CN103169669B - Agomelatine covered pellet and drug composition capable of being dispersed in mouth - Google Patents
Agomelatine covered pellet and drug composition capable of being dispersed in mouth Download PDFInfo
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Abstract
The invention belongs to the fields of pharmacology and pharmaceutical engineering and relates to an agomelatine covered pellet and a drug composition capable of being dispersed in the mouth. Concretely, the agomelatine covered pellet comprises an agomelatine main drug and a polyvinylpyrrolidone binding agent. According to the invention, agomelatine covered pellets are hardly adhered, so that pellet coating efficiency is improved and the problem that a spray gun is blocked is avoided; and the agomelatine-containing drug composition capable of being dispersed in the mouth can disintegrate quickly and is good in taste and high in bioavailability. The agomelatine-containing covered pellet and the drug composition capable of being dispersed in the mouth, which are provided by the invention, are easy to prepare, cost is reduced, and the agomelatine-containing covered pellet and the drug composition capable of being dispersed in the mouth are especially applicable to industrial production.
Description
Technical field
The invention belongs to materia medica and galenic pharmacy field, the pharmaceutical composition relating to a kind of agomelatine coated micropill and can disperse in mouth.
Background technology
Agomelatine, chemistry N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide by name, its structural formula is as shown in formula I below.Agomelatine is a kind of selective agonist of melatonin receptor, is also 5-HT
2cthe antagonist of receptor, these character, to the activity it provided central nervous system, especially have activity in the treatment of Serious depression, seasonal affective disorder, sleep disordered, cardiovascular disease, digestive system disease, the insomnia caused by the time difference and fatigue, appetite disorder and obesity.
Agomelatine, its preparation method and purposes in the treatment has been described in European patent application EP 0447285 and EP 1564202.
The advantage that oral cavity disintegration tablet has to improve rapidly the blood drug level of medicine, and the medicine tachymetabolism simultaneously first pass effect of hepar can also being avoided to cause, improves bioavailability.The rapid disintegrate of oral cavity disintegration tablet or dissolving, not only can fast onset drug effect, and convenient drug administration, is beneficial to particular patients ' and takes, be particularly suitable for the psychotic mismatching administration.Oral cavity disintegration tablet fater disintegration also after being scattered in oral cavity, namely entering in stomach with swallowing act and plays drug effect, the situation that before preventing, medicine spues again after taking medicine by psychotic, and the burden decreasing medical personnel, improve the cure rate of disease.In order to the fater disintegration of existing oral cavity disintegration tablet and dispersed, become grading factors for different activities, select suitable disintegrating agent most important.
In addition, mouthfeel is one of important parameter of oral cavity disintegration tablet, has very strong bitterness and can cause obvious sensation at oral mucosa thus limit the extensive use of this medicine due to agomelatine self.
Conventional method at present for taste masking has: add correctives, prepare clathrate and utilize coated micropill to carry out taste masking, but simple adds bitterness and the excitement that correctives and enclose means effectively can not cover principal agent.
Freeze Drying Technique prepares the routine techniques of oral cavity disintegration tablet, is prepared into " the oral lyophilization thing " of porous by lyophilization, can rapid disintegrate dispersion in mouth.This technology performs to get up to need complete set and the commercial run of complexity, and equipment requirements is very high, causes manufactured medicine cost greatly to improve.
Coated micropill has lot of advantages, such as: increase at gastrointestinal tract surface distributed area, can reduce zest, improves bioavailability; Belong to multiple agent type, therefore can be made into slow controlled release micro pill, zero level or one-level or fast release preparation, without time delay; Do not affect by gastric emptying factor, drug absorption in vivo is even, and individual variation is little; Different objects can be reached, as covered adverse drug taste etc. by different coating materials.
The preparation method of micropill comprises coating pan mixing/coating, fluidized bed coating, centrifugal granulator mixing/coating, extrudes-round as a ball pelletize, liquid phase knot is poly-, melting cohesion, melting high-speed stirred mixing granulation, fluidisation melt granulation etc.
But, in the process of spray coating solution, easily stick together between micropill, affect the uniformity of coating and reduce coating efficiency, also easily blocking spray gun.
In addition, pharmacokinetic studies shows, for parental routes, the bioavailability of being carried out the agomelatine of administration by oral route is very low, and difference in same individuality and between Different Individual is quite large.This is because the water solublity of agomelatine is very poor, have impact on the stripping of medicine, and its stripping is the speed limit process absorbed, and is usually the main factor affecting bioavailability.
Therefore, the new pharmaceutical composition that can disperse in mouth containing agomelatine is needed badly.
Summary of the invention
The present inventor, through deep research and performing creative labour, obtains a kind of agomelatine coated micropill and a kind of pharmaceutical composition that can disperse in mouth containing agomelatine.The present inventor is surprised to find, and is not easy adhesion, improves coating of pellets efficiency between agomelatine coated micropill of the present invention, and avoids the problem of blocking spray gun; The present inventor is also surprised to find, and the pharmaceutical composition good mouthfeel that can disperse in mouth containing agomelatine of the present invention, disintegrate stripping is rapid, can improve bioavailability.Thus provide following invention:
One aspect of the present invention relates to a kind of agomelatine coated micropill, comprises containing the pill heart and taste mask layer, and wherein, the described pill pericardium that contains is containing the agomelatine as principal agent and the polyvinylpyrrolidone as binding agent.
Coated micropill according to any one of the present invention, wherein, the weight ratio of agomelatine and polyvinylpyrrolidone is 10: 1 to 1: 1; Be preferably 6: 1 to 4: 1, be more preferably 5.5: 1 to 4.5: 1 (such as 5.5: 1,5.4: 1,5.3: 1,5.2: 1,5.1: 1,5.0: 1,4.9: 1,4.8: 1,4.7: 1,4.6: 1 or 4.5: 1); More preferably 5: 1.
Coated micropill according to any one of the present invention, wherein, using alcoholic solution as the solvent of agomelatine and polyvinylpyrrolidone, obtained containing the pill heart, the concentration of wherein said alcoholic solution is 70%-100% (w/w); Be preferably 80%-98% (w/w); Be more preferably 85%-98% (w/w); More preferably 90%-98% (such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98%w/w); Be particularly preferably 95% (w/w).
Coated micropill according to any one of the present invention, wherein, the content of agomelatine in alcoholic solution is 5%-15% (w/w); Be preferably 8%-12% (w/w) (such as 8%, 9%, 10%, 11% or 12%w/w); Be more preferably 10% (w/w).
Coated micropill according to any one of the present invention, wherein, the material containing the pill heart blank pill heart used is microcrystalline Cellulose.
Coated micropill according to any one of the present invention, wherein, the diameter of the blank pill heart used is 100-200 micron.
Coated micropill according to any one of the present invention, wherein, the mean diameter of described coated micropill is for being less than or equal to 300 microns; Be preferably 100-200 micron.
Coated micropill according to any one of the present invention, wherein, taste mask layer material therefor comprises Eudragit E (such as Eudragit E100, Chinese is also called Youteqi E100) and/or Eudragit L; Preferably, Pulvis Talci is not contained in described taste mask layer.
Preferably, the preparation of taste mask layer comprises the steps: by coating material dissolves used for taste mask layer in the ethanol of 95%, and coating material concentration is in ethanol 10%-15% (w/w), is preferably 10% (w/w).
Coated micropill according to any one of the present invention, wherein, the weightening finish of taste mask layer is 20% for being not less than 20% containing pill heart weight; Be preferably 20%-24%; Be more preferably 20%.
The preparation method of coated micropill of the present invention: first the agomelatine of recipe quantity is coated on blank pill in the heart, is prepared into containing the pill heart, then by the taste mask layer containing the above-mentioned any one of pill pericardium one deck, is prepared into the coated micropill with taste masking effect.Wherein, fluid bed or extrusion spheronization mechanism can be utilized for containing the pill heart and coated micropill.
Another aspect of the present invention coated micropill related to described in any one of the present invention contains the purposes in the pharmaceutical composition that can disperse in mouth of agomelatine in preparation; Particularly, described pharmaceutical composition is tablet, such as cavity disintegrating tablet.
A kind of pharmaceutical composition that can disperse in mouth containing agomelatine of another aspect of the invention, comprising: as the agomelatine of principal agent, and associating disintegrating agent.
Pharmaceutical composition according to any one of the present invention, wherein, described associating disintegrating agent is microcrystalline Cellulose and crospolyvinylpyrrolidone.
Pharmaceutical composition according to any one of the present invention, wherein, the content of described associating disintegrating agent is 25%-35% (w/w).
Pharmaceutical composition according to any one of the present invention, wherein, the weight ratio of microcrystalline Cellulose and crospolyvinylpyrrolidone is 3: 2 to 4: 1; Be preferably 2: 1 to 3.5: 1; Be more preferably 2.5: 1 to 3.5: 1 (such as 2.5: 1,2.6: 1,2.7: 1,2.8: 1,2.9: 1,3.0: 1,3.1: 1,3.2: 1,3.3: 1,3.4: 1 or 3.5: 1.); More preferably 3: 1.
Pharmaceutical composition according to any one of any one of the present invention, wherein, described pharmaceutical composition comprises the coated micropill according to any one of the present invention.
Pharmaceutical composition according to any one of the present invention, wherein, the content of described coated micropill is 55%-70% (w/w).
Pharmaceutical composition according to any one of the present invention, wherein, coated micropill: associating disintegrating agent=25: 12 (w/w).
Pharmaceutical composition according to any one of the present invention, it also comprises the filler of 20%-40% (w/w).
Pharmaceutical composition according to any one of the present invention, it is tablet, such as cavity disintegrating tablet.
The disintegration of cavity disintegrating tablet of the present invention is less than 3 minutes, is preferably less than 1 minute; Be more preferably and be less than 30 seconds; More preferably be less than 20 seconds.
Pharmaceutical composition according to any one of the present invention, wherein, the hardness of described tablet is 35-45 newton.Be preferably 40 newton.
The preparation method of cavity disintegrating tablet of the present invention: the agomelatine coated micropill above described in any one taking recipe quantity, then the adjuvant (such as filler, disintegrating agent, correctives or lubricant etc.) of recipe quantity is added, mix homogeneously, tabletting and get final product.
Term used herein " compositions " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.
The actual dose level of active component in pharmaceutical composition of the present invention can be changed, so that the amount of the reactive compound of gained can effectively for concrete patient.Dosage level must according to the patient's condition and medical history etc. of the order of severity of the treated patient's condition and patient to be treated because usually selecting.But the usual way of this area is, the dosage of compound, from lower than for obtaining level that required therapeutic effect requires, increases dosage, gradually until obtain required effect.Also the amount of the use of pharmaceutical composition of the present invention can be determined according to the current usual using dosage of agomelatine and the content of agomelatine in pharmaceutical composition of the present invention.
Another aspect of the invention relates to the coated micropill according to any one of the present invention or the pharmaceutical composition according to any one of the present invention is preparing selective agonist or the 5-HT of melatonin energy system receptor
2cpurposes in the antagonist of receptor.
Another aspect of the invention relates to the coated micropill according to any one of the present invention or the pharmaceutical composition according to any one of the present invention regulates the purposes in the medicine of central nervous system activity in preparation.
Another aspect of the invention relate to the coated micropill according to any one of the present invention or the pharmaceutical composition according to any one of the present invention preparation prevent and/or treat and/auxiliary treatment Serious depression, seasonal affective disorder, sleep disordered, cardiovascular disease, digestive system disease, the insomnia caused by the time difference and fatigue, appetite disorder or obesity medicine in purposes.
Another aspect of the invention relate to a kind of prevent and/or treat and/auxiliary treatment Serious depression, seasonal affective disorder, sleep disordered, cardiovascular disease, digestive system disease, the insomnia caused by the time difference and fatigue, appetite disorder or obesity method, comprise the step of the coated micropill according to any one of the present invention giving effective dose or the pharmaceutical composition according to any one of the present invention.
Those skilled in the art know, and agomelatine is a kind of selective agonist of melatonin receptor, are also 5-HT
2cthe antagonist of receptor, these character, to the activity it provided central nervous system, especially have activity in the treatment of Serious depression, seasonal affective disorder, sleep disordered, cardiovascular disease, digestive system disease, the insomnia caused by the time difference and fatigue, appetite disorder and obesity.So those skilled in the art can expect, coated micropill of the present invention or pharmaceutical composition can have above-mentioned purposes.
Total consumption per day of pharmaceutical composition of the present invention must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the order of severity of this obstacle; The concrete pharmaceutical composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time adopted, route of administration and excretion rate; The treatment persistent period; The medicine simultaneously used with adopted concrete pharmaceutical composition; And the known similar factor of medical field.
Various disease of the present invention or disease effectively can be prevented and/or treated according to pharmaceutical composition of the present invention.
In the present invention, term " effective dose " refers to the dosage that can realize treating, prevent, alleviate and/or alleviating disease of the present invention or disease in experimenter.
In the present invention, described agomelatine includes but not limited to: agomelatine, its officinal salt, its hydrate, its solvate or its various crystal formations etc.
The beneficial effect of the invention
Be not easy adhesion between agomelatine coated micropill of the present invention, improve coating of pellets efficiency, and avoid the problem of blocking spray gun; The pharmaceutical composition disintegrate that can disperse in mouth containing agomelatine of the present invention is rapid, good mouthfeel, and bioavailability is high.Coated micropill containing agomelatine of the present invention is simple with the preparation manipulation of the pharmaceutical composition that can disperse in mouth, and cost reduces, and is very suitable for suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1: the preparation of the oral cavity disintegration tablet sample 1 containing agomelatine
The preparation prescription of oral cavity disintegration tablet:
Preparation technology:
Take the agomelatine of recipe quantity and various adjuvant, cross 60 mesh sieves, to progressively increase method mix homogeneously by equivalent, then add lubricant Pulvis Talci, after mixing, direct compression and get final product.
embodiment 2: the preparation of the oral cavity disintegration tablet sample 2 containing agomelatine
(1) containing pill heart prescription:
Wherein, each percentage ratio in consumption refers to that composition weight accounts for the percentage ratio containing pill heart gross weight (i.e. the gross weight of agomelatine, polyvinylpyrrolidone, blank pill heart three).Also similar understanding can be done in the following examples.
Preparation containing the pill heart: the blank pill heart is dropped in fluid bed, makes it to be in fluidized state, then the principal agent solution pump be dissolved in ethanol is entered in fluid bed, be prepared into containing the pill heart.
(2) coated micropill prescription:
Coated micropill consumption
Containing the pill heart 83%
Eudragit E100 17％
95% ethanol consumption is 9 times of E100 weight
Wherein, each percentage ratio in consumption refers to that composition weight accounts for the percentage ratio of coated micropill gross weight (namely containing the gross weight of the pill heart and Eudragit E100).Also similar understanding can be done in the following examples.
The preparation of coated micropill: gained is placed in fluid bed containing the pill heart, makes it to be in fluidized state, then Eudragit E100 is dissolved in ethanol, be sprayed on containing pill in the heart, obtained coated micropill.
(3) tablet formulation:
Tablet producing technology:
Take the various adjuvants of recipe quantity, cross 60 mesh sieves, progressively increase with agomelatine coated micropill equivalent and mix homogeneously, then add lubricant Pulvis Talci, after mixing, direct compression (hardness is 40 newton) and get final product.
embodiment 3: the preparation of the oral cavity disintegration tablet sample 3 containing agomelatine
(1) containing pill heart prescription:
Prepare containing the pill heart: the blank pill heart is dropped in fluid bed, makes it to be in fluidized state, then the principal agent solution pump be dissolved in ethanol is entered in fluid bed, must the pill heart be contained.
(2) coated micropill prescription:
The preparation of coated micropill: gained is placed in fluid bed containing the pill heart, makes it to be in fluidized state, then hypromellose is dissolved in cold water, be sprayed on containing pill in the heart, obtained coated micropill.
(3) tablet formulation:
Tablet producing technology:
Take the various adjuvants of recipe quantity, cross 60 mesh sieves, progressively increase with agomelatine coated micropill equivalent and mix homogeneously, then add lubricant Pulvis Talci, after mixing, direct compression and get final product.
embodiment 4: mouthfeel, disintegration and dissolution detect
1. laboratory sample: sample 1-3 prepared by embodiment 1-3 above.
2. experimental technique:
(1) mouthfeel experiment:
Get an oral disintegrating tablet formulation and put into healthy volunteer oral cavity, start to clock, treat its imperceptible stone existence in the oral cavity, during in loose pasty state, end is clocked, swallow and record and swallow comfort level, and with bitterness (obviously, slight, nothing), to the zest of oral mucosa (obviously, slight, nothing) and grittiness (obviously, slight, nothing) for evaluation index, its mouthfeel of difference records appraisal.
(2) disintegration time mensuration method:
Get a container, its internal diameter is about 2.0cm, height is about 3.5cm, 2.0ml water is medium, temperature is (37 ± 1) DEG C, adopts static method (tablet is immersed in medium completely), observes to the complete disintegrate of tablet can all by the time limit of 26 mesh sieves, must not more than 1min, every batch sample measures 6 times.
(3) Dissolution experiments:
Get this preparation, by dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), with the hydrochloric acid 1000ml of 0.1mol/L for solvent, rotating speed is 100r/min, temperature (37 ± 1) DEG C, operate in accordance with the law, respectively at 2,5,10,15,20,25,30min time, get solution 5ml (after getting liquid at every turn, add the hydrochloric acid 5ml of 0.1mol/L all in time), filter, sample introduction measures.
3. experimental result:
As shown in Table 1 below:
Table 1: mouthfeel, disintegration and dissolution test experience result
Can be proved by above embodiment, the oral cavity disintegration tablet that the adjuvant such as disintegrating agent, filler obsession obtains is added again after adopting the method for coating of pellets first to obtain the coated micropill (particularly employing binding agent polyvinylpyrrolidone of the present invention and/or coating material Eudragit E100) containing agomelatine, the bitterness of principal agent can not only be covered, and the dissolution of agomelatine can be improved, method simple possible, is conducive to suitability for industrialized production.
embodiment 5: the preparation of the oral cavity disintegration tablet sample 4 containing agomelatine
(1) containing pill heart prescription:
Preparation containing the pill heart: the blank pill heart is dropped in fluid bed, makes it to be in fluidized state, then the principal agent solution pump be dissolved in ethanol is entered in fluid bed, be prepared into containing the pill heart.
(2) coated micropill prescription:
The preparation of coated micropill: gained is placed in fluid bed containing the pill heart, makes it to be in fluidized state, then Eudragit E100 is dissolved in ethanol, be sprayed on containing pill in the heart, obtained coated micropill.
(3) tablet formulation:
Tablet producing technology:
Take the various adjuvants of recipe quantity, cross 60 mesh sieves, progressively increase with agomelatine coated micropill equivalent and mix homogeneously, then add lubricant Pulvis Talci, after mixing, direct compression and get final product.
embodiment 6: the preparation of the oral cavity disintegration tablet sample 5 containing agomelatine
(1) containing pill heart prescription:
Preparation containing the pill heart: the blank pill heart is dropped in fluid bed, makes it to be in fluidized state, then the principal agent solution pump be dissolved in ethanol is entered in fluid bed, be prepared into containing the pill heart.
(2) coated micropill prescription:
The preparation of coated micropill: gained is placed in fluid bed containing the pill heart, makes it to be in fluidized state, then Eudragit E100 is dissolved in ethanol, be sprayed on containing pill in the heart, obtained coated micropill.
(3) tablet formulation:
Tablet producing technology:
Take the various adjuvants of recipe quantity, cross 60 mesh sieves, progressively increase with agomelatine coated micropill equivalent and mix homogeneously, then add lubricant Pulvis Talci, after mixing, direct compression and get final product.
embodiment 7: the preparation of the oral cavity disintegration tablet sample 6 containing agomelatine
(1) containing pill heart prescription:
Preparation containing the pill heart: the blank pill heart is dropped in fluid bed, makes it to be in fluidized state, then the principal agent solution pump be dissolved in ethanol is entered in fluid bed, be prepared into containing the pill heart.
(2) coated micropill prescription:
The preparation of coated micropill: gained is placed in fluid bed containing the pill heart, makes it to be in fluidized state, then Eudragit E100 is dissolved in ethanol, be sprayed on containing pill in the heart, obtained coated micropill.
(3) tablet formulation:
Tablet producing technology:
Take the various adjuvants of recipe quantity, cross 60 mesh sieves, progressively increase with agomelatine coated micropill equivalent and mix homogeneously, then add lubricant Pulvis Talci, after mixing, direct compression and get final product.
embodiment 8: adhesion situation, coating efficiency and stifled rifle situation detect
Laboratory sample: sample 2,4-6 prepared by embodiment 2 above, 5-7.
Experimental technique:
The sample of above-described embodiment is carried out coating, and the adhesion situation in observation coating process between micropill and spray gun, with or without clogging, complete mutually commensurability coating required time to investigate its coating efficiency (Coating times) under recording different condition respectively.
Experimental result:
As shown in Table 2 below:
Table 2: the survey result of adhesion situation, coating efficiency and stifled rifle situation inspection
| Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 2 | |
| Adhesion situation | Between micropill, adhesion is tight | Existing without adhesion | Inviscid existing | Without adhesion |
| Heavy, affect coating and carry out | Resemble | Resemble | Phenomenon | |
| Coating times | 24h | 48h | 18h | 18h |
| Stifled rifle situation | Nothing | Nothing | Seriously | Nothing |
Result shows, and be not easy adhesion between the coated micropill using polyvinylpyrrolidone to prepare as binding agent, improve coating of pellets efficiency, and avoid the problem of blocking spray gun, method simple possible, is conducive to suitability for industrialized production.Result also shows, and using the ethanol of 95% not conform to as solvent or taste mask layer has Pulvis Talci to be also conducive to reducing adhesion and improving coating efficiency and alleviate blocking spray gun.
embodiment 9: comparative experiments disintegration of different disintegrating agent combination
1. specimen in use: with reference to the method preparation in embodiment 2, and except disintegrating agent kind (shown in the table 3 of specific as follows) difference, other component used and content all in the same manner as in Example 2, and the consumption of disintegrating agent is also identical with ratio (mass ratio 3: 1 of the former with the latter).
2. disintegration time mensuration method is identical with embodiment 4.
3. experimental result as shown in Table 3 below.
Table 3: the disintegration of different disintegrating agent combination
In table 3, microcrystalline Cellulose-MCC; Crospolyvinylpyrrolidone-PVPP; Cross-linking sodium carboxymethyl cellulose-CCNa; Carboxymethyl starch sodium-CMS-Na; Low-substituted hydroxypropyl cellulose-L-HPC.
Result shows, and microcrystalline Cellulose and crospolyvinylpyrrolidone are the most remarkable as the effect of associating disintegrating agent.
embodiment 10: mobility is tested
1. specimen in use: with reference to the method preparation in embodiment 2, and except agomelatine coated micropill: microcrystalline Cellulose: except ratio (shown in the table 4 of the specific as follows) difference of crospolyvinylpyrrolidone, other component used and content all in the same manner as in Example 2, and agomelatine coated micropill, microcrystalline Cellulose are also identical with the gross weight of crospolyvinylpyrrolidone.
2. experimental technique:
Powder body to be injected in the centrifugal disc of a finite diameter in the heart, until the material of powder body accumulation horizon hypotenuse flows out automatically along disk border, to stop injecting, measure the tiltangleθ that material forms coniform accumulation body in horizontal circle card, be angle of repose.
Angle of repose is less, proves that its mobility is better.It is generally acknowledged the good fluidity of powder when being less than 40 ° angle of repose.
3. experimental result as shown in Table 4 below.
Table 4: angle of repose determination experiment result
| Proportioning | 25∶9∶3 | 25∶12∶3 | 25∶15∶3 | 25∶9∶6 |
| Angle of repose (°) | 30 | 46 | 52 | 48 |
Result shows, and selects microcrystalline Cellulose and crospolyvinylpyrrolidone to be conducive to improving mobility as associating disintegrating agent, and microcrystalline Cellulose: crospolyvinylpyrrolidone is preferably 3: 2 to 4: 1, is more preferably 2: 1 to 3.5: 1.
Especially, when agomelatine coated micropill: microcrystalline Cellulose: when the consumption proportion of crospolyvinylpyrrolidone is 25: 9: 3, the angle of repose of material is less, and mobility is better, is convenient to direct compression, so be particularly preferred technical scheme.
embodiment 11: the compliance test result experiment of taste mask layer weightening finish
1. specimen in use: with reference to the method preparation in embodiment 2, and except coating weight gain (shown in the table 5 of specific as follows) difference, other condition is all in the same manner as in Example 2, and coating material is also identical.
2. experimental technique:
Determined by the taste masking effect of the micropill detecting different taste mask layer coating weight gain, mouthfeel experimental technique used is identical with embodiment 3.
3. experimental result:
As shown in Table 5 below.
Table 5: taste mask layer weightening finish confirmatory experiment result
| Coating weight gain | 16％ | 18％ | 20％ | 22％ | 24％ |
| Taste masking effect | There is bitterness | There is bitterness | Without bitterness | Without bitterness | Without bitterness |
Result shows, when taste mask layer coating (such as using Eudragit E100) weightening finish reaches more than 20%, the bitterness of principal agent can be covered preferably, but consider the too high particle diameter that can increase micropill of coating weight gain, so that produce grains of sand sense, affect final mouthfeel, so the coating weight gain of taste mask layer is particularly preferably 20%.
embodiment 12: the compliance test result experiment of hardness
1. specimen in use: with reference to the method preparation in embodiment 2, and except hardness (shown in the table 6 of the specific as follows) difference of tabletting, other condition is all in the same manner as in Example 2.
2. experimental technique:
In the same manner as in Example 4.
3. experimental result:
As shown in Table 6 below.
Table 6: different hardness is on the impact of disintegration
| Hardness (N) | 20 | 30 | 40 | 50 |
| Disintegration (s) | 7 | 10 | 14 | 32 |
Note: hardness be 40 be the obtained sample 2 of embodiment 2.
Usually, the higher medicine of hardness (such as disintegrating tablet) is firmer non-friable, is convenient to transport and storage, but disintegration can be lower; The disintegration of the lower medicine of hardness (such as disintegrating tablet) is lower, but easily broken, is not easy to transport and storage.
Result proves, hardness is 35-45 Newtonian time, disintegrating tablet in hardness (firmness degree) and achieve good balance between disintegration.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (30)
1. an agomelatine coated micropill, comprises containing the pill heart and taste mask layer, and wherein, the described pill pericardium that contains is containing the agomelatine as principal agent and the polyvinylpyrrolidone as binding agent; Wherein, the weight ratio of agomelatine and polyvinylpyrrolidone is 10:1 to 1:1; And obtained containing the pill heart as the solvent of agomelatine and polyvinylpyrrolidone using alcoholic solution, the concentration of described alcoholic solution is 70%-100% (w/w); Not containing Pulvis Talci in described taste mask layer.
2. coated micropill according to claim 1, wherein, the weight ratio of agomelatine and polyvinylpyrrolidone is 6:1 to 4:1.
3. coated micropill according to claim 1, wherein, the weight ratio of agomelatine and polyvinylpyrrolidone is 5:1.
4. coated micropill according to any one of claim 1 to 3, wherein, the concentration of described alcoholic solution is 90%-98% (w/w).
5. coated micropill according to any one of claim 1 to 3, wherein, the concentration of described alcoholic solution is 95% (w/w).
6. coated micropill according to any one of claim 1 to 3, wherein, the content of agomelatine in alcoholic solution is 5%-15% (w/w).
7. coated micropill according to any one of claim 1 to 3, wherein, the content of agomelatine in alcoholic solution is 8%-12% (w/w).
8. coated micropill according to any one of claim 1 to 3, wherein, the content of agomelatine in alcoholic solution is 10% (w/w).
9. coated micropill according to any one of claim 1 to 3, wherein, the material containing the pill heart blank pill heart used is microcrystalline Cellulose.
10. coated micropill according to claim 9, wherein, the diameter of the described blank pill heart is 100-200 micron.
11. coated micropills according to claim 1, wherein, the mean diameter of described coated micropill is for being less than or equal to 300 microns.
12. coated micropills according to claim 1, wherein, the mean diameter of described coated micropill is 100-200 micron.
13. coated micropills according to claim 1, wherein, taste mask layer coating material used comprises Eudragit E and/or Eudragit L.
14. coated micropills according to claim 13, wherein, described Eudragit E is Eudragit E100.
15. coated micropills according to claim 13, wherein, the weightening finish of taste mask layer is be not less than 20% containing pill heart weight.
16. coated micropills according to claim 13, wherein, the weightening finish of taste mask layer is the 20%-24% containing pill heart weight.
17. coated micropills according to claim 13, wherein, the weightening finish of taste mask layer is containing pill heart weight 20%.
Coated micropill according to any one of 18. claim 1 to 17 contains the purposes in the pharmaceutical composition that can disperse in mouth of agomelatine in preparation.
19. purposes according to claim 18, wherein, described pharmaceutical composition is tablet.
20. 1 kinds of pharmaceutical compositions that can disperse in mouth containing agomelatine, comprising: as the agomelatine of principal agent, and associating disintegrating agent, and wherein, described pharmaceutical composition comprises the coated micropill according to any one of claim 1 to 17.
21. pharmaceutical compositions according to claim 20, wherein, described associating disintegrating agent is microcrystalline Cellulose and crospolyvinylpyrrolidone.
22. pharmaceutical compositions according to claim 21, wherein, the content of described associating disintegrating agent is 25%-35% (w/w).
23. pharmaceutical compositions according to claim 22, wherein, the weight ratio of microcrystalline Cellulose and crospolyvinylpyrrolidone is 3:2 to 4:1.
24. pharmaceutical compositions according to claim 22, wherein, the weight ratio of microcrystalline Cellulose and crospolyvinylpyrrolidone is 2:1 to 3.5:1.
25. pharmaceutical compositions according to claim 22, wherein, the weight ratio of microcrystalline Cellulose and crospolyvinylpyrrolidone is 3:1.
26. pharmaceutical compositions according to claim 20, wherein, the content of described coated micropill is 55%-70% (w/w).
27. pharmaceutical compositions according to claim 26, wherein, coated micropill: associating disintegrating agent=25:12 (w/w).
28. pharmaceutical compositions according to claim 26, it also comprises the filler of 20%-40% (w/w).
29. pharmaceutical compositions according to any one of claim 20 to 28, it is tablet.
30. pharmaceutical compositions according to claim 29, wherein, the hardness of described tablet is 35-45 newton.
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| CN201110440302.7A CN103169669B (en) | 2011-12-26 | 2011-12-26 | Agomelatine covered pellet and drug composition capable of being dispersed in mouth |
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| CN201110440302.7A CN103169669B (en) | 2011-12-26 | 2011-12-26 | Agomelatine covered pellet and drug composition capable of being dispersed in mouth |
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| CN103169669B true CN103169669B (en) | 2015-06-17 |
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| CN104546733B (en) * | 2013-10-21 | 2019-04-19 | 广东东阳光药业有限公司 | A kind of benproperine odor-masking pellet |
| CN109589313A (en) * | 2017-10-01 | 2019-04-09 | 万特制药(海南)有限公司 | Agomelatine dispersible tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1622804A (en) * | 2002-01-23 | 2005-06-01 | 瑟维尔实验室 | Orodispersible pharmaceutical composition of agomelatine |
| CN1981752A (en) * | 2005-12-14 | 2007-06-20 | 瑟维尔实验室 | Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine |
| CN102949376A (en) * | 2011-08-25 | 2013-03-06 | 天津药物研究院 | Medicinal composition of agomelatine-containing enteric capsule |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1622804A (en) * | 2002-01-23 | 2005-06-01 | 瑟维尔实验室 | Orodispersible pharmaceutical composition of agomelatine |
| CN1981752A (en) * | 2005-12-14 | 2007-06-20 | 瑟维尔实验室 | Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine |
| CN101919800A (en) * | 2005-12-14 | 2010-12-22 | 瑟维尔实验室 | What be used for the oral mucosa of agomelatine or sublingual administration can be at the dispersive pharmaceutical composition of mouth |
| CN102949376A (en) * | 2011-08-25 | 2013-03-06 | 天津药物研究院 | Medicinal composition of agomelatine-containing enteric capsule |
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Inventor after: Mei Xingguo Inventor after: Xie Xiangyang Inventor after: Liu Hongyu Inventor after: Zhang Hui Inventor after: Li Zhiping Inventor after: Gong Wei Inventor after: Li Ying Inventor after: Yang Yang Inventor after: Yu Fanglin Inventor after: Wang Zhiyuan Inventor before: Mei Xingguo Inventor before: Liu Hongyu |
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