CN101006990A - Slow release preparation of cilostazol - Google Patents
Slow release preparation of cilostazol Download PDFInfo
- Publication number
- CN101006990A CN101006990A CNA2006101530797A CN200610153079A CN101006990A CN 101006990 A CN101006990 A CN 101006990A CN A2006101530797 A CNA2006101530797 A CN A2006101530797A CN 200610153079 A CN200610153079 A CN 200610153079A CN 101006990 A CN101006990 A CN 101006990A
- Authority
- CN
- China
- Prior art keywords
- sustained
- cilostazol
- release
- matrix material
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a slow release preparation of cilostazol and its preparing process, wherein the raw materials of the preparation include cilostazol of a predetermined proportion, slow release matrix material and medicinal material, the preparation can be prepared into solid dispersing agent, wherein the medicament can be released slowly and continuously after being administrated, the effective concentration in blood can be maintained, and long action can be achieved. The advantages of the invention include decreased frequency of medicinal administration, improved patient's adaptability, lowered blood concentration peak-valley, increased medicinal effect and safety, and reduced total medicinal dose, thereby optimum curative effect can be achieved through minimum dose, thus the preparation is more suitable for patients.
Description
[technical field] the present invention relates to slow releasing preparation of cilostazol and preparation method thereof.
[background technology]
The research and development of slow releasing preparation, the history surplus in the of existing so far 40 year, it is in environment provided, non-lentamente on request constant release, the preparation that medication every day number of times and corresponding ordinary preparation reduce once more at least or prolong to some extent blanking time of medication.This preparation can make human body keep this kind blood drug level to reach the long time, do not descend quickly the ordinary preparation and do not resemble, thereby " peak valley " phenomenon that can avoid the ordinary preparation frequent drug administration to be occurred, safety, effectiveness or the adaptability of medicine are increased, thereby reduced the medication number of times, greatly facilitate the patient, particularly the patient of long-term prescription.Peroral dosage form commonly used has matrix tablet, micropore bag pellicle controlled release tablet, laser osmotic pumps, composite particles chamber capsule, label chamber capsule, Entogastric lingering preparation, controlled release suspensoid, drop pill etc.; External preparation has eye therapy system, oral cavity sticking tablet, transdermal drug delivery system etc.; Injection has water suspension, Emulsion, liposome, microsphere etc.Tablet is with its taking convenience, and preparation technology is simple relatively, and quality is easy to advantage such as control becomes most widely used, the most sophisticated dosage form of technology of slow releasing preparation research and development.Capsule is also with its taking convenience, and preparation technology is simple relatively, and quality such as is easy to control at advantage becomes a wider dosage form of slow releasing preparation research and development application prospect.Film coating sustained-release and controlled release preparation packs the suitable clothing layer of one deck on the surface of label and piller, it is dissolved under certain condition or be partly dissolved and discharge medicine, can reach the sustained-release and controlled release effect.Its principle belongs to diffusion and discharges, and the energy is based on the osmotic pressure of film intracavity, or the stripping dispersal behavior coated slow release controlled release preparation of drug molecule in polymer is one of type of extensive use in the oral sustained release controlled release preparation.
Slow releasing preparation belongs to third generation preparation in the development process of pharmaceutics.In recent years, the research and development development of slow releasing preparation rapidly, the slow releasing preparation that with the Western medicine is material medicine has carried out a large amount of research at pharmacokinetics design principle, adjuvant and moulding process, biopharmaceutics characteristic aspects such as (comprising medicine inside and outside release rule and influence thereof), and existing many sophisticated kinds such as aminophylline slow releasing tablet, cefaclor slow releasing tablet, cefalexin slow releasing capsule etc. are widely used in clinically.Chinese medicine is more complicated in this regard, the Chinese medicine compound preparation active component is often indeterminate, thereby cause in its dissolubility, partition coefficient, the stability in Digestive system and the body and the logical suitable property of the combination rate of blood plasma, medicine pK value and biomembrane between relation etc. indeterminate, thereby increased the difficulty of preparation, but it is clinical that more existing at present sophisticated kinds are used for, as ZHENGQINGFENGTONGNING slow releasing tablet, aescine gel sustained-release preparation etc.
According to its preparation technology's difference, slow releasing preparation can be divided into tablet, capsule, sustained-release dropping pill etc.Used substrate comprises hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible sustained-release matrix material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble sustained-release matrix material is as ethyl cellulose, zein etc.Along with being on the increase of substrate kind, preparation technology's is ripe day by day perfect, and slow releasing agent is extensive day by day in the application of Chinese-western medicine preparation, therefore existing medicine is carried out modified form, produce more medicament slow release dosage form, will greatly enrich drug market, improve quality of medical care.
Cilostazol is a kind of selectivity camp-phosphodiesterase 3 inhibitor, by the cyclic adenosine monophosphate concentration in platelet increasing and the vascular smooth muscle, reaches the effect of blood vessel dilating, inhibition biologically active pdgf and inhibition smooth muscle cell proliferation.Therefore, cilostazol is microcirculation improvement effectively, increases the microcirculatory perfusion of peripheral nerve tissue, improves the hypoxic-ischemic state, thereby recovers nervous tissue's function.The cilostazol indication is clear and definite, is used to improve owing to the ulcer, the acroesthesia that cause of chronic arteria occlusion disease, feel cold and ischemic symptom such as the intermittent row of crossing mountains, and be the drug of first choice of intermittent this symptom of row of crossing mountains of treatment.The curative effect of cilostazol on the old thrombotic disease patient platelet aggregation of treatment is better than aspirin, alleviating pain and raising are suffered from the limb blood pressure and are better than ticlopidine, and side effect is littler than ticlopidine, and pain that the treatment vasculopathy of the lower extremity in diabetes becomes and the intermittent row symptom curative effect of crossing mountains obviously are better than dipyridamole.
The preparation of having succeeded in developing of this medicine has tablet, injection etc.The cilostazol serum half-life is two phasic properties, α is 2.2 hours mutually, β is 18.0 hours mutually, single administration dosage is 100mg, need administration 2-3 time general every day, using to the patient makes troubles, simultaneously because the influence of factors such as the length of one's sleep, affect the medicine steady plasma-drug concentration, thereby influence drug effect.The technology of the present invention is the cilostazol release formulation, can be administered once in 24 hours at interval, keeps best steady plasma-drug concentration, improves drug effect, the convenient use.
[summary of the invention]
The purpose of this invention is to provide slow releasing preparation of cilostazol and preparation method thereof.
The present invention studies by experiment cilostazol has been carried out modified form, changes slow releasing preparation into from existing tablet, capsule etc.Utilize medicament slow release framework material hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible sustained-release matrix material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble sustained-release matrix material, be aided with other common drug adjuvant as substrate such as ethyl cellulose, zein and selected medicine material and make solid preparation, make the non-lentamente as requested constant release of medicine, safety, effectiveness or the adaptability of medicine are increased, thereby reduced the medication number of times, greatly facilitate the patient, particularly the patient's of long-term prescription use.
Wherein, selected medicine has the chemical compound and its esters (as sodium salt, potassium salt, hydrochlorate, sulfate, hydrobromate, tartrate, the fumarate etc.) derivant of following feature:
Chinese: cilostazol
English name: Cilostazol
Chemical name: 6-[4-(1-hexamethylene-1H-tetrazolium-5-yl)-Ding oxygen]-3,4 dihydro-2 (1H) quinolizidine morpholine ketone.
Molecular formula: C
20H
27N
5O
2=369.46
Wherein said slow releasing tablet is formed its Chinese medicine by cilostazol and salt derivative thereof and substrate: sustained-release matrix material=1: 0.10-1: 10.0.Described substrate comprises the medicament slow release framework material: hydrophilic gel medicament slow release framework material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible medicament slow release framework material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble drug sustained-release matrix material comprises as ethyl cellulose, zein etc. and other additional materials:
1, diluent (filler): for example Icing Sugar, gelatin, glycerol, arabic gum, starch, dextrin, lactose, glucose, mannitol, calcium sulfate, calcium hydrogen phosphate, tricalcium phosphate, gelatinized corn starch, syrup, maltose, gelatine size, cellulose, Kaolin, sodium chloride, modified starch (Sta-RX1500), microcrystalline Cellulose etc., wherein Icing Sugar has sucrose, maltose, dextrinose, dextrinose oligosaccharide, panose, cottonseed sugar, stachyose, oligofructose, fructose, inulin, protein sugar, stevioside, xylitol, maltose alcohol, sorbitol;
2, binding agent: for example water, ethanol, starch, gelatin, sucrose, glucose, dextran, syrup, lactose, arabic gum, sodium alginate, gelatine size, polyvinylpyrrolidone, Polyethylene Glycol, methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, maltose, sucrose dextrin copolymer;
3, disintegrating agent: for example starch (corn and potato starch), cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, pectin, carboxymethyl cellulose, microcrystalline Cellulose, tween 80, lauric acid sodium sulfate, stearic acid sodium sulfonate, kaolin.
4, lubricant: for example stearic acid, calcium stearate, magnesium stearate, zinc stearate, hydrogenated vegetable oil, polyoxyethylene monostearate, light mineral oil, liquid paraffin, boric acid, sodium chloride, sodium benzoate, sodium acetate, enuatrol, lauric acid sodium sulfate (magnesium), single Laurel sucrose acid ester, adipic acid, fumaric acid, three triacetins, Polyethylene Glycol
1500～20000
5, fluidizer: for example starch, purified talc, micropowder silica gel, pyrolytic silicon dioxide, hydrated sodium aluminosilicate.
By the preparation method of following slow releasing tablet provided by the present invention, can further understand the present invention, but following description not a limitation of the invention:
1, the preparation method of slow releasing tablet:
With the medicine is primary raw material, according to certain ratio, adds medicament slow release framework material and additional materials as substrate, is prepared from through specific technology, apparatus processing again.Specific as follows:
(1) prescription: medicine+substrate;
Medicine: be foregoing medicine and its esters (as sodium salt, potassium salt, hydrochlorate, sulfate, hydrobromate, tartrate, fumarate etc.) derivant.
Substrate: include the medicament slow release framework material: hydrophilic gel medicament slow release framework material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible medicament slow release framework material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble drug sustained-release matrix material is as one or more composition and additional materials of ethyl cellulose, zein etc., its Chinese medicine: sustained-release matrix material=1: 0.10-1: 10.0.
(2) preparation technology: concrete implementation step is as follows:
Method one: according to certain ratio with medicine, erodible sustained-release matrix material, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc. and the additives mix homogeneously of milling, direct compression or dry granulation behind the adding lubricant, tabletting or elder generation add typical binders granulation, drying behind the adding lubricant, add the lubricant tabletting again.
Method two: according to certain ratio with medicine, erodible sustained-release matrix material, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and additives mill jointly mix after, again with hydrophilic gel sustained-release matrix material, as mixing such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomers, direct compression or dry granulation behind the adding lubricant, tabletting or elder generation add typical binders granulation, drying behind the adding lubricant, add the lubricant tabletting again.
Method three: according to certain ratio with medicine, additives and water-insoluble sustained-release matrix material, alcoholic solution mix homogeneously as ethyl cellulose, zein etc., add hydrophilic gel sustained-release matrix material, as mixing granulations such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomers, dry, add lubricant, tabletting gets finished product.
Method four: according to certain ratio with water-soluble components in medicine, the described additives and water-insoluble sustained-release matrix material, alcoholic solution mix homogeneously or dissolving as ethyl cellulose, zein etc., vacuum drying, pulverize, add hydrophilic gel sustained-release matrix material, as mixing such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomers, add the lubricant tabletting again behind adding lubricant direct compression or the dry granulation and get finished product.
Method five: with medicine, water-insoluble sustained-release matrix material, even with additives and mix lubricant as ethyl cellulose, zein etc., tabletting gets finished product according to certain ratio.
2, the preparation method of slow releasing capsule
With the medicine is primary raw material, according to certain ratio, adds medicament slow release framework material and additional materials as substrate, is prepared from through specific technology, apparatus processing again.Specific as follows:
(1) prescription: medicine+substrate;
Medicine: be foregoing medicine and its esters (as sodium salt, potassium salt, hydrochlorate, sulfate, hydrobromate, tartrate, fumarate etc.) derivant.
Substrate: include the medicament slow release framework material: hydrophilic gel medicament slow release framework material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible medicament slow release framework material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble drug sustained-release matrix material is as one or more composition and additional materials of ethyl cellulose, zein etc., its Chinese medicine: sustained-release matrix material=1: 0.10-1: 10.0.
(2) preparation technology: concrete implementation step is as follows:
Method one: according to certain ratio with medicine, erodible sustained-release matrix material, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc. and the additives mix homogeneously of milling, dry method or wet method are made slow-release pill or granule, add or do not add additives, be packed in the hard capsule.
Method two: according to certain ratio with medicine and additives mill jointly mix after, make slow-release pill or granule with dry method or wet method, the erodible sustained-release matrix material of reuse, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and/or hydrophilic gel sustained-release matrix material, as solution such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomers is that coating material is to ball pericardium clothing, add or do not add additives, be packed in the hard capsule.
Method three: according to certain ratio with medicine, erodible sustained-release matrix material, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc. and the additives mix homogeneously of milling, dry method or wet method are made slow-release pill or granule, the erodible sustained-release matrix material of reuse, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and/or hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, solution such as carbomer are that coating material is to ball pericardium clothing, add or do not add additives, be packed in the hard capsule
Method four: according to certain ratio with water-soluble components in medicine, the described additives and water-insoluble sustained-release matrix material, alcoholic solution mix homogeneously or dissolving as ethyl cellulose, zein etc., vacuum drying, pulverize, add hydrophilic gel sustained-release matrix material, as mixing such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomers, dry method or wet method are made slow-release pill or granule, add or do not add additives, be packed in the hard capsule.
Method five: according to certain ratio with medicine, water-soluble components in the described additives and water-insoluble sustained-release matrix material, as ethyl cellulose, the alcoholic solution mix homogeneously or the dissolving of zein etc., vacuum drying, pulverize, add hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, mixing such as carbomer, dry method or wet method are made slow-release pill or granule, the erodible sustained-release matrix material of reuse, as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc. and/or hydrophilic gel sustained-release matrix material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, solution such as carbomer are that coating material is to ball pericardium clothing, add or do not add additives, be packed in the hard capsule.
For the prolong drug per os is taken in the time of staying of back at gastric, guarantee that medicine discharges fully before small intestinal is left in transhipment, to improve bioavailability of medicament, cilostazol can further be made gastric retention type slow releasing preparation, prolong drug time of staying under one's belt whereby, medicine is discharged before leaving small intestinal fully, transport gradually, reach the purpose that abundant absorption improves bioavailability by duodenum and small intestinal.
But gastric retention system is the drug-supplying system of a kind of prolong drug at gastric transit time, comprises stomach floating system, gastric expansion system, bioadhesion system etc., and the most commonly used with the floating in stomach preparation.The floating in stomach drug-supplying system is meant can keep autologous density less than gastric content density after oral, is the preparation of floating state in gastric juice.It is to adopt that the present invention is designed to cilostazol floating in stomach preparation: (1) adds suitable floating material, as hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, take off ethylene chitin, polyvinyl alcohol, octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flava etc.; (2) add foaming agent, unite use, meet gastric acid and produce CO as carbonate, bicarbonate or carbonate, bicarbonate and citric acid, tartaric acid
2Gas, bag quilt and surface gel layer are to reach the effect that reduces preparation density.
The present invention adds hydrophilic gelatin polymer, as hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, take off the ethylene chitin, the lipid that polyvinyl alcohol and density are little, aliphatic alcohols, fatty acid or wax class, as octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flavas etc. are as floating material, add foaming agent, as carbonate, bicarbonate or carbonate, bicarbonate and citric acid, tartaric acid is united use, make preparation in gastric juice, meet the carbon dioxide that acid produces trace, all the time under one's belt floating, cilostazol is made the intragastric floating sustained-release tablet agent, thereby avoid medicine to enter the small intestinal section, thereby improved the curative effect of medicine by metabolism.In order to make preparation more effective, the medicine in the intragastric floating sustained-release tablet agent of described cilostazol: floating and ratios other auxiliary material are 1: 0.1-1: 5.
The slow released cilostazol sheet that [beneficial effect] is involved in the present invention utilizes the sustained-release matrix material to comprise hydrophilic gel medicament slow release framework material, as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer etc.; Erodible medicament slow release framework material is as stearic acid, hexadecanol, octadecanol, Polyethylene Glycol etc.; Water-insoluble drug sustained-release matrix material, as ethyl cellulose, zein etc. and floating and expanded material, as hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, take off the ethylene chitin, the lipid that polyvinyl alcohol and density are little, aliphatic alcohols, fatty acid or wax class, as octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flavas etc. are as floating material, add foaming agent, as carbonate, bicarbonate or carbonate, bicarbonate and citric acid, tartaric acid is united to use to wait and is made solid preparation as substrate and medicine material, make medicine medicine after administration can be on request slowly continue to discharge keeping effective blood concentration, thereby reach long-acting.
Compare with conventional formulation, medication preparation becomes to have its special advantages after the slow releasing tablet: (1) reduces administration number of times, improves patient's compliance of taking medicine; (2) reduce the blood concentration peak valley phenomenon, improve drug effect and drug safety: (3) reduce the accumulated dose of medication, so that minimum dose reaches greatest treatment efficacy; (4) after medicine is made slowly released and controlled-drug delivery system with suitable carrier, the absorption of medicine and the main character decision that distributes by carrier, therefore select the appropriate carriers material according to clinical requirement, not only can conduct drugs to the particular target organ, can also improve the physicochemical property and the pharmacologically active of medicine to a certain extent, have broad clinical application prospect.
[specific implementation method]
By following concrete embodiment, can further understand the present invention, but following example not a limitation of the invention.
The preparation of embodiment 1-slow released cilostazol sheet (1)
Method: get cilostazol 50 grams, hydroxypropyl cellulose 50 grams, hypromellose 15 grams, lactose 10 grams, microcrystalline Cellulose 10 grams, carbomer 1 gram, Macrogol 4000 30 grams respectively, mix homogeneously, dry granulation, adding magnesium stearate mixes, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (1) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 1, meet the requirements.
The dissolution of table 1 slow released cilostazol sheet (1)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 11.4 | 15.6 | 27.8 | 31.1 | 47.8 | 59.4 | 72.3 | 89.1 | 96.5 |
The preparation of embodiment 2-slow released cilostazol sheet (2)
Method: get cilostazol 50 gram, hydroxypropyl cellulose 10 grams, octadecanol 20 grams, hypromellose 15 grams, carbomer 1 gram, lactose 10 grams respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule drying at room temperature 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (2) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 2, meet the requirements.
The dissolution of table 2 slow released cilostazol sheet (2)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 8.1 | 16.2 | 27.4 | 39.6 | 50.5 | 67.2 | 73.4 | 85.5 | 90.3 |
The preparation of embodiment 3-slow released cilostazol sheet (3)
Method: get cilostazol 50g, hypromellose 35g, microcrystalline Cellulose 5g, carbomer 1g respectively, cross 80 mesh sieves respectively, mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, crosses 16 mesh sieves and granulates, 60 ℃ of dryings of granule 1 hour, 16 mesh sieve granulate add magnesium stearate 2.5 grams, mixing again, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (3) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 3, meet the requirements.
The dissolution of table 3 slow released cilostazol sheet (3)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 15.6 | 27.6 | 31.4 | 43.3 | 49.7 | 61.5 | 80.2 | 89.5 | 93.4 |
The preparation of embodiment 4-slow released cilostazol sheet (4)
Method: get cilostazol 50 grams, octadecanol 20 grams respectively, lactose 10 restrains, crosses respectively 80 mesh sieves, grind mixing, add hydroxypropyl cellulose 10 grams, hypromellose 15 grams, carbomer 1 gram, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, crossing 16 mesh sieves granulates, 60 ℃ of dryings of granule 1 hour, 16 mesh sieve granulate add magnesium stearate 4.5 grams, micropowder silica gel 2 grams, mixing again, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (4) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 4, meet the requirements.
The dissolution of table 4 slow released cilostazol sheet (4)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 15.2 | 20.8 | 30.6 | 45.5 | 53.3 | 66.6 | 82.3 | 85.4 | 90.6 |
The preparation of embodiment 5-slow released cilostazol sheet (5)
Method: get cilostazol 50 grams, lactose 10 grams, ethyl cellulose 30 grams (alcoholic solution) respectively, mix homogeneously adds hydroxypropyl cellulose 10 grams, carbomer 1 gram, mix homogeneously, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule drying at room temperature 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (5) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 5, meet the requirements.
The dissolution of table 5 slow released cilostazol sheet (5)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 7.6 | 17.7 | 29.8 | 37.5 | 54.4 | 63.4 | 79.3 | 80.5 | 97.1 |
The preparation of embodiment 6-slow released cilostazol sheet (6)
Method: get cilostazol 50 grams, lactose 10 grams, ethyl cellulose 30 grams (alcoholic solution) respectively, mix homogeneously, dry, pulverize, add hydroxypropyl cellulose 10 grams, carbomer 1 gram, mix homogeneously, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule room temperature ℃ drying 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (6) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 6, meet the requirements.
The dissolution of table 6 slow released cilostazol sheet (6)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 8.9 | 20.4 | 28.7 | 35.2 | 52.7 | 68.2 | 76.4 | 77.8 | 86.6 |
The preparation of embodiment 7-slow released cilostazol sheet (7)
Method: get cilostazol 50 grams, lactose 10 grams, ethyl cellulose 10 grams (alcoholic solution) respectively, mix homogeneously, drying is pulverized, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule drying at room temperature 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (7) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 7, meet the requirements.
The dissolution of table 7 slow released cilostazol sheet (7)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 13.6 | 15.7 | 42.3 | 56.7 | 75.1 | 84.5 | 89.6 | 90.2 | 93.4 |
The preparation of embodiment 8-slow released cilostazol sheet (8)
Method: get cilostazol 50 gram, hydroxypropyl cellulose 10 grams, octadecanol 20 grams, hypromellose 15 grams, carbomer 1 gram, lactose 10 grams respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule room temperature ℃ drying 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (8) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 8, meet the requirements.
The dissolution of table 8 slow released cilostazol sheet (8)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 6.7 | 13.7 | 24.5 | 43.2 | 54.8 | 69.8 | 80.7 | 87.6 | 97.2 |
The preparation of embodiment 9-slow released cilostazol sheet (9)
Method: get cilostazol 50 gram, hydroxypropyl cellulose 10 grams, octadecanol 50 grams, hypromellose 25 grams, carbomer 1 gram, lactose 10 grams respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule room temperature ℃ drying 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (9) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 9, meet the requirements.
The dissolution of table 9 slow released cilostazol sheet (9)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 12.9 | 19.6 | 27.4 | 38.7 | 50.2 | 59.7 | 72.1 | 83.5 | 89.4 |
The preparation of embodiment 10-slow released cilostazol sheet (10)
Method: get cilostazol 50 gram, hydroxypropyl cellulose 10 grams, octadecanol 50 grams, hypromellose 25 grams, carbomer 1 gram, lactose 10 grams respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, cross 16 mesh sieves and granulate granule room temperature ℃ drying 2 hours, 16 mesh sieve granulate, add magnesium stearate 4.5 grams, micropowder silica gel 2 grams again, mixing, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure the dissolution of slow released cilostazol sheet (10) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 10, meet the requirements.
The dissolution of table 10 slow released cilostazol sheet (10)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 10.9 | 13.2 | 24.1 | 30.1 | 45.5 | 52.8 | 67.6 | 87.2 | 94.7 |
The capsular preparation of embodiment 11-slow released cilostazol
Method: get cilostazol 50 grams, hydroxypropyl methylcellulose 50 grams, lactose 10 grams, ethyl cellulose 15 grams, carbomer 2 grams, calcium hydrogen phosphate 50 grams respectively, cross 80 mesh sieves respectively, put the mixer mixing, add concentration and be 60% ethanol water as wetting agent and stir and make soft material, cross 16 mesh sieves and granulate, 60 ℃ of dryings of granule 1 hour, 16 mesh sieve granulate add magnesium stearate 0.5 gram and Pulvis Talci 0.5 gram, mixing again, encapsulated, containing medication amount is the 50mg/ grain.Measure the dissolution of slow released cilostazol capsule (11) in 37 ℃ of 900ml water then.Through drug release determination, the results are shown in Table 11, meet the requirements.
The dissolution of table 11 slow released cilostazol sheet (11)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 14.4 | 26.3 | 33.4 | 48.1 | 62.1 | 78.6 | 89.4 | 92.4 | 94.3 |
The preparation of embodiment 12-cilostazol intragastric floating tablets
Method: get cilostazol 50 grams, hypromellose 40 grams, sodium carboxymethyl cellulose 5g, carbomer 15 grams, octadecanol 10 grams, sodium bicarbonate 10g respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, crosses 16 mesh sieves and granulates, granule drying at room temperature 2 hours, 16 mesh sieve granulate add magnesium stearate 3 grams, mixing again, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure dissolution and the flotation time of cilostazol intragastric floating tablets in 37 ℃ of 900m1 simulated gastric fluids then.Through drug release determination, the results are shown in Table 12, meet the requirements.The flotation time of table 13 in 37 ℃ of simulated gastric fluids met the floating requirement of administration greater than 24 hours.
The dissolution of table 12 cilostazol intragastric floating tablets (12)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 15.4 | 20.6 | 35.3 | 47.7 | 60.5 | 74.9 | 80.7 | 90.3 | 97.2 |
The floating experimental result of table 13 cilostazol intragastric floating tablets
| The test batch | 1 | 2 | 3 |
| Flotation time (hour) | ≥24 | ≥24 | ≥24 |
The preparation of embodiment 13-cilostazol stomach-floating sustained release capsule
Method: get cilostazol 50 grams, hydroxypropyl methylcellulose 50 grams, lactose 10 grams, ethyl cellulose 15 grams, carbomer 2 grams, sodium bicarbonate 10g respectively, cross 80 mesh sieves respectively, grind mixing, 95% alcoholic solution that adds concentration and be 10% polyvinylpyrrolidone is as binding agent and stir and make soft material, crosses 16 mesh sieves and granulates, granule room temperature ℃ drying 2 hours, 16 mesh sieve granulate add magnesium stearate 3 grams, mixing again, tabletting gets finished product, and containing medication amount is the 50mg/ sheet.Measure dissolution and the flotation time of cilostazol intragastric floating tablets in 37 ℃ of 900ml simulated gastric fluids then.Through drug release determination, the results are shown in Table 14, meet the requirements.The flotation time of table 15 in 37 ℃ of simulated gastric fluids met the floating requirement of administration greater than 24 hours.
The dissolution of table 14 cilostazol intragastric floating tablets (14)
| Sample time (hour) | 0.5 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 24 |
| Dissolution (%) | 10.2 | 14.3 | 28.7 | 40.7 | 51.6 | 67.9 | 75.4 | 89.5 | 92.5 |
The floating experimental result of table 15 cilostazol intragastric floating tablets
| The test batch | 1 | 2 | 3 |
| Flotation time (hour) | ≥24 | ≥24 | ≥24 |
Claims (9)
1, the slow releasing preparation of cilostazol is characterized in that: it contains ingredient and the slow release framework material and the additives of cilostazol, its Chinese medicine: sustained-release matrix material=1: 0.10-1: 10.0 substantially.
2, slow releasing preparation according to claim 1 is characterized in that: described sustained-release matrix material is one or more a combination in any of hydrophilic gel sustained-release matrix material, erodible sustained-release matrix material, water-insoluble sustained-release matrix material.
3. slow releasing preparation according to claim 1 is characterized in that: described cilostazol is cilostazol and salt derivative thereof.
4, sustained-release matrix material according to claim 2 is characterized in that: described hydrophilic gel sustained-release matrix material is one or more a combination in any of hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, carbomer; Described erodible sustained-release matrix material is one or more the combination in any in stearic acid, hexadecanol, octadecanol, the Polyethylene Glycol; Described water-insoluble sustained-release matrix material is that ethyl cellulose is or/and zein.
5, slow releasing preparation according to claim 1 is characterized in that: preparation type comprises slow releasing tablet, slow release capsule preparation.
6, slow releasing preparation according to claim 1 is characterized in that: described slow releasing tablet also comprises the intragastric floating sustained-release tablet agent of cilostazol, its Chinese medicine: floating and ratios other auxiliary material are 1: 0.1-1: 10.
7, slow releasing preparation according to claim 1 is characterized in that: additives include lubricant and filler, binding agent, disintegrating agent, lubricant, fluidizer and floating material and expanded material in the described slow releasing tablet.
8, intragastric floating sustained-release preparation according to claim 6 is characterized in that: the floating material of adding is hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, take off ethylene chitin, polyvinyl alcohol, octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flava.
9, intragastric floating sustained-release preparation according to claim 5 is characterized in that: the expanded material of adding is carbonate, bicarbonate or carbonate, bicarbonate and citric acid, tartaricly unites use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101530797A CN101006990A (en) | 2005-09-26 | 2006-09-21 | Slow release preparation of cilostazol |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510104989 CN1957928A (en) | 2005-09-26 | 2005-09-26 | Controlled release preparation of clinical treating medication, and fabricating method |
| CN200510104989.1 | 2005-09-26 | ||
| CNA2006101530797A CN101006990A (en) | 2005-09-26 | 2006-09-21 | Slow release preparation of cilostazol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101006990A true CN101006990A (en) | 2007-08-01 |
Family
ID=38695802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101530797A Pending CN101006990A (en) | 2005-09-26 | 2006-09-21 | Slow release preparation of cilostazol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101006990A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100551369C (en) * | 2007-03-02 | 2009-10-21 | 合肥合源医药科技股份有限公司 | A kind of slow releasing preparation that contains cilostazol and preparation method thereof |
| EP2120887A1 (en) * | 2007-02-15 | 2009-11-25 | Amorepacific Corporation | Controlled-release preparation containing cilostazol and process for the preparation thereof |
| CN102548543A (en) * | 2009-09-23 | 2012-07-04 | 韩国联合制药株式会社 | Slow-release cilostazol tablet having an improved elution rate and minimal side effects |
-
2006
- 2006-09-21 CN CNA2006101530797A patent/CN101006990A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2120887A1 (en) * | 2007-02-15 | 2009-11-25 | Amorepacific Corporation | Controlled-release preparation containing cilostazol and process for the preparation thereof |
| EP2120887A4 (en) * | 2007-02-15 | 2013-05-29 | Amorepacific Corp | Controlled-release preparation containing cilostazol and process for the preparation thereof |
| CN100551369C (en) * | 2007-03-02 | 2009-10-21 | 合肥合源医药科技股份有限公司 | A kind of slow releasing preparation that contains cilostazol and preparation method thereof |
| CN102548543A (en) * | 2009-09-23 | 2012-07-04 | 韩国联合制药株式会社 | Slow-release cilostazol tablet having an improved elution rate and minimal side effects |
| CN102548543B (en) * | 2009-09-23 | 2014-02-12 | 韩国联合制药株式会社 | Slow-release cilostazol tablet having improved elution rate and minimal side effects |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101002737A (en) | Slow release preparation of Kui-Liu-Ping | |
| CN101006989A (en) | Slow release preparation of alginic sodium diester | |
| CN101002747A (en) | Slow release preparation of cefaclor | |
| CN101002744A (en) | Slow release preparation of cefalexin | |
| CN101002741A (en) | Slow release preparation of Sai-Mi-Xi-Bu | |
| CN101015533A (en) | Sustained release preparation of norfloxacin | |
| CN101015532A (en) | Sustained release preparation of phenytoin sodiumslow release | |
| CN101002745A (en) | Slow release preparation of cefdinir | |
| CN101006991A (en) | Slow release preparation of berberine | |
| CN101006990A (en) | Slow release preparation of cilostazol | |
| CN101011363A (en) | Slow release tablet of amoxicillin | |
| CN101011364A (en) | Slow release preparation of metformin rosiglitazone | |
| CN101015530A (en) | Sustained release preparation of doxepin | |
| CN101006988A (en) | Slow release preparation of puerarin | |
| CN101002736A (en) | Slow-release preparation containing polyheteroside of tripterygium wilfordii | |
| CN101015534A (en) | Sustained release preparation of phenprobamate | |
| CN101015531A (en) | Sustained release preparation of dibazole | |
| CN101011368A (en) | Slow release tablet of troxerutin | |
| CN1994282A (en) | Sustained-release preparation of mexiletine | |
| CN101002740A (en) | Slow release preparation of compactin | |
| CN101011366A (en) | Slow release tablet of methylphenidate | |
| CN101002752A (en) | Slow release preparation of tropyone | |
| CN1994283A (en) | Sustained-release preparation of nicorandil | |
| CN113018271B (en) | Tandospirone pharmaceutical composition and preparation method and application thereof | |
| CN101002739A (en) | Slow release preparation of ranitidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |