegration time: 25 seconds;
dissolution rate: 4.7 percent dissolution rate in 15 minutes;
after 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 18.1%.
Example 12: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) Tamsulosin hydrochloride 80g and hydroxypropylmethylcellulose 80g were dissolved in 2000g of purified water. 4000g of microcrystalline cellulose fine particles (Celphere102, Asahi Kasei Co., Ltd., average particle size of about 160 μm, particle size of 95% or more in the range of 100-250 μm) were placed in a fluidized bed granulator, and the solution was coated by a side spray method to obtain tamsulosin hydrochloride particles.
(2) Subsequently, 550g of ethylcellulose (ground and passed through a 200 mesh sieve) and 160g of hydroxypropylmethylcellulose were added to 18000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellet.
(3) Then 4000g of the sustained-release pellets were put into a fluidized bed granulator, and coated with a mixture of 2000g of Aquacoat (U.S. FMC), 4000g of Eudragit L30D55 (trade name, manufactured by Rohm company), 667g of Eudragit NE30D (trade name, manufactured by Rohm company) and 6667g of purified water by a lateral spray method to obtain enteric sustained-release pellets.
(4) 360g of enteric-coated sustained-release pellets, 2400g of mannitol, 640g of lactose and 250g of potassium chloride are granulated and dried (continuous spray drying procedure) by using 30% w/w aqueous solution containing 350g of maltose in a fluidized bed granulator to obtain granules with the moisture content of less than 3%.
(5) And (5) uniformly mixing the granules obtained in the step (4) with 30g of calcium stearate to obtain final mixed granules, measuring the content of the active ingredients to calculate the weight of the tablet when each tablet contains a specified amount of the active ingredients, enabling the hardness of the tablet to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablet containing 0.2mg of tamsulosin hydrochloride per tablet to obtain the tamsulosin hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles to the size particles of the tamsulosin hydrochloride particles obtained in the step (1) is as follows: 0.98 of;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 235 mu m, and the particle size of more than 95 percent of particles is in the range of 150-350 mu m;
hardness: 5.7 kg;
content uniformity: CV% ═ 1.1%;
friability: no fracture, crack and crushed piece, and the weight loss is reduced by 0.33%;
moisture absorption rate: 10.3 percent;
disintegration time: 20 seconds;
dissolution rate: the dissolution rate is 3.8 percent within 15 minutes, the dissolution difference of 50 percent is 5.3 percent, and a first-order release curve is formed within 15 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 13.3%.
Example 3: preparation of memantine hydrochloride orally disintegrating tablet
(1) In 2000g of purified water, 750g of memantine hydrochloride and 100g of polyvinylpyrrolidone were dissolved. 4000g of microcrystalline cellulose fine particles (Celphere102, Asahi chemical, mean particle size of about 80 μm, particle size of 95% or more in the range of 50-120 μm) were put into a fluidized bed granulator, and the solution was coated by side spray to obtain memantine hydrochloride particles.
(2) Subsequently, 600g of ethylcellulose (ground and sieved with a 200 mesh sieve) and 180g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of memantine hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) 360g of the sustained-release pellet, 1800g of mannitol and 180g of sodium dihydrogen phosphate are granulated and dried by a 25% w/w aqueous solution containing 200g of sucrose in a fluidized bed granulator (continuous spray drying procedure) to obtain granules with a water content of less than 3%.
(4) And (4) uniformly mixing the granules obtained in the step (3) with 30g of calcium stearate to obtain final mixed granules, measuring the content of the active ingredients to calculate the weight of the tablets when each tablet contains a specified amount of the active ingredients, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 9mg of memantine hydrochloride, namely the memantine hydrochloride orally disintegrating tablets. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 1.01;
the average particle size of the micropill obtained in the step (2) is about 120 mu m, and the particle size of more than 95 percent of particles is in the range of 80-160 mu m;
hardness: 4.9 kg;
content uniformity: CV% ═ 1.2%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.32 percent;
moisture absorption rate: 8.9 percent;
disintegration time: 30 seconds;
dissolution rate: 2.3 percent of dissolution rate within 15 minutes, 7.3 percent of dissolution difference within 50 percent, and a first-order release curve within 12 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 11.2%.
Example 13: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) Tamsulosin hydrochloride 80g and hydroxypropylmethylcellulose 80g were dissolved in 2000g of purified water. 4000g of microcrystalline cellulose fine particles (Celphere102, Asahi chemical, mean particle size of about 80 μm, particle size of 95% or more in the range of 50-120 μm) were put into a fluidized bed granulator, and the solution was coated by side spray to obtain tamsulosin hydrochloride particles.
(2) Subsequently, 600g of ethylcellulose (ground and sieved with a 200 mesh sieve) and 180g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) Then 4000g of the sustained-release pellets were put in a fluidized bed granulator, and were coated with a mixture of 2000g of Aquacoat (U.S. FMC), 4000g of Eudragit L30D55 (trade name, manufactured by Rohm), 667g of Eudragit NE30D (trade name, manufactured by Rohm) and 6667g of purified water by lateral spray to obtain enteric sustained-release pellets.
(4) 360g of enteric sustained-release pellets, 3000g of mannitol and 200g of sodium dihydrogen phosphate are granulated and dried by using 25% w/w aqueous solution containing 300g of sucrose in a fluidized bed granulator (continuous spray drying procedure), so as to obtain granules with the water content of less than 3%.
(5) And (5) uniformly mixing the granules obtained in the step (4) with 30g of calcium stearate to obtain final mixed granules, measuring the content of the active ingredients to calculate the weight of the tablet when each tablet contains a specified amount of the active ingredients, enabling the hardness of the tablet to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablet containing 0.3mg of tamsulosin hydrochloride per tablet to obtain the tamsulosin hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles to the size particles of the tamsulosin hydrochloride particles obtained in the step (1) is as follows: 1.02;
the average grain diameter of the enteric sustained-release pellet obtained in the step (3) is about 115 mu m, and the grain diameter of more than 95 percent of particles is in the range of 80-170 mu m;
hardness: 5.2 kg;
content uniformity: CV% ═ 1.6%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.37%;
moisture absorption rate: 8.7 percent;
disintegration time: 25 seconds;
dissolution rate: 4.5 percent of dissolution rate within 15 minutes, 3.9 percent of dissolution difference within 50 percent and a first-order release curve within 16 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss reduction increase percentage is only 10.6%.
Example 4: preparation of memantine hydrochloride orally disintegrating tablet
(1) Hydroxypropyl methylcellulose 100g was dissolved in 2000g of purified water. Mixing 3000g of memantine hydrochloride, 1000g of sucrose and 2000g of microcrystalline cellulose together, crushing and sieving by a 200-mesh sieve, putting the mixture into a fluidized bed granulator, and granulating and drying the HPMC solution (continuous spray drying procedure) to obtain granules (the average particle size is about 250 mu m, the particle size of more than 95 percent is in the range of 150-350 mu m), wherein the moisture content is less than 3 percent;
(2) subsequently, 600g of ethylcellulose (ground and sieved with a 200 mesh sieve) and 160g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 5000g of memantine hydrochloride particles are put into a fluidized bed granulator, and the coating liquid is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) Then 5000g of the sustained-release pellet was put into a fluidized bed granulator, and coated with a mixed solution of 4000g of Eudragit L30D55 (trade name, manufactured by Rohm) and 10000g of purified water by a lateral spray method to obtain an enteric sustained-release pellet.
(4) 800g of the enteric sustained-release pellet, 2600g of mannitol and 200g of dipotassium hydrogen phosphate are granulated and dried by using a 20% w/w aqueous solution containing 200g of maltose in a fluidized bed granulator (continuous spray drying procedure), and granules with the water content of less than 3% are obtained.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 30g of magnesium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets containing a specified amount of the active ingredients in each tablet, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into tablets containing 28mg of memantine hydrochloride in each tablet to obtain the memantine hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 0.98 of;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 195 μm, and the particle size of more than 95 percent of particles is in the range of 130-280 μm;
hardness: 5.3 kg;
content uniformity: CV% ═ 0.9%;
friability: no fracture, crack and crushed piece, and the weight loss is reduced by 0.35 percent;
moisture absorption rate: 8.9 percent;
disintegration time: 24 seconds;
dissolution rate: 1.2 percent of dissolution rate within 15 minutes, 4.5 percent of dissolution difference within 50 percent, and a first-order release curve within 18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss reduction increase percentage is only 16.4%.
Example 14: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) Tamsulosin hydrochloride 80g and hydroxypropylmethylcellulose 80g were dissolved in 2000g of purified water. 4000g of microcrystalline cellulose fine particles (Celphere102, Asahi Kasei Co., Ltd., average particle size of about 140 μm, particle size of 95% or more in the range of 100-.
(2) Subsequently, 550g of ethylcellulose (ground and passed through a 200 mesh sieve) and 160g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) Then 4000g of the sustained-release pellet was put into a fluidized bed granulator, and coated with a mixture of 4000g of Eudragit L30D55 (trade name, manufactured by Rohm), 667g of Eudragit NE30D (trade name, manufactured by Rohm) and 10000g of purified water by a lateral spray method to obtain an enteric sustained-release pellet.
(4) 360g of enteric sustained-release pellets, 3000g of mannitol and 200g of dipotassium hydrogen phosphate are granulated and dried (continuous spray drying procedure) by using 20% w/w aqueous solution containing 200g of polyvinylpyrrolidone in a fluidized bed granulator to obtain granules with the water content of less than 3%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 30g of magnesium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets containing a specified amount of the active ingredients in each tablet, enabling the hardness of the tablets to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 0.4mg of tamsulosin hydrochloride in each tablet to obtain the tamsulosin hydrochloride orally disintegrating tablets. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles and the content of the size particles of the tamsulosin hydrochloride particles obtained in the step (1) are as follows: 1.01;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 175 μm, and the particle size of more than 95 percent of particles is in the range of 100-220 μm;
hardness: 5.4 kg;
content uniformity: CV% ═ 1.4%;
friability: no fracture, crack and crushed piece, weight loss reduced by 0.51%;
moisture absorption rate: 11.3 percent;
disintegration time: 20 seconds;
dissolution rate: 3.6 percent of dissolution rate within 15 minutes, 3.3 percent of dissolution difference within 50 percent, and a first-order release curve within 18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 11.3%.
Example 5: preparation of memantine hydrochloride orally disintegrating tablet
(1) Hydroxypropyl methylcellulose 100g was dissolved in 2000g of purified water. Mixing 3000g of memantine hydrochloride and 3000g of cane sugar together, crushing, sieving by a 200-mesh sieve, putting the mixture into a fluidized bed granulator, and granulating and drying the HPMC solution (continuous spray drying procedure) to obtain granules (the average particle size is about 220 mu m, the particle size of more than 95 percent is in the range of 150-310 mu m), wherein the moisture content is less than 3 percent;
(2) next, 750g of ethylcellulose (ground and sieved with a 200 mesh sieve) and 150g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 5000g of memantine hydrochloride particles are put into a fluidized bed granulator, and the coating liquid is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) The sustained-release pellets 500g, mannitol 2400g, lactose 500g, disodium hydrogen phosphate 250g were granulated and dried (continuous spray drying procedure) with a 25% w/w aqueous solution containing 250g of sucrose in a fluidized bed granulator to obtain granules having a moisture content of less than 3%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 25g of calcium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets when each tablet contains a specified amount of the active ingredients, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 21mg of memantine hydrochloride, thus obtaining the memantine hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 1.02;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 270 mu m, and the particle size of more than 95 percent of particles is in the range of 210 and 340 mu m;
hardness: 5.2 kg;
content uniformity: CV% ═ 0.7%;
friability: no fracture, crack and crushed piece, and the weight loss is reduced by 0.41 percent;
moisture absorption rate: 10.6 percent;
disintegration time: 20 seconds;
dissolution rate: the dissolution rate is 1.4% in 15 minutes, the dissolution difference of 50% is 6.1%, and a first-order release curve is formed within 15 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 13.6%.
Example 15: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) 80g of hydroxypropylmethylcellulose was dissolved in 2000g of purified water. Mixing 20g of tamsulosin hydrochloride and 4000g of microcrystalline cellulose, crushing, sieving by a 200-mesh sieve, putting the mixture into a fluidized bed granulator, and granulating and drying the HPMC solution (continuous spray drying process) to obtain granules (the average particle size is about 260 mu m, the particle size of more than 95 percent is in the range of 150-350 mu m), wherein the moisture content is less than 3 percent;
(2) next, 550g of ethylcellulose (ground and passed through a 200-mesh sieve) and 120g of polyvinylpyrrolidone were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the PVP, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellet.
(3) Then 4000g of the sustained-release pellets were put into a fluidized bed granulator, and coated with a mixture of 2000g of Aquacoat (U.S. FMC), 4000g of Eudragit L30D55 (trade name, manufactured by Rohm corporation), 667g of Eudragit NE30D (trade name, manufactured by Rohm corporation), and 6667g of purified water by a lateral spray method to obtain enteric sustained-release pellets (measured, active ingredient content was 0.28%).
(4) 360g of enteric-coated sustained-release pellets, 2400g of mannitol, 500g of sorbitol and 250g of disodium hydrogen phosphate are granulated and dried (continuous spray drying procedure) by using 25% w/w aqueous solution containing 300g of trehalose in a fluidized bed granulator to obtain granules with the moisture content of less than 3%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 30g of magnesium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets containing a specified amount of the active ingredients in each tablet, enabling the hardness of the tablets to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 0.2mg of tamsulosin hydrochloride in each tablet to obtain the tamsulosin hydrochloride orally disintegrating tablets. And (4) simulating the packaging form of a commercial product, and hermetically packaging to obtain the tablet.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles to the size particles of the tamsulosin hydrochloride particles obtained in the step (1) is as follows: 0.99;
the average grain diameter of the enteric sustained-release pellet obtained in the step (3) is about 290 mu m, and the grain diameter of more than 95 percent of particles is within the range of 250-350 mu m;
hardness: 4.9 kg;
content uniformity: CV% ═ 1.3%;
friability: no fracture, crack and crushed piece, and the weight loss is reduced by 0.47 percent;
moisture absorption rate: 12.2 percent;
disintegration time: 32 seconds;
dissolution rate: 2.4 percent of dissolution rate within 15 minutes, 3.6 percent of dissolution difference within 50 percent, and a first-order release curve within 18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 11.7%.
Example 6: preparation of memantine hydrochloride orally disintegrating tablet
(1) 150g of hydroxypropylmethylcellulose was dissolved in 2000g of purified water. 3000g of memantine hydrochloride and 3000g of microcrystalline cellulose are mixed together, crushed and sieved by a 200-mesh sieve, and the mixture is put into a fluidized bed granulator for granulation and drying (continuous spray drying process) of HPMC solution to obtain granules (the average grain diameter is about 210 mu m, the grain diameter of more than 95 percent is in the range of 160-290 mu m), and the moisture content is less than 3 percent;
(2) 5000g of the granules were then placed in a fluidised bed granulator and coated by side spraying with a 20% w/w aqueous solution containing 400g of hydroxypropylmethylcellulose to give coated pellets.
(3) 250g of the coated pellets, 2500g of mannitol, 500g of lactose and 200g of monopotassium phosphate were granulated and dried (continuous spray drying procedure) in a fluidized bed granulator using 25% w/w aqueous solution containing 300g of sucrose to obtain granules having a moisture content of less than 3%.
(4) And (3) uniformly mixing the granules obtained in the step (3) with 25g of calcium stearate to obtain final mixed granules, measuring the content of active ingredients to calculate the weight of the tablets when each tablet contains a specified amount of the active ingredients, enabling the tablets to reach the hardness of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into tablets containing 6mg of memantine hydrochloride, namely the memantine hydrochloride orally disintegrating tablet. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small particles of the memantine hydrochloride particles obtained in the step (1) is as follows: 0.99;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 280 μm, and the particle size of more than 95 percent of particles is in the range of 230-340 μm;
hardness: 5.7 kg;
content uniformity: CV% ═ 1.4%;
friability: no fracture, crack and crushed pieces, and weight loss reduction of 0.48 percent;
moisture absorption rate: 9.1 percent;
disintegration time: 20 seconds;
dissolution rate: dissolution rate of 4.2% in 15 minutes;
after 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 13.5%.
Example 16: preparation of tamsulosin hydrochloride orally disintegrating tablets
(1) 160g of hydroxypropylmethylcellulose was dissolved in 2000g of purified water. Mixing and crushing 200g of tamsulosin hydrochloride and 4000g of microcrystalline cellulose together, sieving with a 200-mesh sieve, putting the mixture into a fluidized bed granulator, and granulating and drying (continuous spray drying process) the HPMC solution to obtain granules (the average particle size is about 250 mu m, the particle size of more than 95 percent is in the range of 150 and 350 mu m), wherein the water content is less than 3 percent;
(2) next, 500g of ethylcellulose (ground and passed through a 200 mesh sieve) and 120g of hydroxypropylmethylcellulose were added to 20000g of water to strongly suspend the ethylcellulose and dissolve the HPMC, resulting in a sustained-release coating suspension. 4000g of tamsulosin hydrochloride particles are put into a fluidized bed granulator, and the coating solution is used for coating by a lateral spraying method to obtain the sustained-release pellets.
(3) Then 4000g of the sustained-release pellets were put into a fluidized bed granulator, and a mixture of 2000g of Aquacoat (U.S. FMC), 3500g of Eudragit L30D55 (trade name, Rohm corporation), 600g of Eudragit NE30D (trade name, Rohm corporation) and 6000g of purified water was coated by a lateral spray method to obtain enteric sustained-release pellets (the content of active ingredient was measured to be 4.2%).
(4) 250g of enteric-coated sustained-release pellets, 2500g of mannitol, 500g of lactose and 200g of monopotassium phosphate are granulated and dried (continuous spray drying procedure) by using 25% w/w aqueous solution containing 300g of sucrose in a fluidized bed granulator to obtain granules with the moisture content of less than 3%.
(5) And (3) uniformly mixing the granules obtained in the step (4) with 35g of calcium stearate to obtain final mixed granules, measuring the content of the active ingredients to calculate the weight of the tablets containing a specified amount of the active ingredients in each tablet, enabling the hardness of the tablets to reach the degree of 5.0-5.5 kg on a rotary tablet press under a certain pressure, and directly pressing the final mixed granules into the tablets containing 0.2mg of tamsulosin hydrochloride in each tablet to obtain the tamsulosin hydrochloride orally disintegrating tablets. The obtained tablet is packaged in a sealed package mode to simulate the package form of a commercial product.
The properties of the intermediate material and the physicochemical properties of the tamsulosin hydrochloride orally disintegrating tablet obtained in this example were measured, and the results were as follows:
the content ratio of the size particles to the size particles of the tamsulosin hydrochloride particles obtained in the step (1) is as follows: 0.99;
the average particle size of the enteric sustained-release pellet obtained in the step (3) is about 290 mu m, and the particle size of more than 95 percent of particles is in the range of 250-340 mu m;
hardness: 5.3 kg;
content uniformity: CV% ═ 1.6%;
friability: no fracture, crack and crushed piece, weight loss is reduced by 0.41%;
moisture absorption rate: 9.4 percent;
disintegration time: 25 seconds;
dissolution rate: 3.7 percent of dissolution rate within 15 minutes, 3.3 percent of dissolution difference within 50 percent, and a first-order release curve within 18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss increase percentage is only 9.4%.
In a supplementary experiment, the above examples 1-6 and examples 11-16 were modified not to perform the pellet making process, but to modify each pellet making process to mix and granulate each solid material in a powder that can pass through 120 mesh directly in the subsequent step with sugar/sugar alcohols, salts, etc., final mixing with lubricants, tableting. As a result, it was found that the tablet thus obtained had no significant change in initial hardness, friability, moisture absorption rate, disintegration time, etc., but had significant changes in hardness and friability after 5 months of stable treatment, with a decrease in hardness and an increase in weight loss percentage of 100% or more.
Example 7: preparing memantine hydrochloride orally disintegrating tablet or tamsulosin hydrochloride orally disintegrating tablet
The compounding and processing were substantially as described in examples 1-6 and examples 11-16, respectively, except that: the salts are dissolved in a binder solution for use in a fluid bed granulator. The physicochemical properties of the obtained orally disintegrating tablet were as follows:
the hardness is within the range of 4-6 kg;
the content uniformity CV percent is within the range of 1-2.5 percent;
friability: no fracture, crack or crushed piece exists, and the weight loss is within the range of 0.3-0.7%;
the moisture absorption rate is less than 12.5 percent;
the disintegration time is less than 45 seconds;
dissolution rate: the dissolution rate is less than 15% in 15 minutes; the tablet with the slow release characteristic has 50% dissolution difference smaller than 12.5%, and shows a first-order release curve within 10-18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are unchanged, and the weight loss reduction increase percentage is less than 15%.
Example 7 a: preparing memantine hydrochloride orally disintegrating tablet or tamsulosin hydrochloride orally disintegrating tablet
The compounding and processing were substantially as described in examples 1-6 and examples 11-16, respectively, except that: instead, the salts are added in powder form by mixing at the stage of lubricant addition. The physicochemical properties of the obtained orally disintegrating tablet were substantially the same as those of example 7 and the corresponding tablet.
Example 8: preparing memantine hydrochloride orally disintegrating tablet or tamsulosin hydrochloride orally disintegrating tablet
The compounding and processing were substantially as described in examples 1-6 and examples 11-16, respectively, except that: mixing excipient sugar and/or sugar alcohol, and salt, granulating with binder solution in fluidized bed granulator, drying, mixing the obtained granules with coated pellet and lubricant to obtain final mixed granule, and tabletting. The physicochemical properties of the obtained orally disintegrating tablet were as follows:
the obtained orally disintegrating tablet has the following physicochemical properties:
the hardness is within the range of 4-6 kg;
the content uniformity CV percent is within the range of 1-2.5 percent;
friability: no fracture, crack or crushed piece exists, and the weight loss is within the range of 0.3-0.6%;
the moisture absorption rate is less than 12 percent;
the disintegration time is less than 40 seconds;
dissolution rate: the dissolution rate is less than 15% in 15 minutes; the 50% dissolution difference of the tablets with the slow release characteristic is less than 12.5%, and the tablets all present a first-order release curve within 10-18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are unchanged, and the weight loss reduction increase percentage is less than 15%.
In addition, in example 8, when salts were added to the binder solution for wet granulation, the physicochemical properties of the tablets thus obtained were substantially the same as those of the tablets of example 8 described above.
Example 8 a: preparing memantine hydrochloride oral disintegrating tablet or tamsulosin hydrochloride oral disintegrating tablet
Ingredients and processes reference essentially to example 8, except that: instead, the salts are added in powder form by mixing at the stage of lubricant addition. The physicochemical properties of the obtained orally disintegrating tablet were substantially the same as those of the tablet of example 8.
Example 21: preparing orally disintegrating tablet
Referring to the formulation and preparation of example 1 of the present invention, except that the active ingredient therein was replaced with one of the following drugs: olanzapine, mirtazapine, risperidone, donepezil hydrochloride, aripiprazole, zolpidem tartrate, zolmitriptan, zaleplon, galantamine hydrobromide, aclzolam, alprazolam, methylphenidate, milnacipran, sodium valproate, flupirtine, and the like,
Ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, and,
Chlorpheniramine maleate, loratadine,
Quinidine nitrate, digitoxin, propafenone hydrochloride, procainamide, nisoldipine, glipizide, glimepiride,
Famotidine, ranitidine, cimetidine, sucralfate, sulpiride, teprenone, praanotol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, domperidone, racecadotril, tolmetin, sulpiride, tiotropine, tolmetin, 5-one, tolmetin, and its,
Pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin,
Doxazosin and terazosin respectively to obtain orally disintegrating tablets of each medicine.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the large and small active drug particles obtained in the step (1) is within the range of 0.98-1.01;
the average particle size of the enteric sustained-release pellets obtained in the step (3) is 140-165 mu m, and the particle size of more than 95% of particles is 100-130 mu m;
hardness: 4.8-5.7 kg;
the content uniformity CV percent is within the range of 0.61-1.7 percent;
friability: no fracture, crack and crushed pieces, and the weight loss reduction amount is less than 0.6 percent;
moisture absorption rate: are all less than 12 percent;
disintegration time: are all less than 45 seconds;
dissolution rate: the dissolution rate is less than 15% in 15 minutes, the 50% dissolution difference is less than 7%, and the first-order release curves are formed within 10-18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss reduction increase percentage is less than 18 percent.
Example 22: preparation of orally disintegrating tablets
Referring to the formulation and preparation method of example 3 of the present invention, except that the active ingredient therein was replaced with one of the drugs listed in example 21, orally disintegrating tablets of each drug were obtained, respectively.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the active drug particles obtained in the step (1) is within the range of 0.98-1.03;
the average particle size of the enteric sustained-release pellets obtained in the step (3) is 110-160 mu m, and the particle size of more than 95% of particles is 80-240 mu m;
hardness: 4.6-6 kg;
the content uniformity CV percent is within the range of 0.55 to 1.8 percent;
friability: no fracture, crack and crushed pieces, and the weight loss reduction amount is less than 0.6 percent;
moisture absorption rate: are all less than 12 percent;
disintegration time: are all less than 50 seconds;
dissolution rate: the dissolution rate is less than 15% in 15 minutes, the 50% dissolution difference is less than 7%, and the first-order release curves are formed within 10-18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are unchanged, and the weight loss reduction increase percentage is less than 16%.
Example 23: preparation of orally disintegrating tablets
Referring to the formulation and preparation method of example 6 of the present invention, except that the active ingredient therein was replaced with one of the drugs listed in example 21, orally disintegrating tablets of each drug were obtained, respectively.
The properties of the intermediate material and the physicochemical properties of the obtained memantine hydrochloride orally disintegrating tablet in this example were determined, and the results were as follows:
the content ratio of the active drug particles obtained in the step (1) is within the range of 0.97-1.02;
the average particle size of the enteric sustained-release pellets obtained in the step (3) is 130-160 mu m, and the particle size of more than 95% of particles is 90-250 mu m;
hardness: 4.6-5.9 kg;
the content uniformity CV percent is within the range of 0.6 to 1.7 percent;
friability: no fracture, crack and crushed pieces, and the weight loss reduction amount is less than 0.5 percent;
moisture absorption rate: are all less than 12 percent;
disintegration time: are all less than 45 seconds;
dissolution rate: the dissolution rate is less than 15% in 15 minutes, the 50% dissolution difference is less than 7%, and the dissolution rates are in a first-order release curve within 10-18 hours.
After 5 months of stability handling, tablets: the hardness, friability, moisture absorption rate, disintegration time and dissolution rate are all unchanged, and the weight loss reduction increase percentage is less than 15%.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims (9)

1. An orally disintegrating tablet, which is a tablet compressed by a tabletting process; the tablet comprises a tablet matrix composed of a plurality of excipients, and a plurality of coated pellets substantially uniformly dispersed in the tablet matrix; the coated pellet comprises a pellet core containing active ingredients and two coatings covering the surface of the pellet core, wherein a slow release coating layer and an enteric coating layer are respectively arranged from inside to outside; the pellet core of the coated pellet is a microcrystalline cellulose pellet core; the active ingredient is basically and evenly coated on the surface of the pill core after being mixed with a binding agent into a solution or a suspension, or the active ingredient is evenly mixed with microcrystalline cellulose and then added with the solution or the suspension containing the binding agent to be made into the pill core by a stirring granulation method or a fluidized bed granulation method so that the active ingredient is basically and evenly dispersed in the pill core, the solvent for preparing the solution or the suspension is water and organic solvent is not included; wherein:
the average particle size of the coated pellets is 100-300 mu m;
the weight of the coated pellets accounts for 5-25% of the total weight of the orally disintegrating tablet;
the weight of the active ingredients accounts for 5-20% of the total weight of the coated pellet;
the excipients forming the tablet matrix include excipients selected from the group consisting of: mannitol, lactose, sucrose, maltose, trehalose, sorbitol, and combinations thereof;
the excipients forming the tablet matrix also include salts selected from the following: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and a combination thereof, wherein the weight of the salts is 2-10% of that of the orally disintegrating tablet;
the active ingredient is selected from:
tamsulosin, tamsulosin hydrochloride, memantine,
Olanzapine, mirtazapine, risperidone, donepezil, aripiprazole, zolpidem, zolmitriptan, zaleplon, galantamine, and mixtures thereof,
Omeprazole, lansoprazole, famotidine, ranitidine, cimetidine, sucralfate, sulpiride,
Domperidone, racecadotril, loratadine,
Nisoldipine, salbutamol sulfate, glipizide, glimepiride,
Granisetron, ondansetron, ramosetron, azasetron,
Alizolam, alprazolam, methylphenidate, milnacipran, sodium valproate,
Chlorpheniramine, quinidine nitrate, digitoxin,
Propafenone hydrochloride, procainamide, teprenone, praenotol, 5-aminosalicylic acid, sulfasalazine, prochloraz, and optionally,
Pravastatin sodium, simvastatin, lovastatin, fluvastatin, atorvastatin;
the orally disintegrating tablet is prepared by the method comprising the following steps:
i) coating the active ingredients on the surface of the pellet core or dispersing the active ingredients in the pellet core uniformly, and coating the obtained drug-containing pellet core to prepare a coated pellet; and
ii) mixing said coated pellets with said salt and excipients forming said tablet matrix and tabletting;
wherein step ii) is performed according to the following iia) or iib):
iia) mixing the coated pellets with an excipient, spraying a binder solution into the mixed material by using a fluidized bed granulation process to make wet granules and dry the wet granules, adding a lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salts are added in three ways selected from: added by mixing with coated pellets together with excipients, added by adding to a binder solution, added in the form of powder at the stage of adding lubricant;
iib) spraying a binder solution into the excipient by using a fluidized bed granulation process to perform wet granulation and drying, adding coated pellets and a lubricant into the obtained dry granules, uniformly mixing, and tabletting; wherein the salts are added in three ways selected from the following: by adding the lubricant in the form of powder at the stage of adding the lubricant, by mixing with an excipient and preparing granules, by adding the mixture to a binder solution, or by adding the mixture to a lubricant.
2. The orally disintegrating tablet of claim 1, said binder used to prepare said pellet core is a polymeric substance selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone, polyvinyl alcohol, and combinations thereof.
3. The orally disintegrating tablet of claim 1, wherein the tablet weight of the orally disintegrating tablet is 100 to 500 mg.
4. The orally disintegrating tablet of claim 1, wherein said excipients forming said tablet matrix comprise a binder, which is the same as the binder used in the preparation of the coated pellets or which is the same as a sugar or sugar alcohol as an excipient.
5. The orally disintegrating tablet of claim 1, wherein the tablet is prepared by preparing a solution of one or more of sugar and sugar alcohol as an excipient with water as a binder, mixing the coated pellets with the excipient, and granulating the mixture with the binder solution.
6. The orally disintegrating tablet of claim 4, wherein the binder forming the tablet matrix is one or more selected from the group consisting of: maltose, trehalose, sorbitol, maltitol, mannitol, sucrose, polyvinylpyrrolidone.
7. The orally disintegrating tablet of claim 1, wherein the excipients forming the tablet matrix further comprise a disintegrant selected from the group consisting of: corn starch, carboxymethylcellulose calcium, pregelatinized starch, cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, cross-linked povidone, low-substitution hydroxypropylcellulose.
8. The orally disintegrating tablet of claim 1, wherein the excipients forming said tablet base further comprise sweeteners, colorants.
9. The orally disintegrating tablet of claim 1, wherein the excipients forming the tablet matrix further comprise a lubricant selected from the group consisting of: magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and combinations thereof.
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