CN102670519B - Quickly-dissolvable dienogest oral preparation and preparation method thereof - Google Patents
Quickly-dissolvable dienogest oral preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmacy, and particularly relates to a quickly-dissolvable dienogest oral preparation and a preparation method thereof. The technical problem to be solved of the invention is to provide a quickly-dissolvable dienogest oral preparation, which can be used for realizing quick dissolving of dienogest by over 95 percent within 5 minutes to fulfill the aim of quick response. The dienogest oral preparation consists of dienogest and medicinal auxiliary materials, and is characterized in that: the particle diameter of the dienogest is 15-50 mum; and the medicinal auxiliary materials are common medicinal auxiliary materials for preparing the oral preparation. The invention provides a quickly-dissolvable dienogest oral preparation and a preparation method thereof. A product has reliable quality, is safe, and can act quickly; and moreover, the preparation method is simple and practicable, and contributes to industrial production.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of dienogest oral formulations that can Fast Stripping and preparation method thereof.
Background technology
Dienogest (17 Beta-methyl gonane-4, beta-hydroxy-13, alfa-cyanomethyl-17,9-diene-3-ketone) is a kind of estrogen of high selectivity, is used at first by the exploitation of German Jenapharm company as oral contraceptive.Mochida Pharm Co., Ltd of Japan has obtained this product in Japanese research license, and the purposes that it is applied to separately to endometriosis was studied, and obtained the approval of Japanese health ministry in 2007, and specification is 1mg, and indication is endometriosis.
Dienogest is a kind of white or micro-yellow crystalline powder, within the scope of water and physiological pH, does not all dissolve.For this within the scope of physiological pH equal undissolved medicines, at least may produce the problem aspect two at gastrointestinal tract after oral: the one, medicine crystal may damage gastrointestinal tract mucous; The 2nd, bioavailability is low, and medicine can not absorb and not reach minimum effective blood drug concentration.This product partition coefficient 2.15～2.17, is fat-soluble medicine, belongs to the Equations of The Second Kind medicine of biopharmaceutics categorizing system, in dissolution in vitro and body, absorbs and has dependency.Therefore, solve the problem of this product bioavailability aspect, make this product absorb rapidly in vivo onset, this product need to be made to quick releasing formulation.For solving the problem of dissolubility and bioavailability, have been reported as follows:
As: held the dienogest fast-release tablet of field pharmaceutical manufacturing by Japan, in water, 5min dissolution can reach more than 90%, but prepares at present the concrete technical method of this Fast Stripping without bibliographical information.
And for example: Chinese patent application CN101926782A discloses a kind of oral solid drug composition containing dienogest, it is that application micronization technology is improved the deliquescent technology of dienogest, this micronization technology is to control the powder diameter scope of dienogest at 1～10 μ m, improves problem poorly soluble under physiological environment by " granule is soluble ".Even if but selected little granule like this, can not reach easily desirable effect, the document is pointed out " by after dienogest micropowder; especially in certain average particle size range; can play a role to the stripping of dienogest ", as will be " reached the quick and complete stripping of medicine ", also must " add again the surfactant of minute quantity ", although the surfactant adding is minute quantity, but to play the effect that makes " the quick and complete stripping of medicine ", adding of surfactant is but very crucial.Therefore, the document is to prepare oral cavity disintegration tablet by " micronized dienogest with the adjuvant that contains surfactant ", realizes " taste is good, without grittiness, and disintegrate is rapid, stripping is complete ".And " solve dienogest stripping slow and incomplete problem ".
Analyze after available data, inventor think dienogest dissolve in vivo become oral dienogest affect its performance drug effect primary key factor, the comparatively ideal state of clinical practice dienogest is: oral dienogest can be absorbed completely and rapidly, absolute bioavailability is greater than 90%, and the time that reaches maximum serum and plasma concentration is about respectively 2 and 1～2 hours.In blood plasma, approximately 10% dienogest exists with free form.
Summary of the invention
Technical problem solved by the invention is to provide a kind of dienogest oral formulations that can Fast Stripping, can realize dienogest and dissolve more than 95% rapidly in 5min, reaches the object of quick acting.
Dienogest oral formulations of the present invention, is made up of dienogest and pharmaceutic adjuvant, it is characterized in that: the particle diameter of controlling dienogest is 15-50 μ m; Pharmaceutic adjuvant is the conventional pharmaceutic adjuvant of preparing oral formulations.
Further preferably, the particle diameter of controlling dienogest is 20～40 μ m.
Applying above-mentioned micronized dienogest, to prepare the pharmaceutic adjuvant used of tablet, granule or capsule be filler, disintegrating agent, binding agent, lubricant.Wherein:
Filler is selected from a kind of or its mixing in lactose, starch, microcrystalline Cellulose, mannitol or pregelatinized Starch; The preferably compositions of lactose, microcrystalline Cellulose, pregelatinized Starch; Wherein lactose consumption is 20-60% (w/w); Microcrystalline Cellulose consumption 20-60% (w/w), pregelatinized Starch are 5-30% (w/w).
Disintegrating agent is selected from a kind of or its mixing in starch, partially pregelatinized starch, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone or carboxymethyl starch sodium; Preferably carboxymethyl starch sodium or partially pregelatinized starch; Partially pregelatinized starch or carboxymethyl starch sodium consumption are 1-8% (w/w).
Binding agent is selected from a kind of or its mixing in polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose or starch slurry; Preferably hydroxypropyl emthylcellulose, consumption is appropriate.
Lubricant is magnesium stearate, sodium lauryl sulphate or Polyethylene Glycol; Preferably magnesium stearate.
Second technical problem solved by the invention has been to provide a kind of method of the dienogest oral formulations of preparing this Fast Stripping, and the dosage form of oral formulations comprises tablet, granule, capsule.
Wherein, the preparation method of dienogest tablet is as follows, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant.
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution and step 3) gained mixture mixes, and granulates, dry;
5) granulate that sieves, adds lubricant, mixes, tabletting, to obtain final product.
In said method, the particle diameter of dienogest is preferably 20～40 μ m; The preferred lactose of filler, the microcrystalline Cellulose adopting, the compositions of pregelatinized Starch; Wherein lactose consumption is 20-60% (w/w); Microcrystalline Cellulose consumption 20-60% (w/w), pregelatinized Starch are 5-30% (w/w).In the time adding above-mentioned filler,, in the time of step 3, be that micronization dienogest is first mixed with lactose, then mix with other filleies, disintegrating agent; And preferably with equivalent progressively increase mode admixed finepowder dienogest and the lactose of method.And then according to conventional method granulate, tabletting can obtain can Fast Stripping dienogest tablet.
Wherein, the preparation method of dienogest granule is as follows, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent.
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution and step 3) gained mixture mixes, and granulates, dry, granulate and get final product.
In said method, the particle diameter of dienogest is preferably 20～40 μ m; The preferred lactose of filler, the microcrystalline Cellulose adopting, the compositions of pregelatinized Starch; Wherein lactose consumption is 20-60% (w/w); Microcrystalline Cellulose consumption 20-60% (w/w), pregelatinized Starch are 5-30% (w/w).In the time adding above-mentioned filler,, in the time of step 3, be that micronization dienogest is first mixed with lactose, then mix with other filleies, disintegrating agent; And preferably with equivalent progressively increase mode admixed finepowder dienogest and the lactose of method.And then according to conventional method granulate can obtain can Fast Stripping dienogest granule.
Wherein, the preparation method of dienogest capsule is as follows, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant.
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution and step 3) gained mixture mixes, and granulates, dry;
5) granulate that sieves, adds lubricant, mixes, encapsulated, to obtain final product.
In said method, the particle diameter of dienogest is preferably 20～40 μ m; The preferred lactose of filler, the microcrystalline Cellulose adopting, the compositions of pregelatinized Starch; Wherein lactose consumption is 20-60% (w/w); Microcrystalline Cellulose consumption 20-60% (w/w), pregelatinized Starch are 5-30% (w/w).In the time adding above-mentioned filler,, in the time of step 3, be that micronization dienogest is first mixed with lactose, then mix with other filleies, disintegrating agent; And preferably with equivalent progressively increase mode admixed finepowder dienogest and the lactose of method.And then according to conventional method granulate, encapsulated can obtain can Fast Stripping dienogest capsule.
Beneficial effect of the present invention is as follows:
1, the key of dienogest oral formulations of the present invention is that the particle size range of controlling dienogest is at 15-50 μ m; Compared with large many of the micronization particle diameter 1-10 μ m of CN101926782A.Generally the less solubility property of microgranule is better, but larger particle diameter has been selected in invention, and in the situation that not adding surfactant, the dissolution in vitro within the scope of water, physiological pH dissolves rapidly more than 95% dienogest in 5min, has reached better result of extraction.
2, reduced technology and equipment requirement, cost-saving and energy consumption.If prepare less granule, process conditions are also harsher, also higher to the requirement of equipment, therefore the larger granule of preparation has much advantage in this respect, can reduce equipment cost and energy consumption.
3, reduced greatly the generation of related substance.Inventor finds that the heat in micronization process is one of principal element of impelling related substance increase, if prepare larger granule, can reduce the heat discharging in micronization process, reduce technological temperature, thereby reduce greatly the generation of related substance, improved quality and the safety of medicine.
4, preparation technology of the present invention is simple to operation, makes reliable product quality, effective, is conducive to industrial-scale production.
To sum up, the invention provides dienogest oral formulations (as tablet, granule, capsule) of a kind of energy Fast Stripping and preparation method thereof, reliable product quality, safety, can play quick-acting effects; And preparation method is simple, is conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: the stripping curve figure of tablet samples in stripping evaluation system 1.
Fig. 2: the stripping curve figure of tablet samples in stripping evaluation system 2.
Fig. 3: the stripping curve figure of tablet samples in stripping evaluation system 3.
Fig. 4: the stripping curve figure of granule sample in stripping evaluation system 1.
Fig. 5: the stripping curve figure of granule sample in stripping evaluation system 2.
Fig. 6: the stripping curve figure of granule sample in stripping evaluation system 3.
Fig. 7: the stripping curve figure of capsule sample in stripping evaluation system 1.
Fig. 8: the stripping curve figure of capsule sample in stripping evaluation system 2.
Fig. 9: the stripping curve figure of capsule sample in stripping evaluation system 3.
The specific embodiment
Illustrate but do not limit the present invention by specific description of embodiments of the present invention below.
Dienogest oral formulations of the present invention is that employing particle diameter is the dienogest of 15-50 μ m, is prepared from according to the conventional method of oral formulations with pharmaceutic adjuvant.
Be below the example of preparing of oral formulations of the present invention, and prove the experiment of oral formulations beneficial effect of the present invention.
One, prepare example
Tablet embodiment:
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-30 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronization dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (microcrystalline Cellulose), disintegrating agent (cross-linked pvp);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of 25-35 μ m scope, obtains micronization dienogest;
2, preparation 3%HPMC (5cp) aqueous solution (binding agent);
3, micronization dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (starch), disintegrating agent (cross-linking sodium carboxymethyl cellulose);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of 35-45 μ m scope, obtains micronization dienogest;
2, preparation 3%HPMC (5cp) aqueous solution (binding agent);
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (microcrystalline Cellulose, pregelatinized Starch), disintegrating agent (carboxymethyl starch sodium);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of mean diameter 40-50 μ m scope, obtains micronization dienogest;
2, preparation 3%PVPk30 aqueous solution;
3, micronized dienogest is mixed with mannitol by the equivalent method of progressively increasing, then mix with other filleies (microcrystalline Cellulose, pregelatinized Starch), disintegrating agent (cross-linking sodium carboxymethyl cellulose);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, i.e. micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with disintegrating agent (cross-linked pvp);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 15-30 μ m scope, i.e. micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with filler microcrystalline Cellulose by the equivalent method of progressively increasing, then mix with disintegrating agent (carboxymethylstach sodium).
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes, tabletting.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 30-50 μ m scope, obtains micronization dienogest;
2, the binder solution (HPMC aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with pregelatinized Starch by the equivalent method of progressively increasing, then mix with disintegrating agent (cross-linking sodium carboxymethyl cellulose).
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, be dried to pellet moisture and meet the requirements;
5, the granulate that sieves, adds lubricant (magnesium stearate), mixes tabletting.
Granule embodiment:
Prescription:
Preparation technology
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with disintegrating agent (carboxymethylstach sodium);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, screening, packs and get final product.
Embodiment 9
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (Microcrystalline cellulose) and disintegrating agent (the fine micro-plain sodium of cross-linked carboxymethyl);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, screening, packs and get final product.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (pregelatinized Starch) and disintegrating agent (the fine micro-plain sodium of cross-linked carboxymethyl);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, screening, packs and get final product.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (pregelatinized Starch) and disintegrating agent (carboxymethylstach sodium);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, screening, packs and get final product.
Capsule embodiment:
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 15-30 μ m scope, obtains micronization dienogest;
2, the binder solution (HPMC aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with disintegrating agent (carboxymethylstach sodium);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, mixs homogeneously with lubricant (magnesium stearate), packs gastric-dissolved capsule into and get final product.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 25-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (Microcrystalline cellulose) and disintegrating agent (the fine micro-plain sodium of cross-linked carboxymethyl);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, mixs homogeneously with lubricant (magnesium stearate), packs gastric-dissolved capsule into and get final product.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 40-50 μ m scope, obtains micronization dienogest;
2, the binder solution (HPMC aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (pregelatinized Starch) and disintegrating agent (the fine micro-plain sodium of cross-linked carboxymethyl);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, mixs homogeneously with magnesium stearate, packs gastric-dissolved capsule into and get final product.
Prescription:
Preparation technology:
1, dienogest is shattered, screening obtains the microgranule of particle diameter 20-40 μ m scope, obtains micronization dienogest;
2, the binder solution (PVPk30 aqueous solution) of preparation 3%;
3, micronized dienogest is mixed with lactose by the equivalent method of progressively increasing, then mix with other filleies (pregelatinized Starch) and disintegrating agent (carboxymethylstach sodium);
4, suitable amount of adhesive solution is added in the powder of above-mentioned mix homogeneously and granulate, dry;
5, the granulate that sieves, mixs homogeneously with magnesium stearate, packs gastric-dissolved capsule into and get final product.
The prior art the most close with dienogest oral formulations of the present invention is the disclosed oral cavity disintegration tablet of CN101926782A, and it is that application micronization dienogest is prepared oral cavity disintegration tablet with the adjuvant that contains surfactant.Wherein, to be crushed to particle size range be 1～10 μ m to dienogest.
Comparative experimental example 1: with reference to CN101926782A preparation, containing surfactant.
Prescription:
Preparation method:
1, dienogest is shattered, screening obtains the microgranule of 1-10 μ m scope, obtains micronization dienogest;
2, after micronized dienogest and lactose equivalent are progressively increased mixing, add all the other adjuvants in prescription to mix;
3, tabletting.
Two, result of extraction contrast experiment
1, test specimen
2, detection method:
Leaching condition: get product prepared by above embodiment, according to 2005 editions two appendix XC the second methods of Chinese Pharmacopoeia, respectively take water, 0.1MHCl, pH6.8 phosphate buffer 900ml as dissolution medium, rotating speed 50r/min.Sample filtration in 5min, 15min, 30min, according to high-efficient liquid phase technique (2005 editions two appendix VD of Chinese Pharmacopoeia) measure, record chromatogram, by external standard method with calculated by peak area dissolution.
Liquid-phase condition: chromatographic column: C18; Mobile phase: 50% acetonitrile; Detect wavelength: 210nm; Flow velocity: 1ml/min.
Table 1 Dissolution Evaluation system
| Numbering | Dissolution medium | Medium volume | |
| 1 | Water | 900ml | 50r/ |
| 2 | 0.1MHCl | 900ml | 50r/ |
| 3 | PH6.8 phosphate buffer | 900ml | 50r/min |
The dissolution (stripping curve with reference to accompanying drawing 1) of table 2 tablet samples in evaluation system 1
| |
1# | 2# | 3# | 4# | 5# | 6# | 7# | 16# | 17 |
| 5min | |||||||||
| 97％ | 96％ | 98％ | 97％ | 95％ | 96％ | 95％ | 93％ | 91％ | |
| 15min | 98％ | 97％ | 99％ | 99％ | 97％ | 98％ | 99％ | 98％ | 97％ |
| 30min | 99％ | 97％ | 98％ | 100％ | 100％ | 97％ | 100％ | 99％ | 98％ |
The dissolution (stripping curve with reference to accompanying drawing 2) of table 3 tablet samples in evaluation system 2
| |
1# | 2# | 3# | 4# | 5# | 6# | 7# | 16# | 17 |
| 5min | |||||||||
| 98％ | 96％ | 97％ | 95％ | 96％ | 96％ | 95％ | 89％ | 92％ | |
| 15min | 99％ | 98％ | 100％ | 97％ | 100％ | 99％ | 97％ | 94％ | 98％ |
| 30min | 100％ | 99％ | 106％ | 99％ | 99％ | 100％ | 99％ | 97％ | 99％ |
The dissolution (stripping curve with reference to accompanying drawing 3) of table 4 tablet samples in evaluation system 3
| |
1# | 2# | 3# | 4# | 5# | 6# | 7# | 16# | 17 |
| 5min | |||||||||
| 97％ | 96％ | 98％ | 96％ | 96％ | 95％ | 95％ | 88％ | 93％ | |
| 15min | 98％ | 97％ | 98％ | 99％ | 98％ | 97％ | 98％ | 91％ | 95％ |
| 30min | 101％ | 99％ | 100％ | 99％ | 98％ | 98％ | 99％ | 95％ | 99％ |
The dissolution (stripping curve with reference to accompanying drawing 4) of table 5 granule sample in evaluation system 1
| |
8# | 9# | 10# | 11# | 16# | 17 |
| 5min | ||||||
| 96％ | 98％ | 99％ | 98％ | 93％ | 91％ | |
| 15min | 100％ | 98％ | 100％ | 99％ | 98％ | 97％ |
| 30min | 99％ | 99％ | 99％ | 100％ | 99％ | 98％ |
The dissolution (stripping curve with reference to accompanying drawing 5) of table 6 granule sample in evaluation system 2
| |
8# | 9# | 10# | 11# | 16# | 17 |
| 5min | ||||||
| 96％ | 99％ | 99％ | 98％ | 89％ | 92％ | |
| 15min | 98％ | 98％ | 101％ | 97％ | 94％ | 98％ |
| 30min | 98％ | 100％ | 100％ | 99％ | 97％ | 99％ |
The dissolution (stripping curve with reference to accompanying drawing 6) of table 7 granule sample in evaluation system 3
| |
8# | 9# | 10# | 11# | 16# | 17 |
| 5min | ||||||
| 100％ | 98％ | 99％ | 97％ | 88％ | 93％ | |
| 15min | 99％ | 99％ | 99％ | 98％ | 91％ | 95％ |
| 30min | 100％ | 99％ | 101％ | 99％ | 95％ | 99％ |
The dissolution (stripping curve with reference to accompanying drawing 7) of table 8 capsule sample in evaluation system 1
| |
12# | 13# | 14# | 15# | 16# | 17 |
| 5min | ||||||
| 96％ | 95％ | 97％ | 99％ | 93％ | 91％ | |
| 15min | 98％ | 99％ | 100％ | 100％ | 98％ | 97％ |
| 30min | 99％ | 99％ | 101％ | 100％ | 99％ | 98％ |
The dissolution (stripping curve with reference to accompanying drawing 8) of table 9 capsule sample in evaluation system 2
| |
12# | 13# | 14# | 15# | 16# | 17 |
| 5min | ||||||
| 97％ | 100％ | 99％ | 98％ | 89％ | 92％ | |
| 15min | 98％ | 98％ | 100％ | 100％ | 94％ | 98％ |
| 30min | 99％ | 100％ | 99％ | 99％ | 97％ | 99％ |
The dissolution (stripping curve with reference to accompanying drawing 9) of table 10 capsule sample in evaluation system 3
| |
12# | 13# | 14# | 15# | 16# | 17 |
| 5min | ||||||
| 95％ | 96％ | 96％ | 97％ | 88％ | 93％ | |
| 15min | 101％ | 98％ | 100％ | 100％ | 91％ | 95％ |
| 30min | 99％ | 99％ | 101％ | 99％ | 95％ | 99％ |
Dissolution interpretation of result: the product that the present invention makes stripping behavior under three kinds of different leaching conditions is reliable and stable, and all can in the time of 5min, can arrive more than 95% by dissolution, dissolution rate is better than the tablet that imported product and prior art (CN10192678A) obtain.
Three, related substance contrast test:
Detection method: chromatographic column: C18; Mobile phase A: acetonitrile: water=20: 80; B: acetonitrile; Adopt gradient elution
The related substance situation of the each sample of table 11
| |
1# | 2# | 3# | 4# | 5# | 6# | 7# | 8# | 9# | 10# | 11# | 12# | 13# | 14# | 15# | 16# | 17# |
| Single maximum contaminant % | 0.04 | 0.03 | 0.05 | 0.03 | 0.03 | 0.04 | 0.02 | 0.05 | 0.04 | 0.03 | 0.03 | 0.02 | 0.04 | 0.03 | 0.05 | 0.25 | 0.05 |
| Total impurities % | 0.12 | 0.10 | 0.11 | 0.12 | 0.13 | 0.10 | 0.09 | 0.14 | 0.10 | 0.12 | 0.10 | 0.09 | 0.10 | 0.13 | 0.14 | 0.40 | 0.13 |
Related substance interpretation of result: the related substance of product of the present invention is much smaller than with prior art (CN10192678A), suitable with imported product, reliable in quality is safe.
Claims (8)
1. dienogest oral formulations, is made up of dienogest and pharmaceutic adjuvant, it is characterized in that: the particle diameter of described dienogest is 15-50 μ m;
Described oral formulations is tablet, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, dry;
5) granulate that sieves, adds lubricant, mixes, tabletting, obtains tablet;
Or
Described oral formulations is granule, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, and dry, granulate obtains granule;
Or
Described oral formulations is capsule, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, dry;
5) granulate that sieves, adds lubricant, mixes, encapsulated, obtains capsule.
2. dienogest oral formulations according to claim 1, is characterized in that: the particle diameter of described dienogest is 20～40 μ m.
3. dienogest oral formulations according to claim 1, is characterized in that:
Described filler is a kind of or its mixing in lactose, starch, microcrystalline Cellulose, mannitol or pregelatinized Starch;
Described disintegrating agent is a kind of or its mixing of starch, partially pregelatinized starch, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone or carboxymethyl starch sodium;
Described binding agent is a kind of or its mixing in polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose or starch slurry;
Described lubricant is magnesium stearate, sodium lauryl sulphate or Polyethylene Glycol.
4. dienogest oral formulations according to claim 3, is characterized in that: described filler is the compositions of lactose, microcrystalline Cellulose, pregelatinized Starch;
In oral formulations, the percentage by weight of lactose, microcrystalline Cellulose, pregelatinized Starch is respectively: lactose 20-60%, microcrystalline Cellulose 20-60%, pregelatinized Starch 5-30%.
5. dienogest oral formulations according to claim 3, is characterized in that: described disintegrating agent is partially pregelatinized starch or carboxymethyl starch sodium; The percentage by weight of partially pregelatinized starch or carboxymethyl starch sodium accounts for the 1-8% of oral formulations principal agent and pharmaceutic adjuvant gross weight.
6. the preparation method of dienogest oral formulations, is characterized in that: after dienogest is crushed to particle diameter and is 15-50 μ m, be prepared into oral formulations according to conventional method;
Described oral formulations is tablet, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, dry;
5) granulate that sieves, adds lubricant, mixes, tabletting, obtains tablet;
Or
Described oral formulations is granule, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, and dry, granulate obtains granule;
Or
Described oral formulations is capsule, and the pharmaceutic adjuvant of employing is filler, disintegrating agent, binding agent, lubricant; Preparation method is as follows:
1) dienogest is made to the microgranule that granularity is 15-50 μ m, be called micronization dienogest;
2) prepare the binder solution of 1-5% concentration;
3) micronization dienogest is mixed with filler, disintegrating agent;
4) by step 2) gained binder solution mixes with step 3) gained mixture, granulates, dry;
5) granulate that sieves, adds lubricant, mixes, encapsulated, obtains capsule.
7. the preparation method of dienogest oral formulations according to claim 6, is characterized in that: the particle diameter of described dienogest is 20～40 μ m.
8. according to the preparation method of the dienogest oral formulations described in claim 6 or 7, it is characterized in that: described filler is the compositions of lactose, microcrystalline Cellulose, pregelatinized Starch; In oral formulations, the percentage by weight of lactose, microcrystalline Cellulose, pregelatinized Starch is respectively: lactose 20-60%, microcrystalline Cellulose 20-60%, pregelatinized Starch 5-30%.
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| CN105769841A (en) * | 2014-08-12 | 2016-07-20 | 烟台市华文欣欣医药科技有限公司 | Application of syringic acid/4-hydroxy-3,5-dimethoxybenzoic acid in preparing drug for pregnancy termination |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101583364A (en) * | 2007-03-01 | 2009-11-18 | 拜耳先灵医药股份有限公司 | Pharmaceutical preparation for the alleviation of endometriosis |
| CN101926782A (en) * | 2009-06-26 | 2010-12-29 | 北京德众万全药物技术开发有限公司 | Oral solid drug compound containing dienogest |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101583364A (en) * | 2007-03-01 | 2009-11-18 | 拜耳先灵医药股份有限公司 | Pharmaceutical preparation for the alleviation of endometriosis |
| CN101926782A (en) * | 2009-06-26 | 2010-12-29 | 北京德众万全药物技术开发有限公司 | Oral solid drug compound containing dienogest |
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