CN104248631A - Agomelatine effervescent dry suspension and preparation method thereof - Google Patents
Agomelatine effervescent dry suspension and preparation method thereof Download PDFInfo
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Abstract
The invention provides an agomelatine effervescent dry suspension and a preparation method thereof. The agomelatine effervescent dry suspension comprises agomelatine, an effervescent disintegrant, a filler, a suspending agent and other optional medicinal auxiliary materials, wherein the other medicinal auxiliary materials are one or more of a flow aid, a sweetener, essence and a colouring agent, the effervescent disintegrant is composed of an acidic substance and an alkali substance, the weight ratio of agomelatine to the acidic substance is 1:(10-40), and the weight ratio of the acidic substance to the alkali substance is 2.5:1 or more. The agomelatine effervescent dry suspension is rapid to disperse, fast in effectiveness, high in bioavailability and good in stability, and has the agomelatine dissolution rate up to 95% or more.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of agomelatine effervescent dry-mixed suspension agent and preparation method thereof.
Background technology
The chemical name of agomelatine (Agomelatine) is N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide (N-[2-(7-methoxynaphth-l-yl) ethyl] acetamide), and its chemical formula is C
15h
17nO
2, molecular weight is 243.31, and chemical structural formula is such as formula shown in I:
Agomelatine (Agomelatine) is melatonin 1,2(MT1, MT2) receptor stimulating agent, also be 5-hydroxy tryptamine 2c(5HT2C simultaneously) receptor antagonist, can directly and the 5HT2C receptors bind of nerve synapse caudacoria, thus play its antidepressant curative effect, and do not increase the 5HT concentration between synapse, thus there is no the common adverse effect of serotonin reuptake inhibitor class medicine and 5-hydroxy tryptamine NRI class medicine.Another unique effect target spot of this medicine, at MT receptor, by the agonism to MT1 and MT2 receptor, 24 circadian rhythm 24s of adjustable patient, improves the sleep quality of patient, thus promotes the improvement of patients with depression overall clinical situation.
A large amount of clinical researches is verified: agomelatine has desirable shot and long term curative effect, and this medicine onset is rapid, and significantly reduces the recurrence recrudescence rate of depressive patient; Safety is significantly better than SSRI, SNRI class medicine, while alleviate depression disease core symptom, significantly improves patient sleeps's quality, and improving daystart wakefulness, is one of ideal chose meeting patient and these demands of doctor.
Agomelatine untoward reaction is less, common are headache, to feel sick and weak etc.No matter be short term therapy or long term maintenance therapy, its adverse reaction rate is similar to placebo, and the untoward reaction of long-term treatment comparatively short term therapy is less, this is also similar to placebo.Agomelatine does not cause the change of body weight, seldom has gastrointestinal side effect yet.
Agomelatine goes on the market as antidepressants.The agomelatine tablet of Shi Weiya company of France development is Film coated tablets, and its commodity are called
specification is 25mg.It is the melatonin receptor agonist antidepressants of first acquisition European Union listing approval in the world.
The kind that agomelatine goes on the market at present is conventional tablet, and clinical practice also needs to take more convenient, the better preparation formulation of patient compliance.Therefore, still need badly at present new stable be easy to the large production of industrialization and patient's agomelatine medicinal composition of more taking like a shot.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of agomelatine effervescent dry-mixed suspension agent and preparation method thereof.
Specifically, the invention provides:
(1) an agomelatine effervescent dry-mixed suspension agent, it comprises agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant, wherein,
Other described pharmaceutic adjuvant is one or more in fluidizer, sweeting agent, essence, coloring agent;
Described gas-producing disintegrant is made up of acidic materials and alkaline matter;
The weight ratio of described agomelatine and described acidic materials is 1:(10-40); And
The weight ratio of described acidic materials and described alkaline matter is more than or equal to 2.5:1.
(2) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, when being disperseed by the agomelatine effervescent dry-mixed suspension agent 20-200 weight parts water described in 1 weight portion, the pH value of the dispersion liquid of the suspensoid of gained is 1-6, is preferably 2-4.
(3) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, described acidic materials are selected from one or more in citric acid, tartaric acid, fumaric acid, adipic acid, malic acid, cinnamic acid, bayer acid, ferulic acid, water-soluble amino acid, Azelaic Acid, decanedioic acid, lauric acid, capric acid, silicic acid and taurine; Be preferably citric acid, tartaric acid or fumaric acid; Be more preferably citric acid.
(4) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, described alkaline matter is carbonate, is preferably selected from one or more in sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and calcium carbonate; Be preferably sodium carbonate or sodium bicarbonate; Be more preferably sodium bicarbonate.
(5) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, the weight ratio of described acidic materials and described alkaline matter is 2.5:1.
(6) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, described suspending agent is selected from one or more in xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, card pool nurse, polyvidone, sodium alginate, polyvinyl alcohol, arabic gum, Resina persicae, pectin, guar gum, chitosan and kieselguhr, is preferably xanthan gum;
Described fluidizer is selected from micropowder silica gel or Pulvis Talci, is preferably micropowder silica gel;
Described sweeting agent is selected from one or more in sucralose, steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin and Sodium Cyclamate, is preferably sucralose;
Described essence is selected from orange taste essence, Fructus Citri Limoniae essence, cherry essence, grape essence, strawberry essence or rose essence;
Described coloring agent is selected from lemon yellow, beta-carotene, red ferric oxide, Brown Ferric Oxide, sunset yellow, amaranth, carmine or erythrosine; And/or
Described filler is selected from one or more in starch, pregelatinized Starch, dextrin, lactose, sucrose, mannitol, microcrystalline Cellulose, glucose, xylitol and sorbitol, is preferably mannitol.
(7) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, one or more other pharmaceutic adjuvants that described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, gas-producing disintegrant 420-700 part, filler, suspending agent and is selected from fluidizer, sweeting agent, essence, coloring agent; The acidic materials of described gas-producing disintegrant are 300-500 part; The alkaline matter of described gas-producing disintegrant is 120-200 part; Wherein, described number is weight portion.
(8) the agomelatine effervescent dry-mixed suspension agent Gen Ju (1), wherein, described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, acidic materials 300-500 part, alkaline matter 120-200 part, filler 200-500 part, suspending agent 1-50 part, fluidizer 1-10 part, sweeting agent 1-10 part, essence 1-10 part and coloring agent 0.01-1 part; Wherein, described number is weight portion.
(9) according to (7) or the agomelatine effervescent dry-mixed suspension agent described in (8), wherein, described acidic materials are citric acid, and weight portion is 300 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 120 parts; Or
Described acidic materials are citric acid, and weight portion is 400 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 160 parts; Or
Described acidic materials are citric acid, and weight portion is 500 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 200 parts.
(10) a kind of preparation method according to the agomelatine effervescent dry-mixed suspension agent in (1)-(9) described in any one, described method comprises:
1) agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves; And
2) agomelatine of step 1) gained, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant are fully mixed, thus obtain described agomelatine effervescent dry-mixed suspension agent.
(11) a kind of preparation method according to the agomelatine effervescent dry-mixed suspension agent in (1)-(9) described in any one, described method comprises:
A) agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves;
B) after the agomelatine of step a) gained, gas-producing disintegrant, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully being mixed, granulate with binding agent, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
(12) a kind of preparation method according to the agomelatine effervescent dry-mixed suspension agent in (1)-(9) described in any one, described method comprises:
I) by the acidic materials in agomelatine, gas-producing disintegrant and the fully drying respectively of alkaline matter, filler, suspending agent and other optional pharmaceutic adjuvant, and the granularity of below 100 mesh sieves is crushed to;
Ii) by step I) agomelatine of gained, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully mix, be divided into 2 parts, respectively with step I) acidic materials in the gas-producing disintegrant of gained and alkaline matter mix homogeneously, granulate respectively with binding agent; And
Iii) by step I i) two parts mix homogeneously of gained, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
(13) according to (11) or the preparation method described in (12), wherein, described binding agent comprises polyvidone k30, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose or hypromellose, is preferably polyvidone k30; Described binding agent uses with its solution form, and solvent wherein comprises: dehydrated alcohol, alcoholic solution or water, is preferably 70%(v/v) ethanol.
The present invention compared with prior art has the following advantages and good effect:
1., in agomelatine effervescent dry-mixed suspension agent of the present invention, the dissolution of agomelatine is high, can up to more than 95%.
Agomelatine of the present invention by adding gas-producing disintegrant component in dry suspension, and the pH value of gained suspension, the way of ionic strength after regulating preparation to add water, further increase agomelatine dissolubility in an aqueous medium and stability.In agomelatine effervescent dry-mixed suspension agent of the present invention, the dissolution of agomelatine can up to more than 95%, and the dissolution of a such as preferred embodiment of the present invention up to 98.9%, can meet the requirement of the quality index of the dry suspension in pharmacopeia.
2. agomelatine effervescent dry-mixed suspension agent dispersion of the present invention is rapid, rapid-action, bioavailability is high, good stability.
Agomelatine effervescent dry-mixed suspension agent of the present invention improves the concentration of acid in gastric juice, is conducive to the stripping of agomelatine at gastric, thus changes the Pharmacokinetic Characteristics of Oral drug absorption, improves bioavailability.In addition, gas-producing disintegrant significantly can shorten the time being dispersed into homogenous suspension after dry suspension adds water, and ensures the high degree of dispersion state of medicine.Several aspect is all conducive to the oral absorption of agomelatine above, improves its bioavailability.
3. what agomelatine effervescent dry-mixed suspension agent of the present invention can meet various patient takes demand.
What agomelatine effervescent dry-mixed suspension agent of the present invention can meet various patient takes demand, and especially for the patient of salivation deficiency, oral cavity disintegration tablet can affect it and take, and the present invention is without this problem.In addition, the present invention's preferred agomelatine effervescent dry-mixed suspension agent mouthfeel is good, is beneficial to the compliance improving patient and take.
4. production technology of the present invention is easy, is beneficial to the large production of industrialization.
The preparation method of agomelatine effervescent dry-mixed suspension agent of the present invention and prior art are (such as, Orodispersible tablets disclosed in Chinese patent application No.200610167070.1) compare, production technology of the present invention is easy, requires low, be beneficial to the large production of industrialization to production equipment.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
In this article, described " part " all refers to " weight portion ".
In this article, described " gas-producing disintegrant " also claims effervescent, for a kind of water of meeting can produce acid, the alkali system that carbon dioxide reaches disintegration.When preparation contacts with water, wherein contained acid and alkali reaction generates carbon dioxide, makes the disintegrate at short notice of whole preparation, dispersion.
In this article, described " citric acid ", has another name called citric acid.Commercially available citric acid is usually containing a part water, i.e. citric acid monohydrate.
In this article, certain component also can not contain this component for " optional " refers in compositions to contain; Certain step also can not comprise this step for " optional " refers in method to comprise.
The object of this invention is to provide a kind of new agomelatine effervescent dry-mixed suspension agent and preparation method thereof.Described agomelatine effervescent dry-mixed suspension agent take agomelatine as active component, adds proper auxiliary materials and makes effervescent dry-mixed suspension agent.
The present inventor has carried out a large amount of experiments for the dissolution of the various dosage forms of agomelatine, have been surprisingly found that the dissolution of the effervescent dry-mixed suspension agent of agomelatine is apparently higher than other dosage form, therefore, the present inventor on this basis, further research has been carried out to each component of agomelatine effervescent dry-mixed suspension agent, have been surprisingly found that the ratio by significantly reducing agomelatine and gas-producing disintegrant middle acid substance in effervescent dry-mixed suspension agent, significantly can improve the dissolution of agomelatine in effervescent dry-mixed suspension agent, the dissolution of gained meets the requirement of the quality index of the dry suspension in pharmacopeia, on the basis that this finds, the present inventor obtains technical scheme of the present invention.
Such as, the weight ratio of common effervescent dosage form Chinese medicine and gas-producing disintegrant is generally (1-2): (1-4), acidic materials in gas-producing disintegrant and the weight ratio of alkaline matter are generally (1-2): (1-2), such as, scientific and technical literature 1: in " Li Yuanxin etc.; the research of Jieyinning effervescent tablet formula technique, " Chinese patent medicine " 04 phase in 2011 ", the acidic materials in gas-producing disintegrant and the weight ratio of alkaline matter are 1.2:1; Scientific and technical literature 2: in " Wan Hongbo, Hubei College Of Traditional Chinese Medicine, Hubei University of Chinese Medicine, master's thesis, the preparation technology of beautiful chrysanthemum effervescent tablet and quality standard research ", tartaric acid and sodium bicarbonate ratio are 1:1, and the ratio of medicine and gas-producing disintegrant is 2:1; Scientific and technical literature 3: in " Wang Wenzhong etc., flat magenblase rises the optimizing research of tablet recipe, " Yunnan Chinese medicine magazine " the 8th phase in 2011 ", citric acid: sodium bicarbonate=0.70:1; Scientific and technical literature 4: in " Zheng Limei etc., Shanghai Metallurgy Inst., Chinese Academy of Sciences, Materials Physics and Chemistry (specialty) thesis for the doctorate 2000 year, vitamin C effervescent tablet Study on Preparation ", sodium bicarbonate 480 grams, 280 grams, tartaric acid; Scientific and technical literature 5: in " Xia Caifu etc., the formulation and technology research of the scorching clearing effervescence tablet of woman, " Chinese experimental pharmacology of Chinese medical formulae magazine ", the 8th phase in 2008 ", the ratio of citric acid and extractum is the ratio of 1.5:1, sodium bicarbonate and extractum is 1.25:1.
And compared with the effervescent formulation of above-mentioned routine, in agomelatine effervescent dry-mixed suspension agent of the present invention, the weight ratio of agomelatine and acidic materials should be less than or equal to 1:10, be preferably 1:(10-40), be more preferably 1:(10-17).If this ratio is too low, then mouthfeel is taken in impact, increases production cost; If this ratio is too high, then stripping is difficult to reach requirement.In agomelatine effervescent dry-mixed suspension agent of the present invention, the weight ratio of acidic materials and alkaline matter should be more than or equal to 2.5:1, is preferably (2.5-10): 1.If this ratio is too low, then stripping is difficult to reach requirement; If this ratio is too high, then mouthfeel is taken in impact, increases production cost.Agomelatine effervescent dry-mixed suspension agent obtained by aforementioned proportion scope, the dissolution of agomelatine can up to more than 95%, the dissolution of a such as preferred embodiment of the present invention up to 98.9%, can meet the requirement of the quality index of the dry suspension in pharmacopeia.
Specifically, the invention provides:
(1) agomelatine effervescent dry-mixed suspension agent
The present invention provide firstly a kind of agomelatine effervescent dry-mixed suspension agent, it comprises agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant, wherein, described pharmaceutic adjuvant be selected from fluidizer, sweeting agent, essence, coloring agent one or more; Described gas-producing disintegrant is made up of acidic materials and alkaline matter; The weight ratio of described agomelatine and described acidic materials is 1:(10-40); And the weight ratio of described acidic materials and described alkaline matter is more than or equal to 2.5:1.
Preferably, the pH value that described agomelatine effervescent dry-mixed suspension agent adds the suspensoid of aqueous dispersion gained is 1-6, is preferably 2-4.Described agomelatine effervescent dry-mixed suspension agent adds water the operation before being separated into traditional oral, and such as, agomelatine effervescent dry-mixed suspension agent 1 part adds water 20-200 part.
Preferably, described acidic materials are selected from one or more in citric acid, tartaric acid, fumaric acid, adipic acid, malic acid, cinnamic acid, bayer acid, ferulic acid, water-soluble amino acid, Azelaic Acid, decanedioic acid, lauric acid, capric acid, silicic acid and taurine; It is further preferred that described acidic materials are citric acid, tartaric acid or fumaric acid; Be more preferably citric acid.Described citric acid is citric acid monohydrate or anhydrous citric acid, is preferably citric acid monohydrate.
Preferably, described alkaline matter is carbonate, is preferably selected from one or more in sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and calcium carbonate; It is further preferred that described alkaline matter is sodium carbonate or sodium bicarbonate; Be more preferably sodium bicarbonate.
Preferably, the weight ratio of described acidic materials and described alkaline matter is (2.5-10): 1.Such as, the weight ratio of described acidic materials and described alkaline matter is 10:1,5:1.Preferably, the weight ratio of described acidic materials and described alkaline matter is 2.5:1.
Preferably, described suspending agent is selected from one or more in xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, card pool nurse, polyvidone, sodium alginate, polyvinyl alcohol, arabic gum, Resina persicae, pectin, guar gum, chitosan and kieselguhr; Be more preferably xanthan gum.
Preferably, described fluidizer is selected from micropowder silica gel or Pulvis Talci; Be more preferably micropowder silica gel.
Preferably, described sweeting agent is selected from one or more in sucralose, steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin and Sodium Cyclamate; Be more preferably sucralose.
Preferably, described essence is selected from orange taste essence, Fructus Citri Limoniae essence, cherry essence, grape essence, strawberry essence or rose essence.
Preferably, described coloring agent is selected from lemon yellow, beta-carotene, red ferric oxide, Brown Ferric Oxide, sunset yellow, amaranth, carmine or erythrosine.
Preferably, described filler is selected from one or more in starch, pregelatinized Starch, dextrin, lactose, sucrose, mannitol, microcrystalline Cellulose, glucose, xylitol and sorbitol; Be more preferably mannitol.
In one embodiment of the invention, described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, gas-producing disintegrant 420-700 part and is selected from one or more other pharmaceutic adjuvants in filler, suspending agent, fluidizer, sweeting agent, essence, coloring agent.The acidic materials of described gas-producing disintegrant are 300-500 part; The alkaline matter of described gas-producing disintegrant is 120-200 part.
Preferably, described acidic materials are citric acid, and weight portion is 300 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 120 parts.
Preferably, described acidic materials are citric acid, and weight portion is 400 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 160 parts.
Preferably, described acidic materials are citric acid, and weight portion is 500 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 200 parts.
In a preferred embodiment of the invention, described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, acidic materials 300-500 part, alkaline matter 120-200 part, filler 200-500 part, suspending agent 1-50 part, fluidizer 1-10 part, sweeting agent 1-10 part, essence 1-10 part, coloring agent 0.01-1 part.
Preferably, described acidic materials are citric acid, and weight portion is 300 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 120 parts.
Preferably, described acidic materials are citric acid, and weight portion is 400 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 160 parts.
Preferably, described acidic materials are citric acid, and weight portion is 500 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 200 parts.
The using method of agomelatine effervescent dry-mixed suspension agent of the present invention: pour in suitable quantity of water by agomelatine effervescent dry-mixed suspension agent of the present invention before use, agitation as appropriate is oral after making dispersion.
(2) preparation method of agomelatine effervescent dry-mixed suspension agent
Method 1:
Present invention also offers a kind of preparation method of described agomelatine effervescent dry-mixed suspension agent, described method comprises:
1) described agomelatine, described gas-producing disintegrant, described filler, described suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves; And
2) agomelatine of step 1) gained, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant are fully mixed, thus obtain described agomelatine effervescent dry-mixed suspension agent.
Method 2:
Present invention also offers a kind of preparation method of described agomelatine effervescent dry-mixed suspension agent, described method comprises:
A) described agomelatine, described gas-producing disintegrant, described filler, described suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves;
B) after the agomelatine of step a) gained, gas-producing disintegrant, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully being mixed, granulate with binding agent, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
Method 3:
Present invention also offers a kind of preparation method of described agomelatine effervescent dry-mixed suspension agent, described method comprises:
I) by the acidic materials in described agomelatine, described gas-producing disintegrant and the fully drying respectively of alkaline matter, described filler, described suspending agent and other optional pharmaceutic adjuvant, and the granularity of below 100 mesh sieves is crushed to;
Ii) by step I) agomelatine of gained, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully mix, be divided into 2 parts, respectively with step I) acidic materials in the gas-producing disintegrant of gained and alkaline matter mix homogeneously, granulate respectively with binding agent; And
Iii) by step I i) two parts mix homogeneously of gained, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
Preferably, described binding agent comprises polyvidone k30, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, is preferably polyvidone k30; The solvent of described binding agent comprises: dehydrated alcohol or alcoholic solution, water, is preferably 70%(v/v) ethanol.
In one embodiment of the invention, described agomelatine effervescent dry-mixed suspension agent is prepared by the following method:
A) agomelatine in prescription is fully dry respectively with all adjuvants comprising gas-producing disintegrant;
B) granularity of below 100 mesh sieves is crushed to; And
C) then fully mix, subpackage.
In another embodiment of the invention, described agomelatine effervescent dry-mixed suspension agent is prepared by the following method:
A) agomelatine in prescription is fully dry respectively with all adjuvants comprising gas-producing disintegrant;
B) granularity of below 100 mesh sieves is crushed to;
C) fully mix, the binding agent being solvent in order to high concentration ethanol is granulated; And
D) subpackage after drying.
In another embodiment of the invention, described agomelatine effervescent dry-mixed suspension agent is prepared by the following method:
A) agomelatine in prescription and all adjuvants comprising gas-producing disintegrant are abundant thousand dry respectively;
B) granularity of below 100 mesh sieves is crushed to;
C) agomelatine is fully mixed with other adjuvant except gas-producing disintegrant, is evenly divided into 2 parts, mix homogeneously with the bronsted lowry acids and bases bronsted lowry in gas-producing disintegrant respectively, with 70%(v/v) ethanol be solvent binding agent granulate; And
D) after drying by two parts mix homogeneously, subpackage.
Mode below by way of example further explains and describes content of the present invention, but these examples are not to be construed as limiting the scope of the invention.
In following example, if no special instructions, each reagent all can derive from Beijing Feng Lijingqiu commerce and trade Co., Ltd.
Embodiment 1-3
The single dosage formulation of embodiment 1-3 can see table 1.
Table 1
| Raw material | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Agomelatine | 30mg | 30mg | 30mg |
| Citric acid monohydrate | 300mg | 400mg | 500mg |
| Sodium bicarbonate | 120mg | 160mg | 200mg |
| Xanthan gum | 10mg | 10mg | 10mg |
| Mannitol | 500mg | 400mg | 200mg |
| Sucralose | 5mg | 5mg | 5mg |
| Micropowder silica gel | 5mg | 5mg | 5mg |
| Orange taste essence | 2mg | 2mg | 2mg |
| Lemon yellow | 0.1mg | 0.1mg | 0.1mg |
Embodiment 1 preparation technology: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, by active component agomelatine and filler, suspending agent, gas-producing disintegrant, correctives (i.e. sweeting agent and essence, lower same) and coloring agent mix homogeneously, with 5%(w/v) ethanol solution of polyvidone k30 is as binding agent granule, the abundant mix homogeneously of fluidizer is added again, by single dose subpackage after particle drying.
The preparation technology of embodiment 2: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, active component agomelatine is mixed homogeneously with filler, suspending agent, gas-producing disintegrant, add correctives, fluidizer and coloring agent again and be fully mixed into pressed powder, by single dose subpackage.
Embodiment 3 preparation technology: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, active component agomelatine is mixed homogeneously with filler, suspending agent, correctives and coloring agent, mixture is divided into 2 parts, respectively with citric acid monohydrate, sodium bicarbonate mix homogeneously, mixture uses 5%(w/v respectively) 70%(v/v of polyvidone k30) alcoholic solution is as binding agent granule, mix homogeneously after 2 partial particulate dryings, add the abundant mix homogeneously of fluidizer again, by single dose subpackage.
Embodiment 4
The single dosage formulation of embodiment 4 can see table 2.
Table 2
| Agomelatine | 30mg |
| Tartaric acid | 400mg |
| Sodium bicarbonate | 160mg |
| Sodium alginate | 10mg |
| Mannitol | 400mg |
| Sucralose | 5mg |
| Micropowder silica gel | 5mg |
| Orange taste essence | 2mg |
| Lemon yellow | 0.1mg |
| The ethanol solution of polyvidone k30 | In right amount |
Preparation technology: in upper table 2 ratio, by each supplementary material respectively drying and crushing cross 100 mesh sieves, active component agomelatine is mixed homogeneously with sodium alginate, tartaric acid, sodium bicarbonate, mannitol, correctives and coloring agent, with 5%(w/v) ethanol solution of polyvidone k30 is as binding agent granule, the abundant mix homogeneously of micropowder silica gel is added again, by single dose subpackage after particle drying.
Embodiment 5
The single dosage formulation of embodiment 5 can see table 3.
Table 3
| Agomelatine | 30mg |
| Fumaric acid | 400mg |
| Sodium bicarbonate | 160mg |
| Card pool nurse 971 | 10mg |
| Mannitol | 400mg |
| Aspartame | 5mg |
| Micropowder silica gel | 5mg |
| Grape essence | 2mg |
| Red ferric oxide | 0.1mg |
| 70% alcoholic solution of polyvidone k30 | In right amount |
Preparation technology: in upper table 3 ratio, each supplementary material respectively drying and crushing crosses 100 mesh sieves, active component agomelatine and card are moored nurse 971, mannitol, correctives and coloring agent mix homogeneously, mixture is divided into 2 parts, respectively with fumaric acid, sodium bicarbonate mix homogeneously, mixture uses 5%(w/v respectively) 70%(v/v of polyvidone) alcoholic solution as binding agent granule, mix homogeneously after 2 partial particulate dryings, add the abundant mix homogeneously of micropowder silica gel again, by single dose subpackage.
Embodiment 6-7
The single dosage formulation of embodiment 6-7 can see table 4.
Table 4
| Raw material | Embodiment 6 | Embodiment 7 |
| Agomelatine | 30mg | 30mg |
| Anhydrous citric acid | 1200mg | 800mg |
| Sodium bicarbonate | 120mg | 160mg |
| Xanthan gum | 10mg | 10mg |
| Mannitol | 500mg | 400mg |
| Sucralose | 5mg | 5mg |
| Micropowder silica gel | 5mg | 5mg |
| Orange taste essence | 2mg | 2mg |
| Lemon yellow | 0.1mg | 0.1mg |
Embodiment 6,7 preparation method is with embodiment 2.
Comparative example 1-3
The formula of comparative example 1-3 can see table 5.
Table 5
| Raw material | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Agomelatine | 30mg | 30mg | 50mg |
| Citric acid monohydrate | 50mg | 100mg | 200mg |
| Sodium bicarbonate | 30mg | 60mg | 120mg |
| Xanthan gum | 10mg | 10mg | 10mg |
| Mannitol | 800mg | 700mg | 600mg |
| Sucralose | 5mg | 5mg | 5mg |
| Micropowder silica gel | 5mg | 5mg | 5mg |
| Orange taste essence | 2mg | 2mg | 2mg |
| Lemon yellow | 0.1mg | 0.1mg | 0.1mg |
The preparation technology of comparative example 1: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, active component agomelatine is mixed homogeneously with filler, suspending agent, gas-producing disintegrant, add correctives, fluidizer and coloring agent again and be fully mixed into pressed powder, by single dose subpackage.
Comparative example 2 preparation technology: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, active component agomelatine is mixed homogeneously with filler, suspending agent, gas-producing disintegrant, correctives and coloring agent, with 5%(w/v) ethanol solution of polyvidone k30 is as binding agent granule, the abundant mix homogeneously of fluidizer is added again, by single dose subpackage after particle drying.
Comparative example 3 preparation technology: supplementary material respectively drying and crushing crosses 100 mesh sieves, weigh in above-mentioned prescription ratio, active component agomelatine is mixed homogeneously with filler, suspending agent, correctives and coloring agent, mixture is divided into 2 parts, respectively with citric acid monohydrate, sodium bicarbonate mix homogeneously, mixture uses 5%(w/v respectively) 70% alcoholic solution of polyvidone k30 is as binding agent granule, mix homogeneously after 2 partial particulate dryings, add the abundant mix homogeneously of fluidizer again, by single dose subpackage.
Test example 1
Carry out quality evaluation to embodiment 1-3 and comparative example 1-3, wherein, the assay method of pH, sedimentation volume ratio, content, loss on drying is see Chinese Pharmacopoeia 2010 editions second annex.
Dissolution determination method: adopt slurry processes, at 37 ± 0.5 DEG C, single dose is using 900ml water as dissolution medium, rotating speed is 50rpm, determined wavelength 236nm, with ZRS-8G type intelligence dissolving-out tester, according to Chinese Pharmacopoeia second annex XC dissolution determination second method, sampling in 30 minutes.
Experimental result is as following table 6.
Table 6
As can be seen from the result of table 6, embodiment 1-3 dissolution determination result is all more than 95%, and every quality index of sample all meets and exceedes dry suspension requirement.
Similarly, the dissolution determination result of embodiment 4-7 is also more than 95%, and every quality index of sample all meets and exceedes dry suspension requirement.
Analytical test result can be found out, in agomelatine effervescent dry-mixed suspension agent, the ratio of agomelatine and acidic materials should be less than or equal to 1:10, preferred 1:(10-17).In agomelatine effervescent dry-mixed suspension agent, the ratio of acidic materials and alkaline matter should be more than or equal to 2.5:1, is preferably (2.5-10): 1, is more preferably 2.5:1.
Claims (13)
1. an agomelatine effervescent dry-mixed suspension agent, it comprises agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant, wherein,
Other described pharmaceutic adjuvant is one or more in fluidizer, sweeting agent, essence, coloring agent;
Described gas-producing disintegrant is made up of acidic materials and alkaline matter;
The weight ratio of described agomelatine and described acidic materials is 1:(10-40); And
The weight ratio of described acidic materials and described alkaline matter is more than or equal to 2.5:1.
2. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, when being disperseed by the agomelatine effervescent dry-mixed suspension agent 20-200 weight parts water described in 1 weight portion, the pH value of the dispersion liquid of the suspensoid of gained is 1-6, is preferably 2-4.
3. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, described acidic materials are selected from one or more in citric acid, tartaric acid, fumaric acid, adipic acid, malic acid, cinnamic acid, bayer acid, ferulic acid, water-soluble amino acid, Azelaic Acid, decanedioic acid, lauric acid, capric acid, silicic acid and taurine; Be preferably citric acid, tartaric acid or fumaric acid; Be more preferably citric acid.
4. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, described alkaline matter is carbonate, is preferably selected from one or more in sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and calcium carbonate; Be preferably sodium carbonate or sodium bicarbonate; Be more preferably sodium bicarbonate.
5. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, the weight ratio of described acidic materials and described alkaline matter is 2.5:1.
6. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, described suspending agent is selected from one or more in xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, card pool nurse, polyvidone, sodium alginate, polyvinyl alcohol, arabic gum, Resina persicae, pectin, guar gum, chitosan and kieselguhr, is preferably xanthan gum;
Described fluidizer is selected from micropowder silica gel or Pulvis Talci, is preferably micropowder silica gel;
Described sweeting agent is selected from one or more in sucralose, steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin and Sodium Cyclamate, is preferably sucralose;
Described essence is selected from orange taste essence, Fructus Citri Limoniae essence, cherry essence, grape essence, strawberry essence or rose essence;
Described coloring agent is selected from lemon yellow, beta-carotene, red ferric oxide, Brown Ferric Oxide, sunset yellow, amaranth, carmine or erythrosine; And/or
Described filler is selected from one or more in starch, pregelatinized Starch, dextrin, lactose, sucrose, mannitol, microcrystalline Cellulose, glucose, xylitol and sorbitol, is preferably mannitol.
7. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, one or more other pharmaceutic adjuvants that described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, gas-producing disintegrant 420-700 part, filler, suspending agent and is selected from fluidizer, sweeting agent, essence, coloring agent; The acidic materials of described gas-producing disintegrant are 300-500 part; The alkaline matter of described gas-producing disintegrant is 120-200 part; Wherein, described number is weight portion.
8. agomelatine effervescent dry-mixed suspension agent according to claim 1, wherein, described agomelatine effervescent dry-mixed suspension agent comprises agomelatine 30 parts, acidic materials 300-500 part, alkaline matter 120-200 part, filler 200-500 part, suspending agent 1-50 part, fluidizer 1-10 part, sweeting agent 1-10 part, essence 1-10 part and coloring agent 0.01-1 part; Wherein, described number is weight portion.
9. the agomelatine effervescent dry-mixed suspension agent according to claim 7 or 8, wherein, described acidic materials are citric acid, and weight portion is 300 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 120 parts; Or
Described acidic materials are citric acid, and weight portion is 400 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 160 parts; Or
Described acidic materials are citric acid, and weight portion is 500 parts; Described alkaline matter is sodium bicarbonate, and weight portion is 200 parts.
10., according to a preparation method for the agomelatine effervescent dry-mixed suspension agent in claim 1-9 described in any one, described method comprises:
1) agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves; And
2) agomelatine of step 1) gained, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant are fully mixed, thus obtain described agomelatine effervescent dry-mixed suspension agent.
11. 1 kinds of preparation methoies according to the agomelatine effervescent dry-mixed suspension agent in claim 1-9 described in any one, described method comprises:
A) agomelatine, gas-producing disintegrant, filler, suspending agent and other optional pharmaceutic adjuvant is fully dry respectively, and be crushed to the granularity of below 100 mesh sieves;
B) after the agomelatine of step a) gained, gas-producing disintegrant, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully being mixed, granulate with binding agent, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
12. 1 kinds of preparation methoies according to the agomelatine effervescent dry-mixed suspension agent in claim 1-9 described in any one, described method comprises:
I) by the acidic materials in agomelatine, gas-producing disintegrant and the fully drying respectively of alkaline matter, filler, suspending agent and other optional pharmaceutic adjuvant, and the granularity of below 100 mesh sieves is crushed to;
Ii) by step I) agomelatine of gained, filler, suspending agent and optional other pharmaceutic adjuvant except fluidizer fully mix, be divided into 2 parts, respectively with step I) acidic materials in the gas-producing disintegrant of gained and alkaline matter mix homogeneously, granulate respectively with binding agent; And
Iii) by step I i) two parts mix homogeneously of gained, optionally add fluidizer mix homogeneously, thus obtain described agomelatine effervescent dry-mixed suspension agent.
13. preparation methoies according to claim 11 or 12, wherein, described binding agent comprises polyvidone k30, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose or hypromellose, is preferably polyvidone k30; Described binding agent uses with its solution form, and solvent wherein comprises: dehydrated alcohol, alcoholic solution or water, is preferably 70%(v/v) ethanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108077698A (en) * | 2018-01-18 | 2018-05-29 | 滁州学院 | A kind of Chrysanthemum Petal suspending beverage based on peach gum dispersion |
| EP3466413A1 (en) * | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Pharmaceutical composition containing agomelatine and process for the preparation thereof |
| CN114366714A (en) * | 2021-04-29 | 2022-04-19 | 山东京卫制药有限公司 | Agomelatine suspension nasal spray and application thereof |
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| CN1935120A (en) * | 2005-08-04 | 2007-03-28 | 昆明杉榆生物技术有限公司 | Effervescent dry-mixed suspension agent |
| CN102557979A (en) * | 2010-12-16 | 2012-07-11 | 北大方正集团有限公司 | Agomelatine crystal form, as well as preparation method, application and medicinal composition thereof |
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- 2013-06-25 CN CN201310256545.4A patent/CN104248631A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1935120A (en) * | 2005-08-04 | 2007-03-28 | 昆明杉榆生物技术有限公司 | Effervescent dry-mixed suspension agent |
| CN102557979A (en) * | 2010-12-16 | 2012-07-11 | 北大方正集团有限公司 | Agomelatine crystal form, as well as preparation method, application and medicinal composition thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3466413A1 (en) * | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Pharmaceutical composition containing agomelatine and process for the preparation thereof |
| CN108077698A (en) * | 2018-01-18 | 2018-05-29 | 滁州学院 | A kind of Chrysanthemum Petal suspending beverage based on peach gum dispersion |
| CN114366714A (en) * | 2021-04-29 | 2022-04-19 | 山东京卫制药有限公司 | Agomelatine suspension nasal spray and application thereof |
| CN114366714B (en) * | 2021-04-29 | 2022-10-11 | 山东京卫制药有限公司 | Agomelatine suspension nasal spray and application thereof |
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