CN102579415A - Agomelatine-containing medicinal composition for oral mucosa or sublingual administration - Google Patents
Agomelatine-containing medicinal composition for oral mucosa or sublingual administration Download PDFInfo
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Abstract
The invention discloses an agomelatine-containing medicinal composition for oral mucosa or sublingual administration and a preparation method thereof. The medicinal composition consists of a main medicament of which the particle diameter is 48-250 mum and is preferably 48-150 mum, and medicinal auxiliary materials. The medicinal composition can be prepared through a simple preparation process without special production equipment, has low manufacturing cost, and is suitable industrial production; moreover, the use compliance of a patient is improved through the excitement of the taken medicament in an oral cavity; and the medicinal composition is absorbed directly through oral mucosa, so that the first pass effect of the conventional oral medicament is avoided, and the bioavailability is high.
Description
Technical field
The present invention relates to the pharmaceutical composition of agomelatine, be specifically related to a kind of main oral or hypoglossis mucous membrane and absorb agomelatine sheet of rapid onset and preparation method thereof.
Background technology
The listing of agomelatine is a new breakthrough in treating depression field.Its novelty is the mechanism of action that it is unique.It is that (MT1, the MT2) agonist of receptor also are the antagonisies of serotonin 2c (5-HT2c) receptor to global first melatonin 1,2 simultaneously.The drug mechanism of agomelatine and the antidepressant drug that generally adopts at present as: selective serotonin reuptake inhibitor (SSRI) and 5-hydroxy tryptamine-NRI (SNRI) are fully different: the antidepressant drug of SSRI and SNRI class antidepressants is realized the antidepressant curative effect through increase 5-hydroxy tryptamine concentration; But this has also brought many side effect; Change like body weight; Sexual dysfunction, withdrawal syndrome etc.And the drug molecular structure of agomelatine is direct and serotonin 2c (5-HT2c) receptors bind of nerve synapse caudacoria, thereby brings into play its antidepressant curative effect, and does not increase the 5-hydroxy tryptamine concentration of synaptic space.The mechanism of action of this uniqueness makes agomelatine when bringing into play its antidepressant curative effect quickly and effectively, has avoided the generation of drug side effect to greatest extent.
The another one unique effect target spot of agomelatine is at melatonin receptors.MT1, MT2 receptor dense distribution be at the mankind's suprachiasmatic nucleus, the sleep rhythm that this nerve nucleus major control is human.Agomelatine is the agonist of MT1, MT2 receptor, and through the agonism to MT1, MT2 receptor, agomelatine has improved patient's sleep quality well, improves patient's wakefulness in the daytime simultaneously.The relation that lapses to reciprocal causation of dormant quality and depression.It is reported that 80% patients with depression all exists the problem of sleep disorder to some extent.The improvement of sleep quality has directly promoted the improvement of patients with depression overall clinical situation.
Yet clinical research shows that the by oral route administration is serious through the agomelatine liver first-pass effect of gastrointestinal absorption; Bioavailability is very low; Be generally 2-4%, be lower than 5%, and between same individuality and Different Individual, all exist difference.Therefore will obtain effective blood drug level in vivo, the dosage of oral administration must maintain a higher level.Include the age at 18～56 years old at one, the major depression obstacle be outbreak first or recurrence in the clinical research participated in to the major depressive disorder adult patients, oral administration once a day during 25-50mg the clinical effectiveness of these article remarkable.But under this dosage, these article have increased the intravital transaminase level of patient.Clinical research shows that for curing depression preferably, the patient should accept at least 6 months long-term treatment, though the report of taking hepatic injury that these article cause and related pathologies thereof at present also seldom, uses the liver function situation that will watch out for the patient before the treatment of these article.
In a carcinogenecity research of agomelatine, when the high dose administration, agomelatine has increased the sickness rate of liver tumor, and has also highly strengthened the risk of optimum mammary gland fibroadenoma morbidity.
In addition; The preparation such as oral tablet, capsule and the dispersible tablet that are known that the agomelatine of oral administration need to go into the onset of blood ability through gastrointestinal absorption; The peak value of blood drug level just can reach in the back of taking medicine in 1 to 2 hour; Onset is slow, and edible high-fat food can strengthen the difference between individuality; Simultaneously, these preparations need just can be swallowed by water.This suicidal tendency that possibly occur at any time for the major depression impaired patients is very disadvantageous.Though need not use water delivery service after the oral cavity disintegration tablet administration, but still need through gastrointestinal absorption, onset is slower, has first pass effect equally.
Therefore, thereby onset rapidly being provided, significantly improve oral mucosa or the pharmaceutical composition that the Sublingual absorbs that bioavailability and curative effect reduce the agomelatine of therapeutic dose, is very necessary for the patient provides a kind of new treatment to select.
Oral mucosa or Sublingual be hypoglossis mucous membrane particularly, and capillary tube is abundant, and VPV is fast.Medicine oral mucosa particularly hypoglossis mucous membrane absorbs, and directly gets into blood circulation through jugular vein and superior vena cava again, and its onset is rapid, and the first pass effect in the time of can avoiding oral administration improves bioavailability, guarantees curative effect.And, discover that oral mucosa or sublingual administration can increase the distribution of medicine in cerebral tissue, for treatment central nervous system disease such as depressive illness etc. better therapeutic is arranged, for providing a kind of new treatment, the depressive illness patient selects.
But the shortcoming that comes from used active component agomelatine that oral mucosa or sublingual administration have is fairly obvious, and agomelatine can cause significant excitement at oral mucosa or Sublingual.
Well known by persons skilled in the art be used to shelter or reduce medicine the method for the stimulation of mucosa is had following several kinds: (1) teleneuron paralysis method; (2) packaging technique; (3) inclusion technique; (4) microcapsule or microsphere technology; (5) adsorption technology such as ion exchange resin.Wherein method 2-5 avoids or reduces the direct contact of medicine to mucosa.Yet all there is certain shortcoming in these methods when the excitement that is used for agomelatine is sheltered.For example, adopt paralysis method itself can bring certain discomfort, simultaneously; When specifically indicating route of administration and be oral mucosa or Sublingual; Because the area of contact, absorption is less, the local concentration of agomelatine increases, and twinge effect meeting increases the weight of; Add a spot of paralyzant and be difficult to solve excitement, addition is crossed the also corresponding enhancing of discomfort that paralyzant itself at most brings.In addition; Avoid or reduce the strategy of medicine based on coating, enclose, microencapsulation, absorption etc. the direct contact of mucosa; For example one Chinese patent application CN101836966A discloses a kind of oral cavity disintegration tablet of agomelatine, adopts the excitement of inclusion technique masking agents to the oral cavity, though when sheltering agomelatine to the excitement of oral cavity or nasal membrane; Usually can obtain better effect than paralysis method; But the cost of bringing thus is that release, the absorption of medicine delayed, and this layout strategy with the pharmaceutical composition that absorbs rapid, rapid-action agomelatine is inconsistent.
One Chinese patent application CN101919800A disclose a kind of agomelatine oral mucosa or sublingual administration can be in mouth dispersive pharmaceutical composition; Its form that adopts double-layer tablet is with in the medicine centering layer; Or the form through clad sheet is with in the medicine centering nuclear; Thereby alleviate the excitement of medicine, it is very big that the medicines structure of this bilayer/Bao Xin is compared difference with the normal packet garment piece, and its skin does not contain active medicine, and only to contain the structure sheaf of adjuvant thicker; Just through this at first dissolving, thereby reduce the excitement that brings behind the internal layer medicine dissolution than thick outer adjuvant layer.The preparation of this preparation is through bi-layer tablet press or the compacting of bag core tablet machine, and the preparation of this structure can't realize that with ordinary coating technology it prepares process relative complex, to sheeting equipment require high.At present optional on the market bi-layer tablet press or bag core tablet machine remain, problems such as yield low, production efficiency low, manufacturing cost height not solution excessive in the sheet type in suitability for industrialized production, so its industrialization cost of the medicine of this class formation is higher relatively.On the other hand, the solid coating is relatively harsher to index requests such as the compressibility of label, coatings, hardness, broken brittleness, and its application is very limited.
Therefore; Can successfully develop a kind of preparation technology simple, be suitable for suitability for industrialized production; Production cost is low; Simultaneously stingless excitation, good mouthfeel, thus onset rapidly, significantly improve bioavailability and curative effect and reduce the oral mucosa of therapeutic dose or the agomelatine preparation that the Sublingual absorbs, become problem demanding prompt solution.
Summary of the invention
Above-mentioned deficiency to prior art exists the object of the present invention is to provide a kind of preparation technology simple, is suitable for suitability for industrialized production; Production cost is low, and the oral mucosa of the agomelatine of stingless excitation, good mouthfeel or the new formulation of sublingual administration solve the complicated process of preparation that existing oral mucosa administration agomelatine preparation exists simultaneously; The shortcoming that cost is high; Its convenient drug administration, onset is rapid, can significantly improve bioavailability and curative effect; For patient's treatment provides new selection, fill a hole in the market.
Through a large amount of tests; The invention provides a kind of compositions that contains the oral mucosa or the sublingual administration of agomelatine; It comprises particle size range is 48 μ m-250 μ m (65 orders-300 order); Be preferably the agomelatine of 48 μ m-150 μ m (100 orders-300 order), and the available excipient of drug world.
The oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing of the present invention: contain the agomelatine that percentage by weight is 0.1%-4%, the diluent of 46%-99.7%, the lubricant of 0.2%-15%, the disintegrating agent of 0%-15%, the correctives of 0%-5%, the antioxidant of 0%-5%, the opacifier of 0%-5%, the penetration enhancer of 0%-5%.
The available excipient of drug world of the present invention, wherein said diluent are selected from sucrose, lactose, glucose, soluble starch, mannitol, contain the complex of mannitol one or more in (like trade name: Pearlitol Flash,
ODT), sorbitol, lactose, xylitol, microcrystalline Cellulose, saccharide, starch, the dextrin; Said lubricant is selected from one or more in hard ester acid, magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycol 6000, Macrogol 4000, sodium lauryl sulphate, Stepanol MG, fumaric acid sodium stearate, the Compritol 888 ATO; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, menthol, stevioside, glycyrrhizin, aspartame, sucralose, cyclamate, Suo Matian, the glucide; Said antioxidant is selected from one or more in ascorbic acid, sodium sulfite, calcium sulfite, Butylated hydroxyanisole, dibenzylatiooluene, ascorbyl palmitate, propyl gallate, tertiarybutylhydroquinone, the two lauryls of thio-2 acid, vitamin E, tea polyphenols, phytic acid, Radix Glycyrrhizae polyphenoils, phospholipid, the AOB; Described penetration enhancer is selected from polysorbas20, sodium lauryl sulphate, poloxamer F68, benzalkonium chloride, cetrimonium bromide, one or more in sodium glycocholate, sodium deoxycholate, sodium taurocholate, oleic acid, capric acid, lauric acid, LYSOLECITHIN SUNLECITHIN A, the lecithin.
Said " lactose " can be to be the screening lactose through what sieving technology obtained, or through grinding technics obtain for grinding lactose, or be spray-dried lactose, and the pharmaceutical lactose that obtains of other technology through what drying process with atomizing obtained.Said " complex that contains mannitol " is meant that one or more pharmaceutic adjuvants of mannitol and other (like starch, cross-linking sodium carboxymethyl cellulose) mix or is total to the premixing auxiliary material that drying obtains.
Pharmaceutical composition of the present invention further is preferably: contain diluent that percentage by weight is 0.1%-4% agomelatine, 46%-99.7%, 0.2%-15% lubricant, the disintegrating agent of 0%-15%, the correctives of 0%-5%, the antioxidant of 0%-5%, the opacifier of 0%-5%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Wherein said diluent is selected from mannitol, contain in the complex of mannitol, lactose, sorbitol, lactose, the xylitol one or more; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, aspartame, the sucralose; Said antioxidant is selected from one or more in Butylated hydroxyanisole, the dibenzylatiooluene; Said opacifier is selected from one or more in titanium dioxide, ferrum oxide, the magnesium oxide; Said penetration enhancer is selected from one or more among sodium lauryl sulphate, the poloxamer F68.
Pharmaceutical composition of the present invention further is preferably: contain the agomelatine that percentage by weight is 0.67%-4%, the diluent of 79.67%-93.67%, the lubricant of 1%-6%, the disintegrating agent of 0%-8%, the correctives of 0%-4%, the antioxidant of 0%-0.1%, the opacifier of 0%-0.1%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Wherein said diluent is selected from mannitol, contain in the complex of mannitol, lactose, lactose, the xylitol one or more; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, the aspartame; Said antioxidant is Butylated hydroxyanisole; Said opacifier is selected from titanium dioxide; Said penetration enhancer is poloxamer F68.
The present invention also provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing: contain the agomelatine that percentage by weight is 0.67%-4%, the diluent of 79.67%-93.67%, the lubricant of 3%-6%, the disintegrating agent of 0%-8%, the correctives of 0%-4%, the antioxidant of 0%-0.1%, the opacifier of 0%-0.1%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Wherein said diluent is mannitol or the complex that contains mannitol; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, the aspartame; Said antioxidant is Butylated hydroxyanisole; Said opacifier is selected from titanium dioxide; Said penetration enhancer is poloxamer F68.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: contain the agomelatine that percentage by weight is 0.67%-1.33%, the diluent of 90.33%-93.67%, 3% lubricant, the disintegrating agent of 2%-3%, the correctives of 0%-3%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Wherein said diluent is a lactose; Said lubricant is selected from one or more in magnesium stearate, the micropowder silica gel; Said disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose; Said correctives is selected from one or more in citric acid, the acesulfame potassium.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 1.33% agomelatine, the diluent of 86.67%-88.67%, 4% lubricant, the disintegrating agent of 6%-8%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Wherein said diluent is for being lactose and the mixture of mannitol or the mixture of lactose, mannitol and xylitol; Said lubricant is the mixture of fumaric acid sodium stearate and micropowder silica gel; Said disintegrating agent is one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 0.67% agomelatine, 90.33% diluent, 3% lubricant, 3% disintegrating agent, 3% correctives; Wherein said agomelatine particle diameter is 48 μ m-75 μ m; Wherein said diluent is lactose or mannitol; Said lubricant is one or more in micropowder silica gel, the magnesium stearate; Said disintegrating agent is a cross-linking sodium carboxymethyl cellulose; Said correctives is one or more in citric acid, the acesulfame potassium.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 1.33% agomelatine, 90.33% mannitol or lactose, 2% cross-linking sodium carboxymethyl cellulose, 2% magnesium stearate, 1% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 1.33% agomelatine, 79.67% mannitol, 8% crospolyvinylpyrrolidone, 5% poloxamer F68,2% magnesium stearate, 4% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 2% agomelatine, 93% the complex that contains mannitol, 3% magnesium stearate, 2% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
The present invention provides a kind of oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing again: containing percentage by weight is 1.33% agomelatine, 80% mannitol, 6.67% lactose, 8% crospolyvinylpyrrolidone, 1.5% fumaric acid sodium stearate, 2.5% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
The oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing of the present invention can adopt the conventional dry method direct powder compression or the method for wet granule compression tablet technology to prepare.
The oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing of the present invention, it comprises following steps when adopting dry method vertical compression technology:
1) with said principal agent, diluent, lubricant, disintegrating agent, correctives, antioxidant, opacifier, penetration enhancer, pulverizing, the pretreatment of sieving.
2) will pass through pretreated principal agent, diluent, lubricant, disintegrating agent, correctives, antioxidant, opacifier, penetration enhancer mix homogeneously;
3) the above-mentioned material tabletting with mix homogeneously promptly gets.
The oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing of the present invention comprises following steps when adopting the wet granule compression tablet prepared:
1) with said agomelatine and pharmaceutic adjuvant pulverize, the pretreatment of sieving;
2) will pass through pretreated pharmaceutic adjuvant and the pretreated agomelatine mix homogeneously of process;
3) binding agent is added in the above-mentioned material of mix homogeneously, process soft material, granulate drying; Or adopt fluidized bed granulation dry;
4) with dried granule mix homogeneously, tabletting promptly gets.
Wet granule compression tablet technology of the present invention further comprises following steps: be that the pharmaceutic adjuvant of 20%-93.33% mixes (adding promptly) with principal agent with percentage by weight earlier; Add suitable amount of adhesive again and process soft material; The system granule; Drying will remain pharmaceutic adjuvant and the dried granule mix homogeneously (promptly adding) that makes again, and tabletting promptly gets; The blended pharmaceutic adjuvant of wherein said elder generation and principal agent is one or more in diluent, the correctives, and said residue pharmaceutic adjuvant is multiple in diluent, disintegrating agent, correctives, the lubricant.This wet granule compression tablet technology can further comprise following steps: be that the diluent of 20%-60% mixes (adding promptly) with principal agent with percentage by weight earlier; Add suitable amount of adhesive again and process soft material; The system granule; Drying, with disintegrating agent, correctives, lubricant and remaining diluent and the dried granule mix homogeneously (promptly adding) that makes, tabletting promptly gets again; Said diluent is lactose or mannitol; Said disintegrating agent is a cross-linking sodium carboxymethyl cellulose; Said correctives is citric acid and acesulfame potassium; Said lubricant is micropowder silica gel and magnesium stearate.
" in add " of the present invention, " adding " are the process operations that formulation art is known, and promptly " in add " is meant that material adds before wet method system granule, and " adding " is meant before total mixing adjuvant is joined in the dried granule that has made.
The oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing of the present invention when it adopts wet granule compression tablet technology, can also contain an amount of binding agent; Wherein said binding agent is selected from one or more in purified water, ethanol, hydroxypropyl emthylcellulose, starch slurry, 30 POVIDONE K 30 BP/USP 30, carbomer, dextrin, gelatine size, mucialga of arabic gummy, sodium alginate and the syrup; Be preferably in 30 POVIDONE K 30 BP/USP 30, the hydroxypropyl emthylcellulose one or more.
Adopt technology of the present invention, have following advantage:
1, its preparation method is simple, and cost is low, is fit to industrialized great production.
The compositions of oral mucosa of the present invention or sublingual administration can through direct powder compression or wet granulation again the method for tablet forming technique realize; Above-mentioned two kinds of methods all are the most conventional method for preparing tablet thereof of pharmaceuticals industry; Production equipment and technology are very ripe; Therefore pharmaceutical composition of the present invention is more suitable for industrialized great production, and is cheap for manufacturing cost.
2, overcome the excitement of medicine in oral mucosa or Sublingual, compliance is good.
The applicant finds through a large amount of experiments; Through to the control of agomelatine particle diameter, screening and the optimization and the optimization of preparation of excipient; Pharmaceutical composition of the present invention can make pharmaceutically active substance keep certain dissolution rate; Thereby overcome agomelatine significant excitement in oral mucosa, good mouthfeel makes it have good patient's compliance.
3, avoid liver first-pass effect, reduced the probability of toxin for liver side effect, improved bioavailability and curative effect.
The compositions of oral mucosa of the present invention or sublingual administration is directly to be absorbed by mucosa, has avoided the process such as first pass effect and gastrointestinal tract enzymolysis, acidolysis of oral drugs, makes bioavailability improve greatly; Compositions provided by the invention has reduced the using dosage of agomelatine, has reduced the probability of toxin for liver side effect; Agomelatine oral and hypoglossis mucous membrane absorb, the influence of unable to take food thing; Drug absorption is after superior vena cava directly gets into blood circulation, and drug absorption is rapid after the administration, and is rapid-action.This dosage form is particularly suitable for the patient of dysphagia such as old man, and the patient of water intaking difficulty takes in the special environment (like the battlefield, go out, tourism etc.).
Can know that to sum up oral mucosa of the present invention or Sublingual tablet are a kind of comparatively ideal novel dosage forms, have not only satisfied present clinical demand, and it is blank to have filled up domestic same domain, has huge market potential.
Through concrete experimental program the present invention is described further below:
In embodiment of the present invention or the specific embodiment to following to the detection method of the evaluation of excitement and dissolution:
Excitement: through the volunteer's oral transmucosal and the sublingual administration of 6 health, estimate its excitement intensity, excitement is divided into: " ++ ++ " excitement is extremely strong strong; " +++" excitement is strong; " ++ " excitement is obvious, can stand; The sense of "+" minimal irritation; "-" no obvious stimulation sense.
Dissolution: getting 6 of these article, according to dissolution determination method (two appendix V of Chinese Pharmacopoeia version in 2010 C three therapeutic methods of traditional Chinese medicine), is dissolution medium with 500ml water; Rotating speed is 50 rev/mins, and temperature is 37 ℃, in accordance with the law operation; In the time of 20 minutes, get solution and filter, getting subsequent filtrate is need testing solution; It is an amount of that other gets the agomelatine reference substance, adds small amount of ethanol dissolving back water and process the solution that every 1ml contains agomelatine 2 μ g, as reference substance solution., precision is measured need testing solution and each 20 μ l of reference substance solution, and (two appendix VD of Chinese Pharmacopoeia version in 2010 measure, and calculate every stripping quantity according to HPLC.Limit is 85% of a labelled amount.
Chromatographic condition and system suitability: use octadecyl silane to be filler; (regulating pH value 3.0 with phosphoric acid)-methanol (30: 70) is mobile phase with the 0.1mol/L sodium dihydrogen phosphate; Detect wavelength 230nm.
Overall merit: when " excitement is obvious, can stand " or " the minimal irritation sense can be accepted " or " no obvious stimulation sense ", and dissolution >=85% be judged to be qualified; When " excitement is extremely strong strong " or " excitement is strong " or dissolution＜85% are judged to be defective.
(1) selection of dosage form
The agomelatine ordinary tablet is oral after gastrointestinal absorption, because the metabolism of liver, first pass effect is obvious, and bioavailability is extremely low, and individual variation is bigger, has caused bigger difficulty to clinical application.The inventor processes spray oral or nasal administration (concrete prescription is seen table 1) through a large amount of tests with agomelatine, and processes membrane oral mucosa or sublingual administration (concrete prescription is seen table 3), to avoid first pass effect.Volunteer through 6 health uses prepared spray and membrane, and its acceptability is estimated.The result finds: excitement is strong after the medication, even add correctives, screening agent also can't tolerate.The result sees table 2, table 4.
Table 1 agomelatine composite spray prescription (by weight percentage)
The method for preparing of more than filling a prescription: agomelatine is added in the PEG400, after 50 ℃ of heating for dissolving, add propylene glycol, citric acid glyceride mixing; Aspartane, citric acid are joined in the solution that contains agomelatine after with water dissolution, and mix homogeneously is potted in after the filtration in the automiser spray and gets final product.
The above-mentioned spray evaluation result that makes is seen table 2.
The acceptable evaluation result of table 2 agomelatine spray
Table 3 agomelatine film compositions prescription (by weight percentage)
The method for preparing of more than filling a prescription: agomelatine is dissolved in 20ml 50% alcoholic solution, in addition polyvinyl alcohol 17-88 is dissolved in the alcoholic solution of 40ml 50%, both mixings add PEG400; Mixing adds correctives, mixing; De-bubbled is filmed, drying; Evenly be cut into small pieces, every contains the about 1mg of agomelatine, promptly gets the agomelatine pelliculae pro cavo oris.
The above-mentioned membrane evaluation result that makes is seen table 4.
The acceptable evaluation result of table 4 agomelatine membrane
The inventor tests again in a large number, through further investigation, when adopting prescription (by weight percentage): agomelatine (particle diameter 125 μ m～200 μ m) 0.3; Mannitol 90.7, cross-linking sodium carboxymethyl cellulose 5.0, citric acid 2.2; Aspartame 0.9, magnesium stearate 0.9.Through following method for preparing: get agomelatine and mannitol, crosslinked cross-linking sodium carboxymethyl cellulose, citric acid, aspartame, magnesium stearate mixing, tabletting makes the tablet of hardness at 50～60N.Through the volunteer's oral transmucosal and the sublingual administration of 6 health, the result does not have the obvious stimulation sense.
(2) selection of principal agent particle diameter
The inventor finds that through a large amount of experiments the excitement of agomelatine is relevant with the moment concentration that it is dissolved in oral cavity or the sublingual liquid, and excitement is strong when excessive concentration, then almost stingless excitation when concentration is lower than a certain value.Medicine is in the oral cavity or the concentration in Sublingual is dissolved total amount, saliva is measured and the influence of mucosa absorption amount.The size of agomelatine and its dissolution velocity in water is inversely proportional to, and bigger its dissolution velocity of particle diameter is slow more, under the influence of saliva dilution and mucosa absorption, is not easy to form high concentration more, and excitement is just not obvious more, and vice versa.
In addition, the difference of pharmaceutically active substance particle diameter, its flowability, bulk density also have certain change, thereby influence mixing uniformity and the dissolution of finished product etc. when preparation is big to be produced.
Therefore, select suitable principal agent particle size range, be realization agomelatine oral mucosa or the stingless excitation of Sublingual tablet, produce mix homogeneously, have key than high-dissolution.
The present invention adopts the agomelatine of different-grain diameter to make an experiment, and prescription is seen table 5.Method for preparing: with agomelatine and mannitol, lactose, crospolyvinylpyrrolidone, magnesium stearate, micropowder silica gel mix homogeneously, direct compression promptly gets.Tasting excitement and dissolution determination value with volunteer's mouth serves as to investigate index, confirms the particle size range that principal agent is suitable, and the result sees table 6.
The present invention adopts agomelatine is pulverized, and the method for screening prepares the raw material of different-grain diameter again, describes the size of particle diameter with whether through the sieve aperture in a certain aperture.＜25 μ m represent can be through the sieve aperture of aperture 25 μ m; 25 μ m-48 μ m represent to pass through the sieve aperture of aperture 48 μ m, but can not be through the sieve aperture of aperture 25 μ m;＞250 μ m represent can not be through the sieve aperture of aperture 250 μ m, and other by that analogy.
Table 5 different-grain diameter agomelatine composite formula (by weight percentage)
Table 6 different-grain diameter agomelatine composite formula evaluation result
Visible by last table, oral mucosa and Sublingual tablet excitement that the particle diameter of principal agent >=48 μ m make can be accepted.During the particle diameter of principal agent≤250 μ m, dissolution is better, and during the particle diameter of principal agent≤150 μ m, dissolution is better.Resultant stimulus sense and dissolution are considered, select the principal agent particle diameter better at 48 μ m-250 μ m, and preferred 48 μ m-150 μ m then can obtain good dissolution degree.
The specific embodiment
Through embodiment the present invention is further described below, but do not limit the invention by any way with it.
Embodiment 1 to 7
Adopt the agomelatine pharmaceutical compositions of different-grain diameter, prescription is seen table 7.Method for preparing (wet granule compression tablet): with agomelatine and mannitol, crospolyvinylpyrrolidone mix homogeneously, add an amount of 5% hypromellose wet granulation, dried granule of gained and magnesium stearate, micropowder silica gel mix homogeneously, tabletting promptly gets.
Table 7 embodiment 1-7 (calculating by weight percentage)
Remarks: every 100g solid material adds the about 8g of 5% hypromellose solution (0.4g), and the hypromellose consumption does not count in the prescription.
Look for the volunteer of 6 health to use, oral mucosa and sublingual administration are estimated its excitement intensity and are detected its dissolution.The result sees table 8.
Table 8 embodiment 1-7 evaluation result
Brief summary: visible by last table, oral mucosa and Sublingual tablet excitement that the particle diameter of principal agent >=48 μ m make can be accepted.During the particle diameter of principal agent≤250 μ m, dissolution is better, and during the particle diameter of principal agent≤150 μ m, dissolution is better.Resultant stimulus sense and dissolution are considered, select the principal agent particle diameter better at 48 μ m-250 μ m, select 48 μ m-150 μ m can obtain good dissolution degree.
Embodiment 8 to 18
The selection of diluent has certain influence to the excitement and the dissolution of these article.It is known to those skilled in the art that solubility adjuvant such as mannitol, sorbitol, lactose, sucrose, lactose, glucose, or insolubility adjuvant such as starch, dextrin, calcium sulfate and microcrystalline Cellulose all can be used as the diluent of tablet.The inventor studies as the situation of diluent of the present invention different auxiliary material through abundant experiment; The result shows; The diluent that is fit to the pharmaceutical composition of agomelatine of the present invention can be drug world any excipient that can be used to dilute commonly used, includes but not limited in the above-mentioned diluent of mentioning one or more.
Through following concrete experiment the present invention is further described: the composite formula of different diluent (seeing table 9, table 10) more than the employing, the agomelatine particle diameter is at 48 μ m-150 μ m in each prescription.
The different diluent combined composition formulas one of table 9 (by weight percentage)
Annotate: the lactose that embodiment 12 uses is spray-dried lactose; The lactose that embodiment 13 uses is for grinding lactose.
The different diluent combined composition formulas two of table 10 (by weight percentage)
The method for preparing of above table 9 and table 10 prescription:
The 1st step: said principal agent, diluent, lubricant, disintegrating agent, correctives are pulverized the pretreatment of sieving.
The 2nd step: will pass through pretreated principal agent, diluent, lubricant, disintegrating agent, correctives mix homogeneously;
The 3rd step: the above-mentioned material tabletting of mix homogeneously is promptly got.
The tablet that above-mentioned table 9 and table 10 are prepared; Through the excitement evaluation; The result shows: prepared tablet excitement all is acceptables; When particularly using lactose, mannitol, sorbitol, lactose as diluent, excitement and dissolution overall merit are better, and it is relatively poor as its excitement of prescription and the dissolution overall merit of diluent to use starch, calcium carbonate, calcium sulfate, microcrystalline Cellulose.Concrete outcome is seen table 11, table 12.
The evaluation result of the different diluent combined composition formulas one of table 11
The evaluation result of the different diluent combined composition formulas two of table 12
Embodiment 19-38
Pharmaceutical composition of the present invention can also contain the other drug excipient except containing diluent, disintegrating agent, lubricant, concrete prescription sees that table 13, table 14, the agomelatine particle size range of its use are 48 μ m-150 μ m.Method for preparing is following:
The 1st step: with said principal agent, diluent, lubricant, disintegrating agent, correctives, antioxidant, opacifier, penetration enhancer, pulverizing, the pretreatment of sieving.
The 2nd step: will pass through pretreated principal agent, diluent, lubricant, disintegrating agent, correctives, antioxidant, opacifier, penetration enhancer mix homogeneously;
The 3rd step: the above-mentioned material tabletting of mix homogeneously is promptly got.
Table 13 embodiment 19-29 (calculating by weight percentage)
Annotate: the lactose that embodiment 22,24 uses is for grinding lactose; The lactose that embodiment 29 uses is spray-dried lactose.
Table 14 embodiment 30-38 (calculating by weight percentage)
Look for the volunteer of 6 health to use, oral mucosa and sublingual administration are estimated its excitement intensity.The result sees table 15, table 16.
Table 15 embodiment 18-29 evaluation result
Table 16 embodiment 30-38 evaluation result
Can find out that from table 15 and 16 above-mentioned to have used prepared its excitement of tablet that goes out of different excipient all be to accept.The complex (embodiment 19-21), lactose (embodiment 29), the mannitol (embodiment 25-28) that contain mannitol when use; Or during its mixture (embodiment 22,24); Its excitement and dissolution overall merit are better, and (embodiment 25-27) mouthfeel is better when being added with correctives.When using pregelatinized Starch (embodiment 32), soluble starch (embodiment 30), dextrin (embodiment 31,33), calcium carbonate (embodiment 38), microcrystalline Cellulose (embodiment 37), sucrose (embodiment 23,34) as diluent, excitement and dissolution overall merit are relatively low.
Embodiment 39 to 44
Concrete prescription is seen table 17; Method for preparing: the prescription consumption mix homogeneously of agomelatine (particle size range is 48 μ m-150 μ m) and mannitol, the complex (Pearlitol Flash), spray-dried lactose, grinding lactose, crospolyvinylpyrrolidone, citric acid, magnesium oxide, the poloxamer that contain mannitol being pressed table 11; Add an amount of 10% 30 POVIDONE K 30 BP/USP, 30 wet granulations; Dry granulate adds magnesium stearate, micropowder silica gel mix homogeneously, and tabletting promptly gets.
Table 17 embodiment 39 to 44 (calculating by weight percentage)
Remarks: every 100g solid material adds the about 8g of 10% 30 POVIDONE K 30 BP/USP, 30 solution (0.8g 30 POVIDONE K 30 BP/USP 30), and 30 POVIDONE K 30 BP/USP 30 consumptions do not count in the prescription.
Look for the volunteer of 6 health to use, oral mucosa and sublingual administration are estimated its excitement intensity.The result sees table 18.
Table 18 embodiment 39 to 44 excitement evaluation results
Visible by last table, be that the method for agomelatine and diluent, disintegrating agent, correctives, the short penetrating agent employing wet granulation of 48 μ m-150 μ m is prepared into tablet with preferred particle size range, its excitement can be accepted maybe can tolerate.Adopt and grind lactose (embodiment 41) or mannitol (embodiment 42), contain the prescription of the complex (embodiment 43) of mannitol as diluent, its excitement and dissolution overall merit are better.
Embodiment 45-55
Adopt direct compression and wet granulation technology to make an experiment respectively, the agomelatine particle size range is 48 μ m-75 μ m, and prescription is seen table 19.
Embodiment 45,49 is a direct compression technology, and method for preparing is: principal agent, diluent, lubricant, disintegrating agent, correctives are pulverized the pretreatment of sieving, mix homogeneously, tabletting.
Embodiment 46,47,48,50,51,52,53,54,55 is a wet granule compression tablet technology, and method for preparing is: principal agent, diluent, lubricant, disintegrating agent, correctives are pulverized the pretreatment of sieving; Add in the partial supplementary material and the principal agent mix homogeneously, add the hypromellose solution of weight percentage ratio 5%, process soft material, system granule, drying; All the other adjuvants add and dried granule mix homogeneously, tabletting.
Described " in add ", " adding " are the process operations that formulation art is known, and promptly " in add " is meant that material adds before wet method system granule, and " adding " is meant before total mixing adjuvant is joined in the dried granule that has made.
Table 19 embodiment 45-55 (calculating by weight percentage)
Remarks: the every 100g solid material of (1) wet granulation adds the about 8g of 5% hypromellose solution, and the hypromellose consumption does not count in the prescription.(2) not special dated adjuvant is and adds.(3) embodiment 49-51 uses spray-dried lactose; Embodiment 52,53 uses and grinds lactose; Embodiment 54,55 uses the screening lactose.
Look for the volunteer of 6 health to use, oral mucosa and sublingual administration are estimated its excitement intensity, and measure dissolution.The result sees table 20.
Table 20 embodiment 45-55 evaluation result
Annotate :+
△Represent its excitement evaluation to be better than "+", but "-" is relatively poor relatively, between "+" and "-".
Comprehensive The above results can be found out: earlier with adding in the partial supplementary material and the principal agent mixing granulation; Again with other adjuvants particularly correctives add; The prepared pharmaceutical composition that goes out is because its correctives and the first stripping of partial supplementary material when placing the oral cavity; Principal agent is stripping subsequently, therefore can obtain better mouthfeel.Its zest of the pharmaceutical composition that this prepared goes out is less than the prepared pharmaceutical composition that goes out of direct compression (embodiment 45,49).
Claims (16)
1. one kind contains the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration, it is characterized in that: comprising particle diameter is the agomelatine of 48 μ m-250 μ m, and the available excipient of drug world; The particle diameter of preferred agomelatine is 48 μ m-150 μ m.
2. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 1 is characterized in that: contain the agomelatine that percentage by weight is 0.1%-4%, the diluent of 46%-99.7%, the lubricant of 0.2%-15%, the disintegrating agent of 0%-15%, the correctives of 0%-5%, the antioxidant of 0%-5%, the opacifier of 0%-5%, the penetration enhancer of 0%-5%; Wherein said diluent is selected from one or more in sucrose, lactose, glucose, soluble starch, mannitol, the complex that contains mannitol, sorbitol, lactose, xylitol, microcrystalline Cellulose, saccharide, starch, the dextrin; Said lubricant is selected from one or more in hard ester acid, magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycol 6000, Macrogol 4000, sodium lauryl sulphate, Stepanol MG, fumaric acid sodium stearate, the Compritol 888 ATO; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, menthol, stevioside, glycyrrhizin, aspartame, sucralose, cyclamate, Suo Matian, the glucide; Said antioxidant is selected from one or more in ascorbic acid, sodium sulfite, calcium sulfite, Butylated hydroxyanisole, dibenzylatiooluene, ascorbyl palmitate, propyl gallate, tertiarybutylhydroquinone, the two lauryls of thio-2 acid, vitamin E, tea polyphenols, phytic acid, Radix Glycyrrhizae polyphenoils, phospholipid, the AOB; Described penetration enhancer is selected from polysorbas20, sodium lauryl sulphate, poloxamer F68, benzalkonium chloride, cetrimonium bromide, one or more in sodium glycocholate, sodium deoxycholate, sodium taurocholate, oleic acid, capric acid, lauric acid, LYSOLECITHIN SUNLECITHIN A, the lecithin.
3. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 2 is characterized in that: contain diluent that percentage by weight is 0.1%-4% agomelatine, 46%-99.7%, 0.2%-15% lubricant, the disintegrating agent of 0%-15%, the correctives of 0%-5%, the antioxidant of 0%-5%, the opacifier of 0%-5%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Said diluent is selected from mannitol, contain in the complex of mannitol, lactose, sorbitol, lactose, the xylitol one or more; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, aspartame, the sucralose; Said antioxidant is selected from one or more in Butylated hydroxyanisole, the dibenzylatiooluene; Said opacifier is selected from one or more in titanium dioxide, ferrum oxide, the magnesium oxide; Said penetration enhancer is selected from one or more among sodium lauryl sulphate, the poloxamer F68.
4. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 3 is characterized in that: contain the agomelatine that percentage by weight is 0.67%-4%, the diluent of 79.67%-93.67%, the lubricant of 1%-6%, the disintegrating agent of 0%-8%, the correctives of 0%-4%, the antioxidant of 0%-0.1%, the opacifier of 0%-0.1%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Said diluent is selected from mannitol, contain in the complex of mannitol, lactose, lactose, the xylitol one or more; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is selected from one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, the aspartame; Said antioxidant is Butylated hydroxyanisole; Said opacifier is selected from titanium dioxide; Said penetration enhancer is poloxamer F68.
5. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 4 is characterized in that: contain the agomelatine that percentage by weight is 0.67%-4%, the diluent of 79.67%-93.67%, the lubricant of 3%-6%, the disintegrating agent of 0%-8%, the correctives of 0%-4%, the antioxidant of 0%-0.1%, the opacifier of 0%-0.1%, the penetration enhancer of 0%-5%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Said diluent is mannitol or the complex that contains mannitol; Said lubricant is selected from one or more in magnesium stearate, micropowder silica gel, the fumaric acid sodium stearate; Said disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose; Said correctives is selected from one or more in citric acid, acesulfame potassium, the aspartame; Said antioxidant is Butylated hydroxyanisole; Said opacifier is selected from titanium dioxide; Said penetration enhancer is poloxamer F68.
6. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 4 is characterized in that: contain the agomelatine that percentage by weight is 0.67%-1.33%, the diluent of 90.33%-93.67%, 3% lubricant, the disintegrating agent of 2%-3%, the correctives of 0%-3%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Said diluent is a lactose, and said lubricant is selected from one or more in magnesium stearate, the micropowder silica gel; Said disintegrating agent is crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose; Said correctives is selected from one or more in citric acid, the acesulfame potassium.
7. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 4 is characterized in that: containing percentage by weight is 1.33% agomelatine, the diluent of 86.67%-88.67%, 4% lubricant, the disintegrating agent of 6%-8%; Wherein said agomelatine particle diameter is 48 μ m-150 μ m; Said diluent is the mixture of lactose and mannitol or the mixture of lactose, mannitol and xylitol; Said lubricant is the mixture of fumaric acid sodium stearate and micropowder silica gel; Said disintegrating agent is one or more in crospolyvinylpyrrolidone, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose.
8. the oral mucosa of stating according to claim 4 that contains agomelatine or the pharmaceutical composition of sublingual administration, it is characterized in that: containing percentage by weight is 0.67% agomelatine, 90.33% diluent, 3% lubricant, 3% disintegrating agent, 3% correctives; Wherein said agomelatine particle diameter is 48 μ m-75 μ m; Said diluent is lactose or mannitol; Said lubricant is one or more in micropowder silica gel, the magnesium stearate; Said disintegrating agent is a cross-linking sodium carboxymethyl cellulose; Said correctives is one or more in citric acid, the acesulfame potassium.
9. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 4; It is characterized in that: containing percentage by weight is 1.33% agomelatine, 90.33% mannitol or lactose, 2% cross-linking sodium carboxymethyl cellulose, 2% magnesium stearate, 1% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
10. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 5 is characterized in that: containing percentage by weight is 1.33% agomelatine, 79.67% mannitol, 8% crospolyvinylpyrrolidone, 5% poloxamer F68,2% magnesium stearate, 4% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
11. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 5 is characterized in that: containing percentage by weight is 2% agomelatine, 93% the complex that contains mannitol, 3% magnesium stearate, 2% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
12. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 7 is characterized in that: containing percentage by weight is 1.33% agomelatine, 80% mannitol, 6.67% lactose, 8% crospolyvinylpyrrolidone, 1.5% fumaric acid sodium stearate, 2.5% micropowder silica gel; Wherein said agomelatine particle diameter is 48 μ m-150 μ m.
13., it is characterized in that said preparation of drug combination method is dry method direct compression or wet granule compression tablet according to each the described oral mucosa of agomelatine or pharmaceutical composition of sublingual administration of containing among the claim 1-12.
14. the oral mucosa of agomelatine or the pharmaceutical composition of sublingual administration of containing according to claim 13 when it is characterized in that adopting this pharmaceutical composition of wet granule compression tablet prepared, can also contain an amount of binding agent; Wherein said binding agent is selected from one or more in purified water, ethanol, hydroxypropyl emthylcellulose, starch slurry, 30 POVIDONE K 30 BP/USP 30, carbomer, dextrin, gelatine size, mucialga of arabic gummy, sodium alginate and the syrup; Be preferably in 30 POVIDONE K 30 BP/USP 30, the hydroxypropyl emthylcellulose one or more.
15. the oral mucosa of agomelatine according to claim 14 or the pharmaceutical composition of sublingual administration; It is characterized in that described wet granule compression tablet technology comprises following steps: be that the pharmaceutic adjuvant of 20%-93.33% mixes with principal agent earlier with percentage by weight; Add suitable amount of adhesive again and process soft material, system granule, drying; To remain pharmaceutic adjuvant and the dried granule mix homogeneously that makes again, tabletting promptly gets; The blended pharmaceutic adjuvant of wherein said elder generation and principal agent is one or more in diluent, the correctives, and said residue pharmaceutic adjuvant is multiple in diluent, disintegrating agent, correctives, the lubricant.
16. the oral mucosa of agomelatine according to claim 15 or the pharmaceutical composition of sublingual administration; It is characterized in that described wet granule compression tablet technology comprises following steps: be that the diluent of 20%-60% mixes with principal agent earlier with percentage by weight; Add suitable amount of adhesive again and process soft material, system granule, drying; With disintegrating agent, correctives, lubricant and remaining diluent and the dried granule mix homogeneously that makes, tabletting promptly gets again; Said diluent is lactose or mannitol; Said disintegrating agent is a cross-linking sodium carboxymethyl cellulose; Said correctives is citric acid and acesulfame potassium; Said lubricant is micropowder silica gel and magnesium stearate.
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