CN103656654A - Instant orally-disintegrating tablet and its preparation method - Google Patents
Instant orally-disintegrating tablet and its preparation method Download PDFInfo
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Abstract
The invention discloses an instant orally-disintegrating tablet. According to the invention, a soft material is prepared from active pharmaceutical ingredients, a disintegrating agent which uses nanometer cellulose and modified nanometer cellulose, and other adjuvant for the tablet; any one selected from the group of a single-punch tablet press, a single punch and impact type tablet press and a multiple-punch tablet press is used for pressing so as to prepare the tablet; the tablet has hardness of 39 to 79 N and mass in a range of 200 to 5000 mg and can be rapidly disintegrated and dissolved in an oral cavity within 15 to 30 s. The tablet is convenient to take, has good taste and no grit-like taste and causes no irritation to the mucous membrane of the mouth. The used nanometer cellulose is nanometer microcrystalline cellulose which is white or white-like, odorless, tastelessness, crystalline and flowing powder; the used modified nanometer cellulose is modified nanometer microcrystalline cellulose which is prepared from nanometer microcrystalline cellulose through an esterification reaction, an oxidation reaction and a substitution reaction; the nanometer cellulose and the modified nanometer cellulose are in the shape of a rod and have length of 1 to 500 nm, width of 1 to 30 nm and a length-diameter ratio of 1 to 100, and the usage amounts of the nanometer cellulose and the modified nanometer cellulose are in a range of 1 to 30%.
Description
technical field
?the present invention relates to a kind of oral cavity disintegration tablet and preparation method thereof, relate in particular to a kind of instant oral cavity disintegration tablet and preparation method thereof, belong to technical field of medicine.
Background technology
Tablet means after medicine and proper auxiliary materials are evenly mixed suppresses round sheet or the special-shaped lamellar solid preparation forming, and in can supplying, takes.Tablet be take oral conventional tablet as main, and it is one of dosage form being most widely used in modern medicines preparation.Tablet is compared with other dosage form to be had advantages of a lot, wherein takes, carries, transportation etc. is more convenient is one of its advantage.Along with the prolongation of mankind's average life and the decline of age growth swallow, according to estimates, approximately there is 50% people, especially the elderly patients of dysphagia have any problem to the tablet of swallowing; Infant, child patient and coma patient are difficult for the tablet of swallowing; Mental patient, especially acute attack patient do not swallow because they are usually hidden in Sublingual by tablet, after medical worker walks, tell, and this will affect the curative effect of curing the disease adversely.In addition the oral tablet that wants to swallow under the ambient conditions that, field work person or traveller fetch water in inconvenience is also a difficult thing.Therefore, the problem of swallowing of oral tablet, has caused the concern of pharmaceutical preparation Producer, and has become one of problem urgently to be resolved hurrily.
For not affecting the compliance of Drug therapy, from twentieth century a kind of novel form that grows up the end of the seventies, once be referred to as fast-release tablet, oral cavity quick disintegrating slice etc. abroad, FDA(Food and Drug Admistraton, the Food and Drug Admistraton of FDA (Food and Drug Adminstration) is called for short FDA) the existing unified oral cavity disintegration tablet (orally disintegrating tablets) that is called.Domestic name is once more chaotic, has respectively oral dosage form, oral instant-dissolving tablet, oral cavity quick disintegrating slice etc., existing also unified called after oral cavity disintegration tablet.
Oral cavity disintegration tablet is a kind of special tablet, do not need water or only need use little water, without chewing, tablet is placed in lingual surface, just can be in oral cavity disintegrate (in 15～30s) rapidly, be dispersed or dissolved in saliva, patient only needs several swallowing acts can complete drug administration process, and medicine can enter the tablet of stomach onset.The advantage of the taking convenience of this dosage form, has solved the problem that old people, infant, child patient and coma patient are difficult for swallowing, and can meet the demand in department of pediatrics and geriatrics field; And meet the sick human needs of water inconvenience under special environment, thus greatly improving patient's drug compliance, for general patient, also can improve the quality of living.
At present, the kind of the external oral cavity quick disintegrating slice of having developed is more, there are loratadine (trade name Claritin), acetaminophen, famotidine (trade name PepcidRPD), benzenesulfonic acid rizatriptan (trade name Max2alt), olanzapine (trade name ZyprexaZYDIS), Desloratadine (Aerius, Neoclarityn, Azomyr), risperidone, cetirizine, cisapride, ondansetron and levothyroxine sodium etc.
The oral cavity quick disintegrating slice kind of having gone on the market in China has: granisetron, albuterol, risperidone, ibuprofen, loratadine and ambroxol etc.
Yet the hardness ubiquity of some oral cavity disintegration tablets in China's pharmaceutical preparation market does not reach 19N～69 N, and the easy friability of tablet consequently causes the problem that transportation and storage are inconvenient.
In prior art, disintegrating agent used in the formula of oral cavity disintegration tablet is dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, hydroxypropyl starch, modified starch, microcrystalline Cellulose.Ethyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose.
In prior art, the main technology of preparing of oral cavity disintegration tablet has pressing after freeze-drying, spray drying method, solid solution technology, direct powder compression, wet method pressing and wet granulation, and other technologies of preparing also have half wet process pressed disc method, melt granulation direct compression process, dry granulation direct compression process and direct compression-humidification-seasoning etc.Wherein:
Freeze-drying is that to study be also the comparatively ripe method of preparing oral cavity disintegration tablet the earliest.The oral cavity disintegration tablet of external listing mostly is the method preparation at present.The principle that freeze-drying is prepared oral cavity disintegration tablet is to be frozen into rapidly solid after medicine is made to suspension, then under vacuum condition, from frozen state, without liquid state, directly distils and remove moisture.Products therefrom short texture, the tiny hole of interior richness, thereby the dissolving that can absorb water rapidly.The oral cavity disintegration tablet effect of utilizing freeze drying technology to prepare is fine, and entrance is instant, can in 15s, disintegrate dissolve, and absorbs also fast.But this technology also has the shortcoming of himself.Medicine for the method must meet certain requirement, as dosage and dissolubility etc.Except the restriction of medicine, lyophilization needs large-scale freeze drying equipment when producing, and cost is higher.
Solid solution technology mainly adopts two kinds of solvents.Using the mixture such as gelatin, pectin and glycine etc. as skeleton, add medicine, antioxidant, antiseptic, correctives etc. to be dissolved in the first solvent, then reducing temperature to the first solvent becomes solid-state.Now add the second solvent (the second solvent should can dissolve each other with the first solvent, but can not dissolve each other with skeleton), by the first solvent exchange out, the temperature that then slightly raises makes the second solvent evaporates, obtains the carrier framework of high porosity.This technology is very strict to the selection of medicine, solvent, carrier, meet the following conditions: between (1) medicine, solvent, carrier, nothing interacts; (2) the second solvent freezing point should be higher than the first solvent; (3) medicine and carrier are dissolved in the first solvent, but are insoluble to the second solvent.This kind of medicine skeleton hardness is large compared with freeze-drying product, and can in seconds dissolve.But this technique suitability for industrialized production difficulty is larger, high cost.If employing organic solvent, the residual and safety problem of solvent is also very important.
Because instant oral cavity disintegration tablet has vast market for old, pediatrics, therefore pharmaceutical preparation industry is urgently developed a kind of higher hardness at present, friability greatly reduces and has oral cavity disintegration tablet of intraorally rapidly disintegrating and preparation method thereof, the weak point existing to overcome prior art.
Summary of the invention
Object of the present invention, the weak point existing for prior art, provide a kind of by active pharmaceutical ingredient (principal agent) with nano micro crystal cellulose, modified Nano microcrystalline Cellulose evenly makes the soft material of tablet after mixing as disintegrating agent and other additive of tablet, adopt the preparation method of common prilling process and tablet machine compressed tablets, and make a kind of instant oral cavity disintegration tablet, this tablet is the tabletting tablet that bears 30N and the compacting of 75N pressure, its hardness reaches 39N～79N, every tablet quality is within the scope of 200～5000mg, this disintegrating tablet does not need water or only need use little water, without chewing, tablet is placed in lingual surface, just can disintegrate and dissolving rapidly in oral cavity in 15～30s.
Another object of the present invention, is to provide a kind of preparation method of instant oral cavity disintegration tablet, and the party's preparation method is for adopting cost low, and technical process is simple and be easy to realize the preparation method of common prilling process and the tablet machine compressed tablets of suitability for industrialized production.
For achieving the above object, the technical scheme adopting is in the present invention:
An instant oral cavity disintegration tablet, is comprised of active pharmaceutical ingredient and additive of tablet, and wherein additive of tablet comprises disintegrating agent, filler, binding agent, lubricant and correctives, described disintegrating agent, it is conventional dried starch, carboxymethyl starch sodium (CMC-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa), polyvinylpolypyrrolidone (PVPP), gas-producing disintegrant and surfactant, is characterized in that:
Described active pharmaceutical ingredient, be selected from the active pharmaceutical ingredient amoxicillin of antibiolics amoxicillin, for analgesia and antipyretic aspirin active pharmaceutical ingredient aspirin, be used for intestinal infection as the active pharmaceutical ingredient berberine hydrochloride of the berberine hydrochloride of gastroenteritis, there is antiinflammatory, indomethacin active pharmaceutical ingredient indomethacin and the antianaphylactic loratadine active pharmaceutical ingredient loratadine of analgesia and the performance of bringing down a fever, described disintegrating agent, for nano micro crystal cellulose and modified Nano microcrystalline Cellulose, by the active pharmaceutical ingredient of selecting, respectively with nano micro crystal cellulose or modified Nano microcrystalline Cellulose disintegrating agent and other filler, binding agent, lubricant and correctives adjuvant mix system batching, wet granulation, dry, granulate, adopt conventional tablet machine, with 30N or 75N pressure tabletting, the amoxicillin making respectively, aspirin, berberine hydrochloride, the instant oral cavity disintegration tablet of indomethacin and loratadine, it is 1%～30% that described disintegrating agent accounts for tablet weight percentage ratio, the hardness of measuring tablet with Meng Shandou (Monsanto) durometer is 39N～79N, every tablet quality is within the scope of 200～5000mg, tablet can be in the quick disintegrate of 15～30s and dissolving in oral cavity.
Described amoxicillin, aspirin, berberine hydrochloride, indomethacin and loratadine, its active pharmaceutical ingredient and chemical name are as follows respectively:
Amoxicillin, active pharmaceutical ingredient amoxicillin, chemical name (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino] three hydrations of-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid, molecular formula C
16h
19n
3o
5s3H
2o, molecular weight 419.46, is Penicillin antibiotics;
Aspirin, active pharmaceutical ingredient aspirin, chemical name Aspirin, molecular formula C
9h
8o
4, molecular weight 180.16, for analgesia and antipyretic;
Berberine hydrochloride, active ingredient hydrochloric acid berberine, chemical name 5,6-dihydro-9,10-dimethoxy phenyl [g]-1,3-benzo dioxole [5,6-α] quinolizine chlorination dihydrate, molecular formula C
20h
18cLNO
42H
2o, molecular weight 407.85, is anti-enteritis class antimicrobial drug;
Indomethacin, active pharmaceutical ingredient indomethacin, chemical name: 2-methyl isophthalic acid-(4-chlorobenzene formacyl)-5-methoxyl group-1H-indole-3-acetic acid, molecular formula: C
19h
16cINO
4molecular weight: 357.79, arthritis, can alleviating pain and swelling, soft tissue injury and inflammation;
Loratadine active pharmaceutical ingredient loratadine, chemical name 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-alkene)-1-piperidine carboxylate, molecular formula C
22h
23clN
2o
2, molecular weight 382.89, for antiinflammatory class medicine, is usually used in allergic rhinitis and urticaria.
Described nano micro crystal cellulose disintegrating agent, by leaf wood wood fiber raw material, adopt mechanical treatment to make, or enzyme (bioanalysis) is processed, or acid hydrolysis makes white or off-white color, odorless, tasteless crystalline mobile powder, its planform is bar-shaped, length is 1～500nm, width is 1～30nm, draw ratio 1～100, and consumption is 1%～30% (percentage by weight).
Described modified Nano microcrystalline Cellulose disintegrating agent, by nano micro crystal cellulose, by esterification, oxidation reaction, substitution reaction, make its surface contain sulfonic group, or carboxymethyl, or carboxyl, or ethoxy, or hydroxypropyl is made sulfonic group nano micro crystal cellulose, carboxymethyl nano micro crystal cellulose, carboxyl nano micro crystal cellulose, ethoxy nano micro crystal cellulose and hydroxypropyl nano micro crystal cellulose, its length is 1～500nm, width is 1～30nm, draw ratio 1～100, and consumption is 1%～30% (percentage by weight).
Described additive of tablet, comprises filler, other disintegrating agent, and binding agent, lubricant and correctives are for separating agent, wherein:
Described filler, for mannitol, sugar part xylitol, sorbose, sucrose, lactose, maltose alcohol, starch, microcrystalline Cellulose, dextrin, calcium phosphate, calcium hydrogen phosphate, gelatin, amylum pregelatinisatum, calcium sulfate, calcium carbonate, optional wherein a kind of or wherein several combination filleies, consumption 20%～95%(weight percent meter);
Described other disintegrating agent is dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, hydroxypropyl starch, modified starch, microcrystalline Cellulose, ethyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, one or any several combinations in optional, wherein: described dried starch, be divided into Nei Jia and additional two kinds of usages, inside with dried starch amount, account for disintegrating agent total amount 50%～75% (percentage by weight), additional dried starch amount accounts for disintegrating agent total amount 25%～50%, described carboxymethyl starch sodium consumption 1%～10%, hydroxypropyl content 5%～25% in described low-substituted hydroxypropyl cellulose, described low-substituted hydroxypropyl cellulose consumption 1%～8% (percentage by weight),
Described binding agent, for starch slurry, dextrin, cellulose derivative comprises sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose (HPMC), gelatin, sucrose, polyethylene adjoin the one or any several combinations in pyrrolidone, consumption 0.001%～2% (percentage by weight), wherein:
Described starch slurry concentration is 5%～20%, described sodium carboxymethyl cellulose concentration 0.5%～3%, described hypromellose concentration 1%～8%, described sucrose concentration 30%～90%, described polyvinylpyrrolidone concentration 1%～8%, the hydroxypropyl content 50%～80% of described hydroxypropyl cellulose, the methoxyl content 25%～35% of described methylcellulose, the ethyoxyl content 40%～55% of described ethyl cellulose;
Described lubricant, is the one or any several combinations in magnesium stearate, micropowder silica gel, Pulvis Talci, sodium stearyl fumarate, hydrogenated vegetable oil, ultra micro polyoxyethylene glycol, month extension alcohol magnesium sulfate, consumption 0.1%～5% (percentage by weight), wherein:
Described magnesium stearate consumption 0.1%～1.5% (percentage by weight), micropowder silica gel consumption 0.1%～1% (percentage by weight), amount of talc 0.1%～5% (percentage by weight), described sodium stearyl fumarate, hydrogenated vegetable oil, ultra micro polyoxyethylene glycol, month extension alcohol magnesium sulfate consumption, be respectively 0.1%～5% (percentage by weight);
Described correctives, is sucralose, aspartame, stevioside, aspartame, citric acid, malic acid, Fructus Citri tangerinae essence, Fructus Citri Limoniae essence and Mint Essence, consumption 0.01～3.0 (percentage by weight).
A preparation method for instant oral cavity disintegration tablet, comprises soft material processed, wet granular processed and tabletting, it is characterized in that: its preparation methods steps comprises 1) formula and 2) soft material and wet granular prepared and the method for compressed tablets, and concrete operations are as follows
1) formula
1-1 active pharmaceutical ingredient consumption, %(percentage by weight) preferable amount, %(percentage by weight)
Amoxicillin 1～60 10～50
(amoxicillin)
Berberine hydrochloride 1～60 10～50
(berberine hydrochloride)
Aspirin 1～60 10～50
(aspirin)
Indomethacin 1～60 10～50
(indomethacin)
Loratadine 1～60 10～50
(loratadine)
1-2 additive of tablet
Disintegrating agent
Nano micro crystal cellulose 1.0～30 5.0～20
Modified Nano microcrystalline Cellulose 1.0～30 5.0～20
Other disintegrating agents (being conventional disintegrating agent)
Carboxymethyl starch sodium 1～10 2～6
Low-substituted hydroxypropyl cellulose 1～8 2～5
(its hydroxypropyl content 5%～25%,
Preferably 10%～15%)
Filler 20～95 50～85
Binding agent 0.001～2.0 0.01～1.5
Binding agent used, wherein
Hydroxypropyl cellulose 0.001～2 0.01～1.5
(wherein hydroxypropyl content 50%～80%)
Methylcellulose 0.001～2 0.01～1.5
(wherein methoxyl content 25%～35%)
Ethyl cellulose 0.001～2 0.01～1.5
(wherein ethyoxyl content 40%～55%)
Lubricant 0.1～1.5 0.1～1.0
Correctives 0.01～3.0 0.1～2.0
2) method of soft material and wet granular preparation and compressed tablets
2-1 soft material and wet granular processed preparation
By formula, take respectively active pharmaceutical ingredient and additive of tablet, cross screen cloth, standby.First disintegrating agent and filler are sieved and mix to obtain adjuvant mixture with the equivalent method of progressively increasing, described screen cloth, its type is Polyamide Yarns, stainless steel silk, galvanized wire, 8～40 meshes;
Active pharmaceutical ingredient is joined to adjuvant mixture, and sieve and mix, add binding agent soft material processed, in soft material, add lubricant, fully mix homogeneously sieves, and soft material is pressed through to suitable screen cloth and once can be made into wet granular, forced air drying, baking temperature is generally 50 ℃～60 ℃ and is advisable, granulate;
The method of 2-2 compressed tablets
Adopt tablet machine by granulate compressed tablets, obtain the instant oral cavity disintegration tablet of complete bright and clean, the non-variegation speckle in surface and foreign body, described tablet machine, selects single punch tablet machine, or one-shot colliding tablet press, or rushes rotary tablet machine more, optionally wherein a kind of.
Beneficial effect
The instant oral cavity disintegration tablet of the present invention, taking convenience, mouthfeel is good, without grit sense, and non-stimulated to oral mucosa, take without water, in oral cavity, disintegrate can improve drug effect and play a role rapidly rapidly, is applicable to the patient of dysphagia and takes under hydropenia environment.The hardness of tablet reaches 39N～79N, without fracture, be full of cracks and pulverizing.Production process does not need special tablet machine, and production cost is low, has both been convenient to packed and transported and has stored, and is convenient to again suitability for industrialized production.
The specific embodiment
Below in conjunction with specific embodiment, the present invention is further described.Below for embodiment should be understood to only illustrate, but not limit the scope of the invention in any form.
Embodiment 1
1) formula
1-1 active pharmaceutical ingredient consumption, %(percentage by weight) preferable amount, %(percentage by weight)
Amoxicillin 1～60 10～50
(amoxicillin)
Berberine hydrochloride 1～60 10～50
(berberine hydrochloride)
Aspirin 1～60 10～50
(aspirin)
Indomethacin 1～60 10～50
(indomethacin)
Loratadine 1～60 10～50
(loratadine)
1-2 additive of tablet
Disintegrating agent
Nano micro crystal cellulose 1.0～30 5.0～20
Modified Nano microcrystalline Cellulose 1.0～30 5.0～20
Other disintegrating agents (being conventional disintegrating agent), wherein
Carboxymethyl starch sodium 1～10 2～6
Low-substituted hydroxypropyl cellulose 1～8 2～5
(its hydroxypropyl content 5%～25%,
Preferably 10%～15%)
Filler 20～95 50～85
Binding agent 0.001～2.0 0.01～1.5
Binding agent used, wherein
Hydroxypropyl cellulose 0.001～2 0.01～1.5
(wherein hydroxypropyl content 50%～80%)
Methylcellulose 0.001～2 0.01～1.5
(wherein methoxyl content 25%～35%)
Ethyl cellulose 0.001～2 0.01～1.5
(wherein ethyoxyl content 40%～55%)
Lubricant 0.1～5 0.3～2.0
Correctives 0.01～3 0.1～2
2) method of soft material and wet granular preparation and compressed tablets
2-1 soft material and wet granular processed preparation
By formula, take respectively active pharmaceutical ingredient and additive of tablet, cross screen cloth, standby.First disintegrating agent and filler are sieved and mix to obtain adjuvant mixture with the equivalent method of progressively increasing, described screen cloth, its type is Polyamide Yarns, stainless steel silk, galvanized wire, 8～40 meshes, the present embodiment is selected stainless steel wire sieve, 8 meshes;
Active pharmaceutical ingredient is joined to adjuvant mixture, and sieve and mix, add binding agent soft material processed, in soft material, add lubricant, 0.5% magnesium stearate, 0.75% aspartame, 0.5% Mint Essence and the abundant mix homogeneously of starch sieve, and soft material is pressed through to 30 eye mesh screens and once can be made into wet granular, granulate, forced air drying temperature is 50 ℃～60 ℃, dry 45min, 55 ℃ of the present embodiment baking temperature designs;
The method of 2-2 compressed tablets
Adopt tablet machine by granulate compressed tablets, obtain complete, bright and clean instant oral cavity disintegration tablet, described tablet machine, select single punch tablet machine, or one-shot colliding tablet press, or rushing wherein a kind of of rotary tablet machine more, the present embodiment is selected and is rushed rotary tablet machine more, compressed tablets under 40N pressure, makes the instant oral cavity disintegration tablet in amoxicillin.
The composition that adds the instant oral cavity disintegration tablet in amoxicillin of nano micro crystal cellulose, in Table 1.
Table 1
| Component | Unit content (mg) | Component percentages |
| Amoxicillin | 72 | 36.00% |
| Nano micro crystal cellulose | 20 | 10.00% |
| Mannose | 98 | 49.00% |
| Polyethylene adjoins pyrrolidone | 1 | 0.50% |
| Sodium carboxymethyl cellulose | 1 | 0.50% |
| Starch | 4.5 | 2.25% |
| Magnesium stearate | 1 | 0.50% |
| Aspartame | 1.5 | 0.75% |
| Mint Essence | 1 | 0.50% |
| Add up to | 200 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79 N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds, and friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Embodiment 2
Repeat the operating procedure step of the preparation method of embodiment 1, be different: select the composition of the instant oral cavity disintegration tablet in amoxicillin that carboxymethyl nano micro crystal cellulose disintegrating agent of the present invention makes identical with embodiment 1 table 1, its quality index is identical with embodiment 1.
Embodiment 3
The operating procedure step that repeats the preparation method of embodiment 1 is different: do not add any disintegrating agent.With the composition of the amoxicillin oral cavity disintegration tablet of disintegrating agent, see part table 2.
Table 2
| Component | Unit content (mg) | Component percentages |
| Amoxicillin | 72 | 42.00% |
| Mannose | 98 | 53.00% |
| Polyethylene adjoins pyrrolidone | 1 | 0.50% |
| Sodium carboxymethyl cellulose | 1 | 0.50% |
| Starch | 4.5 | 2.25% |
| Magnesium stearate | 1 | 0.50% |
| Aspartame | 1.5 | 0.75% |
| Mint Essence | 1 | 0.50% |
| Add up to | 200 | 100% |
Tablet hardness is 9～40 N.Intraoral disintegration time is 0.5～1.5 hour, and the disintegration time in disintegration tester is 0.5～2 hour.Friability is 0.4%～0.8%.Mouthfeel is nice and cool, grittiness sense.
From above-mentioned performance indications, show, do not add the quality of the instant Orally-disintegrating tablet in the prepared amoxicillin of any disintegrating agent far below the index performance of embodiment 1 and embodiment 2.
Embodiment 4
The operating procedure step that repeats the preparation method of embodiment 1 is different: the disintegrating agent of selecting is conventional microcrystalline Cellulose disintegrating agent.The composition that adds the instant oral cavity disintegration tablet in amoxicillin that microcrystalline Cellulose disintegrating agent obtains, in Table 3.
Table 3
| Component | Unit content (mg) | Component percentages |
| Amoxicillin | 72 | 38.00% |
| Mannose | 98 | 48.00% |
| Microcrystalline Cellulose | 18 | 9.00% |
| Polyethylene adjoins pyrrolidone | 1 | 0.50% |
| Sodium carboxymethyl cellulose | 1 | 0.50% |
| Starch | 4.5 | 2.25% |
| Magnesium stearate | 1 | 0.50% |
| Aspartame | 1.5 | 0.75% |
| Mint Essence | 1 | 0.50% |
| Add up to | 200 | 100% |
The tablet of according to said method preparing, tablet hardness is at 19～59 N.Intraoral disintegration time is 25～40 seconds, and the disintegration time in disintegration tester is 30～45 seconds.Friability is 0.3%～0.5%.Mouthfeel is nice and cool, comfortable, without sand type.
From above-mentioned performance indications, show, be added with the quality of the instant chamber of mouth, the prepared amoxicillin of microcrystalline Cellulose disintegrating agent disintegrating agent, far below the index performance of embodiment 1 and embodiment 2.
Embodiment 5
Repeat the operating procedure step of the preparation method of embodiment 1, be different: the active pharmaceutical ingredient of selecting is berberine hydrochloride active component, select nano micro crystal cellulose disintegrating agent of the present invention to mix the disintegrating agent forming, hydroxypropyl content 13% in selected low-substituted hydroxypropyl cellulose with conventional low-substituted hydroxypropyl methylcellulose disintegrating agent.Selected polyvinylpyrrolidone concentration is 5%.Sodium carboxymethyl cellulose concentration used is 2%.The composition of the instant oral cavity disintegration tablet of berberine hydrochloride that the disintegrating agent that adds nano micro crystal cellulose and low-substituted hydroxypropyl methylcellulose to mix composition makes, in Table 4.
Table 4
| Component | Unit content (mg) | Component percentages |
| Berberine hydrochloride | 1800 | 36.00% |
| Nano micro crystal cellulose | 300 | 6.00% |
| Low-substituted hydroxypropyl cellulose | 200 | 4.00% |
| Mannose | 2400 | 48.00% |
| Polyvinylpyrrolidone | 37.5 | 0.75% |
| Sodium carboxymethyl cellulose | 37.5 | 0.75% |
| Starch | 100 | 2.00% |
| Magnesium stearate | 25 | 0.50% |
| Aspartame | 50 | 1.00% |
| Mint Essence | 50 | 1.00% |
| Add up to | 5000 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds.Friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Embodiment 6
Repeat the operating procedure step of the preparation method of embodiment 1, be different: the active pharmaceutical ingredient of selecting is aspirin active component, select nano micro crystal cellulose disintegrating agent of the present invention and mix with carboxymethyl nano micro crystal cellulose the disintegrating agent forming, filler is 0.5% sucralose, and correctives is 0.5% Fructus Citri tangerinae essence, 0.5% Mint Essence.The composition of the instant oral cavity disintegration tablet of prepared aspirin, in Table 5.
Table 5
| Component | Unit content (mg) | Component percentages |
| Aspirin | 76 | 38.00% |
| Nano micro crystal cellulose | 12 | 6.00% |
| Carboxymethyl nano micro crystal cellulose | 8 | 4.00% |
| Lactose | 92 | 46.00% |
| Starch | 4 | 2.00% |
| Sodium carboxymethyl cellulose | 4 | 2.00% |
| Magnesium stearate | 1 | 0.50% |
| Sucralose | 1 | 0.50% |
| Fructus Citri tangerinae essence | 1 | 0.50% |
| Mint Essence | 1 | 0.50% |
| Add up to | 200 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds.Friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Embodiment 7
Repeat the operating procedure step of the preparation method of embodiment 1, be different: the active pharmaceutical ingredient of selecting is aspirin active component, select carboxymethyl nano micro crystal cellulose disintegrating agent of the present invention to mix the disintegrating agent forming, hydroxypropyl content 13% in low-substituted hydroxypropyl cellulose used with conventional low-substituted hydroxypropyl cellulose disintegrating agent.Filler is 0.5% sucralose, and correctives is 0.5% Fructus Citri tangerinae essence, 0.5% Mint Essence.The composition of the instant oral cavity disintegration tablet of prepared aspirin, in Table 6.
Table 6
| Component | Unit content (mg) | Component percentages |
| Aspirin | 76 | 38.00% |
| Carboxymethyl nano micro crystal cellulose | 12 | 6.00% |
| Low-substituted hydroxypropyl cellulose | 8 | 4.00% |
| Lactose | 92 | 46.00% |
| Starch | 4 | 2.00% |
| Sodium carboxymethyl cellulose | 4 | 2.00% |
| Magnesium stearate | 1 | 0.50% |
| Sucralose | 1 | 0.50% |
| Fructus Citri tangerinae essence | 1 | 0.50% |
| Mint Essence | 1 | 0.50% |
| Add up to | 200 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds.Friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Embodiment 8
Repeat the operating procedure step of the preparation method of embodiment 1, be different: the active pharmaceutical ingredient of selecting is indomethacin active component, select carboxyl nano micro crystal cellulose disintegrating agent of the present invention to mix the disintegrating agent forming with conventional crospolyvinylpyrrolidone and hydroxypropyl emthylcellulose disintegrating agent, filler is xylitol, lubricant is 0.5% magnesium stearate, 0.25% Pulvis Talci, correctives is 0.5% aspartame, 0.25% Mint Essence, 0.75% Fructus Citri tangerinae essence, starch, the composition of the instant oral cavity disintegration tablet of prepared indomethacin, in Table 7.
Table 7
| Component | Unit content (mg) | Component percentages |
| Indomethacin | 76 | 38.00% |
| Carboxyl nano micro crystal cellulose | 14 | 7.00% |
| Crospolyvinylpyrrolidone | 8 | 4.00% |
| Xylitol | 92 | 46.00% |
| Starch | 4 | 2.00% |
| Hypromellose | 1.5 | 0.75% |
| Magnesium stearate | 1 | 0.50% |
| Pulvis Talci | 0.5 | 0.25% |
| Aspartame | 1 | 0.50% |
| Mint Essence | 1.5 | 0.25% |
| Fructus Citri tangerinae essence | 0.5 | 0.75% |
| Add up to | 200 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds.Friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Embodiment 9
Repeat the operating procedure step of the preparation method of embodiment 1, be different: the active pharmaceutical ingredient of selecting is loratadine active component, select ethoxy nano micro crystal cellulose of the present invention disintegrate to mix the disintegrating agent forming, hydroxypropyl content 13% in low-substituted hydroxypropyl cellulose used with conventional low substituted hydroxy-propyl fiber disintegrating agent.Filler is dextrin, and correctives is sucralose, Mint Essence, and the composition of the instant oral cavity disintegration tablet of prepared loratadine, in Table 8.
Table 8
| Component | Unit content (mg) | Component percentages |
| Loratadine | 1800 | 36.00% |
| Ethoxy nano micro crystal cellulose | 300 | 6.00% |
| Low-substituted hydroxypropyl cellulose | 200 | 4.00% |
| Lactose | 2200 | 44.00% |
| Sodium carboxymethyl cellulose | 100 | 2.00% |
| Starch | 100 | 2.00% |
| Dextrin | 200 | 4.00% |
| Magnesium stearate | 25 | 0.50% |
| Sucralose | 25 | 0.50% |
| Mint Essence | 50 | 1.00% |
| Add up to | 5000 | 100% |
The tablet of according to said method preparing, tablet hardness is at 39～79N.Intraoral disintegration time is 15～30 seconds, and the disintegration time in disintegration tester is 20～35 seconds.Friability is 0.2%～0.4%.Mouthfeel is nice and cool, comfortable, without sand type.
Make a general survey of embodiment 1,2,5,6,7,8 and 9, selecting in different active pharmaceutical ingredient situations, add and select nano micro crystal cellulose of the present invention, or and carboxymethyl nano micro crystal cellulose disintegrating agent, the instant oral cavity disintegration tablet of the various different activities ingredients that make by soft material processed, granulation and tablet machine, its hardness, disintegration time, friability and mouthfeel, be all better than the instant Orally-disintegrating tablet that embodiment 3 does not add conventional disintegrating agent and embodiment 4 to select conventional microcrystalline Cellulose disintegrating agent to make.Thereby solved problem old, young, child patient dysphagia.Compressed tablets does not need special sheeting equipment, is convenient to suitability for industrialized production.
In the present invention, inventor studies rear discovery to the physical characteristic of the nano micro crystal cellulose as disintegrating agent, nano micro crystal cellulose not only has macromolecular compound structure and the character of similar microcrystalline Cellulose, and with it as the distinctive character of nanoparticle.Further after research, find, the tablet hardness that different nano micro crystal cellulose samples and varigrained nano micro crystal cellulose are suppressed under different pressures, to same raw material, the intensity pressure of its tablet raises and improves.To same raw material, under same pressure, granularity is less, and contact area is larger, and the intensity of tablet is also higher.Nano micro crystal cellulose also easy moisture absorption profit rises, formation coagulant liquid soluble in water.Therefore, using nano micro crystal cellulose as disintegrating agent can be made into that hardness is high, disintegrate oral cavity disintegration tablet rapidly, thereby realized the present invention.
In the present invention, durometer used and friability instrument, be respectively Meng Shandou (Monsanto) durometer and sieve and permitted (Roche) friability instrument.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. an instant oral cavity disintegration tablet, is comprised of active pharmaceutical ingredient and additive of tablet, and wherein additive of tablet comprises disintegrating agent, filler, binding agent, lubricant and correctives, described disintegrating agent, it is conventional dried starch, carboxymethyl starch sodium (CMC-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa), polyvinylpolypyrrolidone (PVPP), gas-producing disintegrant and surfactant, is characterized in that:
Described active pharmaceutical ingredient, be selected from the active pharmaceutical ingredient amoxicillin of antibiolics amoxicillin, analgesia and antipyretic aspirin active pharmaceutical ingredient aspirin, be used for intestinal infection as the active pharmaceutical ingredient berberine hydrochloride of the berberine hydrochloride of gastroenteritis, there is antiinflammatory, the indomethacin active pharmaceutical ingredient indomethacin of analgesia and the performance of bringing down a fever, antiallergic agent loratadine active pharmaceutical ingredient loratadine, described disintegrating agent, for nano micro crystal cellulose and modified Nano microcrystalline Cellulose, by the active pharmaceutical ingredient of selecting, respectively with nano micro crystal cellulose or modified Nano microcrystalline Cellulose disintegrating agent and other filler, binding agent, lubricant and correctives adjuvant mix system batching, wet granulation, dry, granulate, adopt conventional tablet machine, with 30N and 30N with upward pressure tabletting, the amoxicillin making respectively, aspirin, berberine hydrochloride, the instant oral cavity disintegration tablet of indomethacin and loratadine, it is 1%～30% that described disintegrating agent accounts for tablet weight percentage ratio, tablet hardness is 39N～79N, every tablet quality is within the scope of 200～5000mg, tablet can be in the quick disintegrate of 15～30s and dissolving in oral cavity.
2. instant oral cavity disintegration tablet according to claim 1, is characterized in that: described amoxicillin, and aspirin, berberine hydrochloride, indomethacin and loratadine, its active pharmaceutical ingredient and chemical name, as follows respectively:
Amoxicillin, active pharmaceutical ingredient amoxicillin, chemical name (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino] three hydrations of-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid, molecular formula C
16h
19n
3o
5s3H
2o, molecular weight 419.46, is Penicillin antibiotics;
Aspirin, active pharmaceutical ingredient aspirin, chemical name Aspirin, molecular formula C
9h
8o
4, molecular weight 180.16, for analgesia and antipyretic;
Berberine hydrochloride, active ingredient hydrochloric acid berberine, chemical name 5,6-dihydro-9,10-dimethoxy phenyl [g]-1,3-benzo dioxole [5,6-α] quinolizine chlorination dihydrate, molecular formula C
20h
18cLNO
42H
2o, molecular weight 407.85, is anti-enteritis class antimicrobial drug;
Indomethacin, active pharmaceutical ingredient indomethacin, chemical name: 2-methyl isophthalic acid-(4-chlorobenzene formacyl)-5-methoxyl group-1H-indole-3-acetic acid, molecular formula: C
19h
16cINO
4molecular weight: 357.79, arthritis, can alleviating pain and swelling, soft tissue injury and inflammation;
Loratadine active pharmaceutical ingredient loratadine, chemical name 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-alkene)-1-piperidine carboxylate, molecular formula C
22h
23clN
2o
2, molecular weight 382.89, for antiinflammatory class medicine, is usually used in allergic rhinitis and urticaria.
3. instant oral cavity disintegration tablet according to claim 1, is characterized in that: described nano micro crystal cellulose disintegrating agent, by leaf wood wood fiber raw material, employing mechanical treatment makes, or enzyme (bioanalysis) processing, or acid hydrolysis makes white or off-white color, odorless, tasteless crystalline mobile powder, its planform is bar-shaped, and length is 1～500nm, and width is 1～30nm, draw ratio 1～100, consumption is 1%～30% (percentage by weight).
4. instant oral cavity disintegration tablet according to claim 1, it is characterized in that: described modified Nano microcrystalline Cellulose disintegrating agent, by nano micro crystal cellulose, passing through esterification, oxidation reaction, substitution reaction makes its surface contain sulfonic group, or carboxymethyl, or carboxyl, or ethoxy, or hydroxypropyl is made sulfonic group nano micro crystal cellulose, carboxymethyl nano micro crystal cellulose, carboxyl nano micro crystal cellulose, ethoxy nano micro crystal cellulose and hydroxypropyl nano micro crystal cellulose, its length is 1～500nm, width is 1～30nm, draw ratio 1～100, consumption is 1%～30% (percentage by weight).
5. instant oral cavity disintegration tablet according to claim 1, is characterized in that: described additive of tablet, comprise filler, and other disintegrating agent, binding agent, lubricant and correctives, wherein:
Described filler, for mannitol, sugar part xylitol, sorbose, sucrose, lactose, maltose alcohol, starch, microcrystalline Cellulose, dextrin, calcium phosphate, calcium hydrogen phosphate, gelatin, amylum pregelatinisatum, calcium sulfate, calcium carbonate, optional wherein a kind of or wherein several combination filleies, consumption 20%～95%(weight percent meter);
Described other disintegrating agent, for dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, hydroxypropyl starch, modified starch, microcrystalline Cellulose, ethyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, one or any several combinations in optional, wherein: described carboxymethyl starch sodium consumption 1%～10%, hydroxypropyl content 5%～25% in described low-substituted hydroxypropyl cellulose, described low-substituted hydroxypropyl cellulose consumption 1%～8% (percentage by weight);
Described binding agent, for starch slurry, dextrin, cellulose derivative comprises sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose (HPMC), gelatin, sucrose, polyethylene adjoin the one or any several combinations in pyrrolidone, consumption 0.001%～2% (percentage by weight), wherein:
Described sodium carboxymethyl cellulose concentration 0.5%～3%, described hypromellose concentration 1%～8%, described sucrose concentration 30%～90%, described polyvinylpyrrolidone concentration 1%～8%, the hydroxypropyl content 50%～80% of described hydroxypropyl cellulose, the ethyoxyl content 40%～55% of ethyl cellulose described in the methoxyl content 25%～35% of described methylcellulose;
Described lubricant, for magnesium stearate, micropowder silica gel, Pulvis Talci, sodium stearyl fumarate, hydrogenated vegetable oil, ultra micro polyoxyethylene glycol, the moon is hung the one or any several combinations in alcohol magnesium sulfate, consumption 0.1%～5% (percentage by weight), wherein: described magnesium stearate consumption 0.1%～1.5% (percentage by weight), micropowder silica gel consumption 0.1%～1% (percentage by weight), amount of talc 0.1%～5% (percentage by weight), described sodium stearyl fumarate, hydrogenated vegetable oil, ultra micro polyoxyethylene glycol, hang alcohol magnesium sulfate consumption the moon, be respectively 0.1%～5% (percentage by weight),
Described correctives, is sucralose, aspartame, stevioside, aspartame, citric acid, malic acid, Fructus Citri tangerinae essence, Fructus Citri Limoniae essence and Mint Essence, consumption 0.01～3.0% (percentage by weight).
6. for realizing the preparation method of instant oral cavity disintegration tablet described in claim 1, comprise soft material processed, wet granular processed and tabletting, it is characterized in that: its preparation methods steps comprises 1) formula and 2) soft material and wet granular prepared and the method for compressed tablets, and concrete operations are as follows:
1) formula
1-1 active pharmaceutical ingredient consumption, %(percentage by weight) preferable amount, %(percentage by weight)
Amoxicillin 1～60 10～50
(amoxicillin)
Berberine hydrochloride 1～60 10～50
(berberine hydrochloride)
Aspirin 1～60 10～50
(aspirin)
Indomethacin 1～60 10～50
(indomethacin)
Loratadine 1～60 10～50
(loratadine)
1-2 additive of tablet
Disintegrating agent
Nano micro crystal cellulose 1.0～30 5.0～20
Modified Nano microcrystalline Cellulose 1.0～30 5.0～20
Other disintegrating agents (being conventional disintegrating agent), wherein
Carboxymethyl starch sodium 1～10 2～6
Low-substituted hydroxypropyl cellulose 1～8 2～5
(wherein hydroxypropyl content 5%～25%
Preferably 10%～15%)
Filler 20～95 50～85
Binding agent 0.001～2 0.01～1.5
Binding agent used, wherein
Hydroxypropyl cellulose 0.001～2 0.01～1.5
(wherein hydroxypropyl content 50%～80%)
Methylcellulose 0.001～2 0.01～1.5
(wherein methoxyl content 25%～35%)
Ethyl cellulose 0.001～2 0.01～1.5
(wherein ethyoxyl content 40%～55%)
Lubricant 0.1～5 0.3～1
Correctives 0.01～3 0.1～2
2) method of soft material and wet granular preparation and compressed tablets
2-1 soft material and wet granular processed preparation
By the load weighted additive of tablet fine powder of formula, be mixed, standby, first disintegrating agent and filler are sieved and mix to obtain adjuvant mixture with the equivalent method of progressively increasing, described screen cloth, its type is Polyamide Yarns, stainless steel silk, galvanized wire, 8～40 meshes;
Active pharmaceutical ingredient is joined to adjuvant mixture, and sieve and mix, add binding agent soft material processed, in soft material, add lubricant, 0.5% magnesium stearate, 0.75% aspartame, 0.5% Mint Essence and the abundant mix homogeneously of starch sieve, and soft material is pressed through to 30 eye mesh screens and once can be made into wet granular, granulate, forced air drying temperature is 50 ℃～60 ℃, dry 45min, granulate;
The method of 2-2 compressed tablets
Adopt tablet machine by granulate compressed tablets, obtain complete, bright and clean instant oral cavity disintegration tablet, described tablet machine, select the single punch tablet machine that drug preparation technique is conventional, or one-shot colliding tablet press, or rush rotary tablet machine more, optionally wherein a kind of, its pressure is more than 30N.
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