CN102293760A - Isosorbide mononitrate timing controlled release preparation and preparation method thereof - Google Patents
Isosorbide mononitrate timing controlled release preparation and preparation method thereof Download PDFInfo
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- CN102293760A CN102293760A CN2011100527637A CN201110052763A CN102293760A CN 102293760 A CN102293760 A CN 102293760A CN 2011100527637 A CN2011100527637 A CN 2011100527637A CN 201110052763 A CN201110052763 A CN 201110052763A CN 102293760 A CN102293760 A CN 102293760A
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- controlled release
- isosorbide mononitrate
- film
- preparation
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- 229960003827 isosorbide mononitrate Drugs 0.000 title claims abstract description 62
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- 238000000034 method Methods 0.000 claims description 23
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- 239000012982 microporous membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000881 verapamil hydrochloride Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Abstract
The invention discloses an isosorbide mononitrate timing controlled release preparation and a preparation method thereof. The isosorbide mononitrate timing controlled release preparation of the present invention has certain time-lag and long-acting stationary release, and comprises a semi-permeable membrane with drug release apertures, an isolating coating and a double layer label including a drug contained layer and a boosting layer. The isosorbide mononitrate timing controlled release preparation of the present invention is an osmotic pump tablet with certain time-lag and long-acting stationary release, and can provide a more lasting and stationary plasma concentration and is bioequivalent compared with a sale long-acting preparation Elantan.
Description
Technical field
The present invention relates to drug preparation technique, be specifically related to a kind of isosorbide mononitrate timing and controlled release preparation and preparation method thereof.
Background technology
Antianginal drug is the important category in the cardiovascular drugs, has occupied 16% proportion in 8 class cardiovascular drugses commonly used.Anti-anginal drug comprises following a few class: 1. nitrate esters is representative with nitroglycerin, isosorbide mononitrate; 2. beta-blocker is as Propranolol; 3. calcium antagonist is as nifedipine, nimodipine (referring to antihypertensive commonly used); 4. other anti-anginal drug is as molsidomine, dipyridamole etc.; 5. Chinese herbal medicine class preparation is as Chinese herbal medicine extract or Chinese patent medicines such as Radix Salviae Miltiorrhizae class, Folium Ginkgo class, Radix Notoginseng class, Moschus classes.Data according to statistics, the medicinal medicine total value of calendar year 2001 whole nation Chinese patent medicine class control angina pectoris class reaches 36.56 hundred million yuan, and wherein hospital terminal accounts for 54.80%, and retail terminal accounts for 45.20%.Control angina pectoris medicine natural drug commonly used accounts for 58.89%; Nitrate esters accounts for 38.14%, and the 5-isosorbide mononitrate (Isosorbide-5-mononitrate, 5-ISMN) pharmacological action is similar to sorbide nitrate, does not need directly to work through first metabolism, and absolute bioavailability reaches 100%.Effective blood drug concentration is stable, and the half-life is 4～5 hours.Effect is held time longer, distributes rapidly after the oral absorption, is the optimal nitrate esters medicine of finding at present, uses extensively.
Patent application CN200410030824.X, a kind of treatment coronary heart disease and anginal isosorbide mononitrate sustained release tablets are disclosed, it comprises isosorbide mononitrate, slow releasing agent, binding agent, filler and lubricant, and its weight ratio is 100: (200～320): (50～160): 30: 1.Preparation technology adopts wet granulation, behind granule oven dry, the granulate, adds moderate lubrication agent mixing, tabletting promptly.
Patent application CN200610145665.7 relates to pharmaceutical sorbide nitrate or the rapid release of isosorbide mononitrate (common)/slow release or preparation that rapid release (common)/controlled release combines.Main gel skeleton and the film prosecutor formula of adopting reaches the design preparation.
Common skeleton and film controlling agent can reach certain releasing effect substantially, but, the isosorbide mononitrate water solublity is fabulous, adopt the preparation medicine release burst effect in early stage of above prepared in one of two ways comparatively obvious, it is more that the drug release of ordinary preparation is subjected to influence factors such as the interior gastrointestinal motility of body, pH value, food effect simultaneously, and inside and outside and interindividual variation are bigger.
And there is very fast drug resistance in nitrate esters medicine, and resistance mechanism is indeterminate, and multiple hypothesis is arranged.Relevant with dosage form, route of administration, dosage and the usage of nitrate esters medicine.There have result of study to show that blood vessel produces drug resistance to isosorbide mononitrate (5-ISMN) to be relevant with its paddy concentration, can very fast generation toleration more than the 300ug/ml, and the long period is lower than 100ug/ml and can avoids toleration.For general formulation, as ordinary tablet blood drug level instability in vivo, form Wave crest and wave trough easily, behind the oral ordinary preparation blood drug level rise too fast, up to 400ng/mL.For fear of drug resistance, the scheme that FDA recommends is with asymmetric interval administration, promptly 8 of every mornings and afternoon takes each a slice of 5-ISMN ordinary tablet to the experimenter at 3.This scheme can effectively be prevented anginal outbreak, and its drug effect continues 12 hours at least, has not both had effect when zero, does not have rebound phenomenon again.But studies show that, have 80% patient in the morning all can be punctual (taking medicine in 7～8 o'clock), but the patient's randomness of taking medicine for the second time is bigger, comparatively disperse medicine time, have only 30% patient to take medicine in the afternoon at 2～3 o'clock, patient dependence is relatively poor, and does not reach expected effect.
Controlled releasing penetrant pump then is as release power with osmotic pressure.It is obvious that it has the zero-order release feature, can avoid other preparations to use the blood concentration fluctuation phenomenon that causes, and reduces the side effect of gastrointestinal tract and whole body, is subjected to the influence of gastrointestinal tract variable factor little, can improve the safety and the effectiveness of medicinal application.Therefore, controlled releasing penetrant pump has become at present the focus of research and development both at home and abroad.The bibliographical information beginning about osmotic pump preparation sees nineteen fifty-five.Along with the development of pharmaceutics basic theories and preparation process, for the research of osmotic pump preparation progressively deeply, especially the seventies Theeuwex etc. outstanding contribution, established the special status of osmotic pump preparation in controlled release preparation.The Alza company of the U.S. is first company that uses the osmotic pumps technology, and its OROSTM technology is still at the forefront in the world so far.The Oros preparation has long history and the number of products listing has been arranged, as albuterol (salbutamol) osmotic pump tablet, pseudoephedrine osmotic pump tablet, osmotic pump tablet and Nifedipine controlled-release tablet etc. when verapamil hydrochloride is selected.Adopt the osmotic pumps technology can effectively control the isosorbide mononitrate burst effect in early stage, but release time lag behavior after entering in the body because prior art suffers for want of medical supplies, it is long to cause blood drug level to be in during the high position, very easily cause chemical sproof generation, have a strong impact on the effectiveness of isosorbide mononitrate the patients with coronary heart disease treatment.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome the burst effect after the isosorbide mononitrate sustained-release preparation enters in the body in the prior art, also be simultaneously for overcome release after the isosorbide mononitrate sustained-release preparation enters in the body in the prior art do not have time-lag effect and cause low blood drug level (＜of short duration during 100ug/ml), easily produce the defective that drug resistance and curative effect reduce; And meet in the sleep cycle that coronary heart disease prolongs gradually the clinical characters of morbidity easily during sleep later stage paradoxical sleep, and a kind of isosorbide mononitrate timing and controlled release preparation and preparation method thereof is provided.Isosorbide mononitrate timing and controlled release preparation of the present invention is a kind ofly to have certain time lag, precisely meet the osmotic pump tablet of clinical treatment needs during the easy tuinga cardiopathia of the sleep cycle physiological and pathological, steady long-acting drug release characteristic, with the different happy phasing ratio of commercially available durative action preparation, the more blood drug level of long lasting and stable can be provided, and bioequivalence.
The inventor has made a kind of isosorbide mononitrate timing and controlled release preparation, and it is compared with existing isosorbide mononitrate slow releasing preparation, has plasma concentration curve more stably.And can comply with the pathophysiology characteristics of sleep cycle and incidence of coronary heart disease dependency, i.e. administered before bed time usefulness, the sleep cycle later stage of prolong gradually in the paradoxical sleep cycle, coronary heart disease easily being sent out discharges; Steadily discharge a whole day by given pace, both satisfied the coronary heart disease treatment needs, have blank phase of one section blood drug level or low blood drug level phase again, effectively prevent chemical sproof generation.
Therefore, the present invention relates to a kind of isosorbide mononitrate timing and controlled release preparation, its each structure sheaf is arranged in order from the inside to the outside and is the semi-transparent clothing film that contains double-deck label, the contagion gown film of boosting layer and medicated layer and have drug release hole;
Isosorbide mononitrate timing and controlled release preparation of the present invention also can comprise moistureproof contagion gown film, and it is at the skin of the semi-transparent clothing film that has drug release hole.
Wherein, described medicated layer comprises isosorbide mononitrate and medicated layer adjuvant.
The weight of the isosorbide mononitrate of described medicated layer is 16～50 weight % of medicated layer weight, and that better is 20～50 weight %.
The weight of described medicated layer adjuvant is 50～84 weight % of medicated layer, and that preferable is medicated layer 50～80 weight %.Described medicated layer accessory package contains one or more in medicine carrier, stable regulator, antiplastering aid, lubricant and the coloring agent, and is better for comprising pharmaceutical carrier and stable regulator at least.
Wherein, described pharmaceutical carrier is selected from one or more in polyvidone, copolyvidone, carbomer, hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, ethyl cellulose and the sodium alginate, one or more of preferred hypromellose, polyvidone and copolyvidone; The content of pharmaceutical carrier is 20%～76% weight % of medicated layer weight, and that better is 30%～70% weight %.
Described stable regulator is one or more in lactose, mannitol, sorbitol, sodium carboxymethyl cellulose and the water-soluble inorganic salt (as sodium chloride and/or potassium chloride), preferred lactose and/or mannitol.The content of stability regulator is 8～50 weight % of medicated layer weight.
Described antiplastering aid is silica colloidal and/or Pulvis Talci, and the content of antiplastering aid is 0～7 weight % of medicated layer adjuvant weight.
Described lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, Polyethylene Glycol and sodium stearyl fumarate.The content of lubricant is 0～2 weight % of medicated layer adjuvant weight.
The content of described coloring agent is 0～2 weight % of medicated layer adjuvant weight.
Among the present invention, described boosting layer comprises one or more in extender, osmotic pressure promoter, lubricant and the coloring agent, wherein extender and osmotic pressure promoter are the key compositions of boosting layer, and therefore better, the boosting layer comprises extender and osmotic pressure promoter at least.
Wherein, described extender is preferable is selected from carboxymethyl starch sodium, hypromellose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, carbomer and the sodium alginate one or more, preferred carboxymethyl starch sodium and/or hypromellose.The content of described extender is 35%～90 weight % of boosting layer weight.
Described osmotic pressure promoter is preferable is selected from sodium chloride, lactose, mannitol, glucose, sucrose and the fructose one or more, preferred sodium chloride.The content of osmotic pressure promoter is 7%～60 weight % of boosting layer weight, and that better is 20%～40 weight %.
The kind of described lubricant is ditto described, and its content is 0～3 weight % of boosting layer weight.
Described coloring agent is one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black.The content of coloring agent is 0～2 weight % of boosting layer weight.
Among the present invention, described contagion gown film is coated on double-deck label skin, is the key substance that produces time lag, and it is by the clothing membrane material, and porogen and/or plasticizer composition, and the clothing membrane material is selected from hypromellose and/or polyvidone; Described plasticizer is selected from one or more in Polyethylene Glycol, Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate and the Oleum Ricini; Described porogen is selected from one or more in ethylene glycol, glycerol, polyvidone, copolyvidone and the hypromellose.
The weight percent content of described contagion gown film is 4.95%～42.17 weight % of whole controlled release preparation weight, preferred 9.68%～33.73 weight %.
Among the present invention, the described semi-transparent clothing film that has drug release hole is at contagion gown film skin, and it is the semi-transparent clothing film with moisture permeability, and the described semi-transparent clothing film that has drug release hole comprises filmogen, also can further comprise porogen and/or plasticizer.Filmogen wherein can be selected from one or more of cellulose acetate, ethyl cellulose and acrylic resin, preferred cellulose acetate.Optional in Polyethylene Glycol, glycerol, polyvidone, copolyvidone and hypromellose one or more of porogen in the described semi-transparent clothing film that has a drug release hole.Optional in Polyethylene Glycol, Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate and Oleum Ricini one or more of plasticizer in the described semi-transparent clothing film that has a drug release hole.
The described content that has the semi-transparent clothing film of drug release hole is 1.7%～67.47 weight % of whole controlled release preparation weight, preferred 3.0%～49.80 weight %.
Drug release hole on the described semi-transparent clothing film that has a drug release hole can be one or more, can adopt the punching of laser boring method or mechanical punching method, and that the pore size of drug release hole is preferable is 0.3mm～1.2mm, and that better is 0.5mm～1.2mm.
Among the present invention, the filmogen of the moistureproof contagion gown film that described semipermeable membrane is outer can be selected from one or more in hypromellose, polyvinyl alcohol and the acrylic resin.The content of described moistureproof contagion gown film is 0～10.44 weight % of whole controlled release preparation weight, preferred 2.76%～8.63 weight %.
The invention still further relates to the preparation method of above-mentioned isosorbide mononitrate timing and controlled release preparation, it comprises the following step: 1. prepare medicated layer and boosting layer respectively; 2. suppress double-deck label; 3. wrap the contagion gown film; 4. wrap semi-transparent clothing film.
In the described preparation method, step 4. after, can also comprise step and 5. wrap moistureproof contagion gown film.
The used condition of above steps all can be this area and prepares normal condition used in the osmotic pump preparation.
Step 1. in, in order to increase the mobile of boosting layer in the tabletting process and to prevent that the medicated layer medicament contg reduces in the tabletting process, need granulate respectively to medicated layer and boosting layer, the granulation mode can comprise dry granulation or wet granulation.
Wherein, preferable, when carrying out wet granulation, adopt fluid bed or after placing a period of time under certain damp condition, granulating.Wherein, medicated layer is carried out the preferred following step of method of wet granulation: isosorbide mononitrate and other adjuvants of medicated layer (removing lubricant) are added fluid bed, behind the mix homogeneously, spray into certain density ethanol water, through spraying and dry, meet the tabletting requirement to granular size and get final product, standby.
To the boosting layer carry out the method for wet granulation preferable comprise the following step: each component of boosting layer (removing lubricant) adds fluid bed, behind the mix homogeneously, spray into certain density ethanol water, through spraying and dry, meet the tabletting requirement to granular size and get final product, standby.
Step 3. and 4. preferable all employings coating pan carry out Cotton seeds.
Preferable as follows of the step of step in 3.: the double-deck label bag contagion gown that 2. step is obtained is to required coating weightening finish, and intensive drying is removed wherein dissolvent residual.
Preferable as follows of the step of step in 4.: with the 3. semi-transparent clothing film of gained preparation outsourcing of step, to required weightening finish, intensive drying is removed wherein dissolvent residual, plays one or more drug release hole by machinery or laser boring mode on the semipermeable membrane of medicated layer one side.
Among the present invention, without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but combination in any promptly get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: isosorbide mononitrate timing and controlled release preparation of the present invention can accurately be complied with the pathophysiology characteristics of sleep cycle and incidence of coronary heart disease dependency, be that hora somni(hs) is taken, prolong gradually in the paradoxical sleep cycle, the sleep cycle later stage that coronary heart disease is easily sent out begins to discharge, steadily discharge a whole day by given pace, satisfy the needs of coronary heart disease treatment, especially satisfy the needs of effective treatment of the high-risk outbreak of sleep cycle later stage coronary heart disease to the blood drug level level, there are blank phase of one section blood drug level or low blood drug level phase again, effectively prevent chemical sproof generation; And take once, treat compliance every day and improve, significantly promote the therapeutic effect of isosorbide mononitrate coronary heart disease, and with the elanfan long bioequivalence.
Description of drawings
Fig. 1 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 1.
Fig. 2 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 2.
Fig. 3 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 3.
Fig. 4 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 4.
Fig. 5 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 5.
Fig. 6 is the release profiles of made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 6.
Blood drug level in the Beagle dog compares Fig. 7 for made osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 6 and elanfan long.
Fig. 8 is the preparation process figure of embodiment 1.
Fig. 9 is the preparation process figure of embodiment 2.
Figure 10 is the preparation method procedure chart of embodiment 3.
Figure 11 is the preparation method procedure chart of embodiment 4.
Figure 12 is the preparation method procedure chart of embodiment 5.
Figure 13 is the preparation method procedure chart of embodiment 6.
The specific embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to conventional method and condition, or is selected according to catalogue.
Embodiment 1
A. medicated layer is write out a prescription
| Title | 1 (mg) |
| |
50 |
| |
20 |
| |
30 |
| Silicon dioxide | 1 |
| Magnesium stearate | 1 |
B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| Carboxymethyl starch sodium | 72 |
| |
20 |
| |
10 |
| Sodium chloride | 45 |
| |
30 |
[0064]?
| Iron oxide red | 1.5 |
| Magnesium stearate | 1.5 |
C. the contagion gown film is write out a prescription
The HPMCE590% alcoholic solution
D. semi-transparent clothing film prescription
Cellulose acetate: PEG400 (3: 1) acetone solution
E. moistureproof contagion gown prescription
| | Consumption |
| Opadry | |
| 5 | |
| Water | 40mL |
Preparation process: see Fig. 8
The drug release determination method:
Get this product, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C) second subtraction unit, slice, thin piece is put into little Metal net basket, with 0.1M hydrochloric acid solution 500ml is solvent, rotating speed is that per minute 50 changes, and operation in accordance with the law is 2,3,4,6,8,10, got solution 5ml in 12,14,16 hours respectively, 0.45 the filtering with microporous membrane of μ m, and in process container, replenish uniform temp immediately, and the solvent 5ml of equal volume, getting above-mentioned subsequent filtrate is need testing solution; It is an amount of that precision takes by weighing 5-isosorbide mononitrate reference substance in addition, adds deionized water and make the solution that contains 100 μ g among every 1ml approximately, in contrast product solution; Measuring the medicine that each time point discharges by the HPLC method, is filler with the octadecylsilane chemically bonded silica, adopts the mode of isocratic elution, is eluant with water-methanol (80: 20), and flow velocity 1.0mL/min detects wavelength 220nm.Get each 20 μ l of above-mentioned need testing solution and contrast solution, injecting chromatograph, the record chromatogram goes out every burst size at different time by external standard method with calculated by peak area.The cumulative release curve is seen accompanying drawing 1.
A. medicated layer is write out a prescription
| Title | 1 (mg) |
| |
50 |
[0077]?
| Polyvidone k90 | 60 |
| |
40 |
| |
70 |
| |
2 |
| Magnesium stearate | 1 |
B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| Sodium alginate | 66 |
| |
20 |
| |
10 |
| |
10 |
| |
30 |
| Iron oxide black | 1.5 |
| Magnesium stearate | 1.5 |
C. the contagion gown film is write out a prescription
The HPMCE590% alcoholic solution
D. semi-transparent clothing film prescription
Cellulose acetate: polyvidone k30 (5: 2) acetone solution
E. moistureproof contagion gown prescription
| | Consumption |
| Opadry | |
| 5 | |
| Water | 40mL |
Preparation process: see Fig. 9
The drug release determination method: with embodiment 1, the release curve is seen accompanying drawing 2.
Embodiment 3
A medicated layer prescription
| Title | 1 (mg) |
| |
50 |
| |
80 |
| Lactose | 145 |
| |
20 |
| |
5 |
[0091] B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| |
50 |
| |
20 |
| Mannitol | 120 |
| |
6 |
| |
4 |
C. the contagion gown film is write out a prescription
The HPMCE590% alcoholic solution
D. semi-transparent clothing film prescription
Cellulose acetate: copolyvidone S630 (5: 2) acetone solution
Preparation method: see Figure 10
The drug release determination method: with embodiment 1, the release curve is seen accompanying drawing 3
A medicated layer prescription
| Title | 1 (mg) |
| |
50 |
| |
70 |
| |
10 |
| |
90 |
| |
2 |
| Magnesium stearate | 1 |
B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| |
70 |
| |
16 |
| |
20 |
| |
50 |
| |
30 |
| Iron oxide red | 1.5 |
| Magnesium stearate | 1.5 |
C. the contagion gown film is write out a prescription
HPMCE5: TEC (5: 1) 90% alcoholic solution
D. semi-transparent clothing film prescription
Ethyl cellulose: glycerol (5: 2) ethanol liquid
Preparation method: see Figure 11
The drug release determination method: with embodiment 1, the release curve is seen accompanying drawing 4
A. medicated layer is write out a prescription
| Title | 1 (mg) |
| |
50 |
| |
20 |
| |
10 |
| |
60 |
| |
2 |
| Magnesium stearate | 1 |
B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| |
70 |
| |
16 |
| |
10 |
| |
50 |
| |
30 |
| Iron oxide red | 1.5 |
| Magnesium stearate | 1.5 |
C. the contagion gown film is write out a prescription
HPMCE5: PVPK30 (10: 1) 90% alcoholic solution
D. semi-transparent clothing film prescription
Acrylic resin RS100: copolyvidone S630 (5: 1) 90% ethanol liquid
Preparation method: see Figure 12
The drug release determination method: with embodiment 1, the release curve is seen accompanying drawing 5
A. medicated layer is write out a prescription
| Title | 1 (mg) |
| |
50 |
| Polyvidone k30 | 190 |
| Sodium carboxymethyl cellulose | 7 |
| |
2 |
| Magnesium stearate | 1 |
B. the boosting layer is write out a prescription
| Title | 1 (mg) |
| |
60 |
| |
10 |
| |
20 |
| |
50 |
| Copolyvidone S630 | 35 |
| Iron oxide red | 1.5 |
| Magnesium stearate | 1.5 |
C. the contagion gown film is write out a prescription
HPMCE5: PEG400 (5: 1) 90% alcoholic solution
D. semi-transparent clothing film prescription
Cellulose acetate: copolyvidone (3: 1)
Preparation method: see Figure 13
The drug release determination method: with embodiment 1, the release curve is seen accompanying drawing 6
Blood drug level detects in embodiment 7 animal bodies
The foregoing description controlled release tablet of writing out a prescription is carried out Beagle dog pharmacokinetics test. (at 6～8 months ages, average weight 9 ± 1.0kg) is carried out labelling to 6 of healthy Beagle dogs, is divided into 2 groups at random, carries out single dose binary cycle cross-over experiment.About fasting 12h, freely drink water before the experiment, give osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) agent for one group, give the elanfan long capsule for one group, about administration time 22:00; Every Canis familiaris L. of 3h extracts the blank blood sample of 2mL before the experiment, and the centrifugal 10min of 4000r/min separates upper plasma, and-20 ℃ of refrigerators are preserved.By experienced poultry raiser tablet or capsule are directly filled in epiglottis portion, the Beagle dog is swallowed automatically and inject the 50mL clear water and send down, fasting in the 2h after the administration, prohibit water, normally feed behind the administration 2h is got the blood time and is carried out blood sample and extract by following.Through the cleaning after date in 1 week, intersect administration, get the blood time and carry out blood sample and extract by following.Tablet: (0h) gathers blank blood sample 2mL before administration, get blood at the inboard venae subcutaneae heeling-in of forelimb remaining needle, supply behind the test preparation respectively at 1.5,2,2.5,3,3.5,4,4.5,5,6,8,10,12,15,19,24h gets blood 2mL, place the heparinization centrifuge tube, the centrifugal 10min of 4000r/min, separate upper plasma ,-20 ℃ of refrigerators are preserved, and are to be measured.Capsule: (0h) gathers blank blood sample 2mL before administration, get blood at the inboard venae subcutaneae heeling-in of forelimb remaining needle, supply behind the test preparation respectively at 0.33,0.67,1,1.5,2,2.5,3,4,6,8,10,12,16,24h gets blood 2mL, place the heparinization centrifuge tube, the centrifugal 10min of 4000r/min, separate upper plasma ,-20 ℃ of refrigerators are preserved, and are to be measured.Adopt high performance liquid chromatogram-second order ms coupling to measure the concentration of 5-isosorbide mononitrate (ISMN) in the dog plasma.Record the Sanguis Canitis concentration, draw the C-t curve, see accompanying drawing 7.On this figure, can see tangible time lag and stable blood concentration, reach the experimental design target.Concrete pharmacokinetic parameters sees attached list 1, and the main pharmacokinetic parameters in the Beagle dog compares table 1 for osmotic pump tablet (being isosorbide mononitrate timing and controlled release preparation of the present invention) among the embodiment 6 and elanfan long
The main pharmacokinetic parameters of table 1 relatively
Claims (10)
1. isosorbide mononitrate timing and controlled release preparation is characterized in that: its each structure sheaf is arranged in order from the inside to the outside and is the semi-transparent clothing film that contains double-deck label, the contagion gown film of boosting layer and medicated layer and have drug release hole;
Wherein, described medicated layer comprises isosorbide mononitrate and medicated layer adjuvant; The weight of the isosorbide mononitrate of described medicated layer is 16～50 weight % of medicated layer weight; The weight of described medicated layer adjuvant is 50～84 weight % of medicated layer; Described medicated layer accessory package contains one or more in medicine carrier, stable regulator, antiplastering aid, lubricant and the coloring agent;
Wherein, described pharmaceutical carrier is selected from one or more in polyvidone, copolyvidone, carbomer, hypromellose, hydroxypropyl cellulose, hydroxyethyl-cellulose, ethyl cellulose and the sodium alginate; The content of pharmaceutical carrier is 20%～76% weight % of medicated layer weight;
Described stable regulator is one or more in lactose, mannitol, sorbitol, sodium carboxymethyl cellulose and the water-soluble inorganic salt; The content of stability regulator is 8～50 weight % of medicated layer weight;
Described antiplastering aid is silica colloidal and/or Pulvis Talci, and the content of antiplastering aid is 0～7 weight % of medicated layer adjuvant weight;
Described lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, Polyethylene Glycol and sodium stearyl fumarate; The content of the lubricant in the medicated layer is 0～2 weight % of medicated layer adjuvant weight;
The content of described coloring agent is 0～2 weight % of medicated layer adjuvant weight;
Described boosting layer comprises one or more in extender, osmotic pressure promoter, lubricant and the coloring agent;
Wherein, the content of described extender is 35%～90 weight % of boosting layer weight;
The content of described osmotic pressure promoter is 7%～60 weight % of boosting layer weight;
Lubricant in the described boosting layer is one or more of stearic acid, magnesium stearate, calcium stearate, Polyethylene Glycol and sodium stearyl fumarate, and its content is 0～3 weight % of boosting layer weight;
Described coloring agent is one or more of iron oxide red, iron oxide yellow, iron oxide purple and iron oxide black; The content of coloring agent is 0～2 weight % of boosting layer weight;
Described contagion gown film is by the clothing membrane material, and porogen and/or plasticizer composition, and the clothing membrane material is selected from hypromellose and/or polyvidone; Described plasticizer is selected from one or more in Polyethylene Glycol, Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate and the Oleum Ricini; Described porogen is selected from one or more in ethylene glycol, glycerol, polyvidone, copolyvidone and the hypromellose;
The weight percent content of described contagion gown film is 4.95%～42.17 weight % of whole controlled release preparation weight;
The described semi-transparent clothing film that has drug release hole comprises filmogen; The described content that has the semi-transparent clothing film of drug release hole is 1.7%～67.47 weight % of whole controlled release tablet weight.
2. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 is characterized in that: described isosorbide mononitrate timing and controlled release preparation also comprises moistureproof contagion gown film, and it is at the skin of the semi-transparent clothing film that has drug release hole; The content of described moistureproof contagion gown film is 0～10.44 weight % of whole controlled release tablet weight.
3. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2, it is characterized in that: the filmogen of described moistureproof contagion gown film is selected from one or more in hypromellose, polyvinyl alcohol and the acrylic resin; The content of described moistureproof contagion gown film is 2.76%～8.63 weight % of whole controlled release preparation weight.
4. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2 is characterized in that:
The weight of the isosorbide mononitrate of described medicated layer is 20～50 weight % of medicated layer weight;
The weight of described medicated layer adjuvant is 50～80 weight % of medicated layer; Described medicated layer adjuvant comprises pharmaceutical carrier and stable regulator at least;
In the medicated layer, described pharmaceutical carrier is selected from one or more of hypromellose, polyvidone and copolyvidone; The content of pharmaceutical carrier is 30%～70% weight % of medicated layer weight;
Described stable regulator is lactose and/or mannitol, and the water-soluble inorganic salt in the stable regulator is sodium chloride and/or potassium chloride.
5. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2, it is characterized in that: in the described boosting layer, at least comprise extender and osmotic pressure promoter, described extender is selected from one or more in carboxymethyl starch sodium, hypromellose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, carbomer and the sodium alginate;
Described osmotic pressure promoter is selected from one or more in sodium chloride, lactose, mannitol, glucose, sucrose and the fructose; The content of osmotic pressure promoter is 20%～40 weight % of boosting layer adjuvant weight.
6. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2 is characterized in that: the weight percent content of described contagion gown film is 9.68%～33.73 weight % of whole controlled release tablet weight.
7. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2 is characterized in that: in the described semi-transparent clothing film that has a drug release hole, filmogen wherein is selected from one or more of cellulose acetate, ethyl cellulose and acrylic resin; The described semi-transparent clothing film that has drug release hole also comprises porogen and/or plasticizer; Porogen in the wherein said semi-transparent clothing film that has a drug release hole is selected from one or more in Polyethylene Glycol, glycerol, polyvidone, copolyvidone and the hypromellose; Plasticizer in the described semi-transparent clothing film that has a drug release hole is selected from one or more in Polyethylene Glycol, Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate and the Oleum Ricini.
8. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2 is characterized in that: the described content that has the semi-transparent clothing film of drug release hole is 3.0%～49.80 weight % of whole controlled release preparation weight.
9. isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2, it is characterized in that: laser boring method or the punching of mechanical punching method are adopted in the drug release hole on the described semi-transparent clothing film that has a drug release hole, and the pore size of drug release hole is 0.3mm～1.2mm.
10. the preparation method of isosorbide mononitrate timing and controlled release preparation as claimed in claim 1 or 2 is characterized in that comprising the following step: 1. prepare medicated layer and boosting layer respectively; 2. suppress double-deck label; 3. wrap the contagion gown film; 4. wrap semi-transparent clothing film; When described isosorbide mononitrate timing and controlled release preparation comprises moistureproof contagion gown film, also comprise step and 5. wrap moistureproof contagion gown film.
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| CN111214454B (en) * | 2018-11-26 | 2023-01-17 | 珠海润都制药股份有限公司 | Isosorbide mononitrate sustained-release pellets capable of preventing crystallization and preparation method thereof |
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| CN102293760B (en) | 2015-03-18 |
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Inventor after: Yang Yijing Inventor after: Gan Yong Inventor after: Jia Guohui Inventor after: Zhu Chunliu Inventor after: Han Jiansheng Inventor after: Ying Li Inventor after: Ma Wendi Inventor after: Pan Hong Inventor after: Gao Kepan Inventor before: Yang Yijing Inventor before: Gan Yong Inventor before: Han Jiansheng Inventor before: Zhu Chunliu Inventor before: Ying Li Inventor before: Pan Hong Inventor before: Gao Kepan |
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