CN1422659A - Musk slow-controlled release preparation and preparation method thereof - Google Patents
Musk slow-controlled release preparation and preparation method thereof Download PDFInfo
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- CN1422659A CN1422659A CN02149617A CN02149617A CN1422659A CN 1422659 A CN1422659 A CN 1422659A CN 02149617 A CN02149617 A CN 02149617A CN 02149617 A CN02149617 A CN 02149617A CN 1422659 A CN1422659 A CN 1422659A
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Abstract
本发明涉及一种麝香缓、控释制剂,旨在以某种设计的速率,在人体的胃肠道内缓慢释放药理活性部分,给患者一日一次剂量服用后能长时间维持有效的血药浓度,以保证患者每天正常的工作和生活的安全；其主要包括如下成分:麝香、羟丙基甲基纤维素和/或乙基纤维素；其中由羟丙基甲基纤维素和/或乙基纤维素这两种不同类型的高分子化合物组成骨架材料来控制药物的释放,调节高分子化合物的规格和用量,可以获得理想的药物释放速率。
The invention relates to a musk slow-release and controlled-release preparation, which aims to slowly release the pharmacologically active part in the gastrointestinal tract of the human body at a certain designed rate, and can maintain an effective blood drug concentration for a long time after taking a dose once a day. , to ensure the safety of patients' normal work and life every day; it mainly includes the following ingredients: musk, hydroxypropyl methylcellulose and/or ethyl cellulose; wherein hydroxypropyl methylcellulose and/or ethyl cellulose Cellulose, two different types of macromolecular compounds, constitutes the framework material to control the release of drugs. By adjusting the specifications and dosage of macromolecular compounds, an ideal drug release rate can be obtained.
Description
Technical field
The present invention relates to medicine.Exactly be that relevant Moschus is slow, controlled release preparation and preparation method thereof.
Background technology
Moschus is a rare Chinese medicine, and the refreshment of having one's ideas straightened out, promoting blood circulation to remove obstruction in the collateral, analgesic effect are arranged, and is used for apoplectic coma (cerebral thrombosis), trusted subordinate's sudden pain diseases such as (ischemic coronary heart disease, angina pectoriss, uncomfortable in chest).So far have the history in more than 2000 year.Moschus has been carried out the research in a century both at home and abroad, its effective ingredient is clear and definite substantially.China has successfully developed the artificial Moschus through the big quantity research in more than 20 years in 1993, and approval is a class production of raw medicine.Specify 12 tame hospitals to carry out 1053 routine experimental studies by Ministry of Public Health, confirmed that artificial Moschus and natural Moschus have analogous components and consistent curative effect with regard to causing resuscitation with aromatic drugs, promoting blood circulation to remove obstruction in the collateral, the pain relieving effect of artificial Moschus's treating cardiac and cerebral vascular diseases.Folk prescription artificial Moschus preparation is good effect not only, the therapeutic index height, and have no side effect.It is rapid that artificial Moschus and natural Moschus bring into play drug effect, absorbs soon, for treatment cardiovascular and cerebrovascular vessel emergency case provides foundation.
The ordinary preparation that artificial Moschus and natural Moschus are arranged in the market and since the Moschus effective ingredient in vivo the half-life short, be about three hours, it is short therefore to keep effective drug duration in vivo, the patient rises rapidly at the back blood drug level of taking medicine, but it is also very fast to descend.The medicine time that plays a role lacks, so need administration for several times every day.Sometimes the patient takes in accordance with regulations blanking time, causes in the body blood concentration fluctuation big, easily is lower than or exceeds the treatment window, and curative effect is reduced or produce toxic and side effects, can not guarantee patients with coronary heart disease normal quality of life.
Goal of the invention
The objective of the invention is to problem at the prior art existence, provide a kind of Moschus slow, controlled release preparation, its efficacy stability, convenient drug administration, said preparation is with the speed of certain design, slow release of pharmacologically active part in the gastrointestinal tract of human body, can keep slow, the controlled release preparation of effective blood drug level after once-a-day dosage is taken to the patient for a long time, to guarantee normal work patient's every day and the safety of living.
The present invention also aims to provide that described Moschus is slow, the preparation method of controlled release preparation.
The effective ingredient that Moschus of the present invention is slow, controlled release preparation mainly comprises following parts by weight:
Moschus 20～200
Hydroxypropyl emthylcellulose and/or ethyl cellulose 10～300
Hydroxypropyl emthylcellulose (Hydroxyl Propyl Methyl Cellulose, HPMC) be white fiber shape or particulate powder, mixed cellulose ethers for non-corpuscular type, be dissolved in cold water, also dissolve in the mixture of second alcohol and water, its viscosity is 2% because of the degree of polymerization of molecule is different in concentration, under 20 ℃ of the temperature, viscosity is from being low to moderate 40～5600MPa.s.Hydroxypropyl emthylcellulose is to adopt the extensive stock that includes hydroxypropyl emthylcellulose.How elegant U.S.A as all size is.
Ethyl cellulose (Ethyl Cellulose; EC) be white runny granule or powder; water insoluble, gastro-intestinal Fluid, glycerol and propylene glycol; can be dissolved in the organic solvents such as ethanol, methanol, acetone, chloroform; in concentration is 5% (is solvent with 60% toluene and 40% (W/W) alcohol mixeding liquid); under 25 ℃ of the temperature, viscosity 7～100MPa.s.
Hydroxypropyl emthylcellulose and/or ethyl cellulose play slow releasing function.
Moschus of the present invention is slow, controlled release preparation can be made the full sheets of powder that comprises hydrogel matrix double-layer tablet, hydrophilic gel single-layer sheet or intra-gastric floating tablet, insoluble gel or the various Tabuleses of solid dispersion sheet, also comprises and makes the various dosage forms that granule, micropill etc. are made preparation more earlier.
In order to make various dosage forms, Moschus of the present invention is slow, controlled release preparation also comprises adjuvant, diluent for example, lubricant, wetting agent, binding agent, porogen or other adjuvants, the technology and the consumption that adopt present technique field those of ordinary skill to know, as adopt medical starch, lactose, dextrin, mannitol is as diluent, starch slurry, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, water, water or alcoholic acid mixed solution are binding agent, lubricant is pharmaceutically useful adjuvant with lubrication, comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, polyethylene glycols.Add the lower lipoid material of density,, improve the floating ability of intra-gastric floating tablet as glyceryl monostearate, stearyl alcohol, Cera Flava.
For controlling slow release speed better, Moschus of the present invention is slow, the controlled release preparation effective ingredient can comprise immediate release section and slow-released part, and wherein immediate release section is made up of artificial Moschus, hydroxypropyl emthylcellulose, lactose; Slow-released part is made up of artificial Moschus, hydroxypropyl emthylcellulose, hydroxypropyl emthylcellulose, starch.
Moschus of the present invention is slow, the preparation method of controlled release preparation tablet: will sieve behind Moschus, hydroxypropyl emthylcellulose and/or ethyl cellulose, the adjuvant pulverize separately, equivalent incremental method mix homogeneously, starch slurry is made soft material as binding agent, cross 20 mesh sieve system granules, be no more than 50 ℃ of aeration-dryings, 16 mesh sieve granulate, dried granule adds the lubricant mixing, and tabletting gets tablet.
Moschus of the present invention is slow, the preparation method of controlled release micro pill dosage form is: adjuvants such as Moschus and lactose are mixed and made into piller; According to dosage be divided into immediate release section and slow-released part, immediate release section is standby; Slow release group piller is used the alcoholic solution and the ethyl cellulose alcoholic solution of Moschus and ethyl cellulose respectively, adopt the bed spray packaging technique to make the piller of different coating thicknesses and different rate of releasing drug, as slow-released part, with immediate release section and slow-released part mixing according to a certain percentage, packing or dress people hard capsule can obtain ideal slow release or controlled release Moschus micropill, and its slow-released part rate of releasing drug is slow one-level and discharges.
The function assessment evaluation test shows, slow releasing preparation of the present invention is through acute toxicity test in mice and rat long term toxication, and indexs such as its behavioristics's change and pathology, physiology, biochemistry are not had obvious influence.Investigate (under the pharmacodynamic study item according to new Chinese medicine pharmacodynamics guide obstruction of qi in the chest and cardialgia disease) with slow releasing preparation of the present invention through pharmacodynamics, by the coronary artery test of blocking-up dog and to its cardiac function and hemodynamics experiment, the result show each dosage group all can significantly reduce the dog coronary artery ligation after ST-T raise degree, dwindle myocardial infarct size, can improve behind the heart infarction left chamber and shrink and diastolic function.Compare with the blank group, difference has statistical significance (P＜0.01).This shows that this slow releasing preparation has protective effect to myocardial ischemia.Can be used for the prevention and the treatment of coronary heart disease.
The present invention has following advantage:
1, can keep Moschus blood drug level in vivo for a long time, reduce dose, solve the problem of Moschus need frequent drug administration.
2, regulate different specification and the consumptions of slow-release auxiliary material, the rate of release of may command medicine.
3, construction cycle weak point, production technology is reasonable in design, and production technology is suitable for suitability for industrialized production.
4, Chinese medicine is made modern slow, controlled release preparation, met the needs of Chinese medicine urgency, serious symptom, help the Chinese medicine modernization process.
Description of drawings
Fig. 1 is that three batches of Moschus of embodiment 1 preparation are slow, the percentage release graphics of controlled release preparation and common Moschus tablet.
The specific embodiment
Embodiment 1 preparation hydrogel matrix double-layer tablet
Prescription:
Immediate release section: artificial Moschus 30g
Starch 50g
Lactose 50g;
Slow-released part: artificial Moschus 70g
Hydroxypropyl emthylcellulose (K4M) 50g
Starch 50g
Make 1000 in tablet.
Its production technology is:
(1) immediate release section: the artificial Moschus, the lactose that take by weighing recipe quantity are crossed 80 mesh sieves (granularity is 25.4mm/80) respectively, equivalent incremental method mix homogeneously, 10% starch slurry is made binding agent, cross 20 mesh sieves (granularity is 25.4mm/20) system granule, 50 ℃ of aeration-dryings, 16 mesh sieves (granularity is 25.4mm/16) granulate adds the magnesium stearate mixing.
(2) slow-released part: hydroxypropyl emthylcellulose, lactose and artificial Moschus are adopted equivalent incremental method mix homogeneously, 95% ethanol system granule, cross 20 mesh sieves (granularity is 25.4mm/20) system granule, 50 ℃ of aeration-dryings, 16 mesh sieves (granularity is 25.4mm/16) granulate adds the magnesium stearate mixing.
(3) immediate release section and slow-released part are pressed into double-layer tablet in the prescription ratio.
(4) tablet is through being up to the standards, and packing promptly.
Preparation is made immediate release section and slow-released part respectively, and after medicine entered gastric juice, the rapid release part can make medicine reach effective blood drug concentration rapidly, and anginal symptom is controlled rapidly; Subsequently, hydroxypropyl emthylcellulose absorbs moisture, forms the hydrophilic gel slow release layer on the surface, stops artificial Moschus's rate of release effectively, can make medicine keep effective blood drug level, make the medicine interaction energy keep the long period (greater than 10 hours) for a long time.
As shown in Figure 1, prepared artificial Moschus's slow releasing tablet is compared with ordinary tablet, just discharges fully substantially when 2h as can be seen.And slow releasing tablet can be kept release for 10h.Can see significantly that from figure slow releasing preparation has slow release, keep long characteristics of blood drug level time.
Table 1 is above-mentioned three batches of Moschus slow releasing tablet average accumulated percentage release tables of data, as shown in table 1, the average accumulated percentage release of artificial Moschus's slow releasing preparation of prepared different batches different time in simulated gastric fluid, medicine just discharges 80%～90% of total amount in 12h as can be seen, has embodied preparation of the present invention and can slowly discharge the blood drug level of keeping the long period.
Table 1: three batches of Moschus slow releasing tablet average accumulated percentage release data (n=6) Lot Time (hr)
0.5 1 2 3.5 5 8 10 12T020729 30.47 42.13 53.47 64.15 72.16 82.34 87.21 92.34T020801 32.72 40.96 50.66 62.87 70.80 81.90 86.78 90.50T020805 28.43 39.41 47.79 58.76 68.33 79.80 84.67 88.63
Table 2 is Moschus conventional tablet average accumulated percentage release data, as shown in table 2, the average accumulated percentage release of prepared artificial Moschus's ordinary tablet different time in simulated gastric fluid just discharges 97.74% of total amount, the weak point of holding time in vivo as can be seen when 1.5h.
Table 2: Moschus conventional tablet average accumulated percentage release data (n=6) Lot Time (hr)
0.25 0.5 0.75 1 1.25 1.5T020728 48.35 69.31 80.12 86.76 95.12 97.74
Embodiment 2 preparation Moschus hydrogel matrix special-shaped tablets
Prescription: artificial Moschus 100g
Hydroxypropyl emthylcellulose (K4M) 50g
Lactose 120g
Starch 80g
Make 1000 altogether
Its production technology is: cross 80 mesh sieves (granularity is 25.4mm/80) after taking by weighing the artificial Moschus, lactose, starch pulverize separately of recipe quantity, adopt equivalent incremental method mix homogeneously, 95% ethanol is wetting agent system soft material, cross 20 mesh sieves (granularity is 25.4mm/20) system granule, 50 ℃ of oven dry in 2 hours, 16 orders (granularity is 25.4mm/16) sieve granulate, add the magnesium stearate mixing, with special-shaped tablet machine tabletting, tablet is through being up to the standards, and packing promptly.
These routine characteristics are with the hydroxypropyl emthylcellulose to be that the water-setting colloidality matrix tablet that substrate makes is the water erodible matrix, in medium, at first form gel at moistened surface, surface drug discharges, then gel layer thickens and makes drug release slow, show drug release rate phenomenon first quick and back slow, in certain scope of medication, can not need to add in addition the rapid release part.According to Ficks diffusion formula as can be known diffusion velocity amass proportional with tablet surface, directly influence the release of medicine, so adopt the method that increases tablet surface long-pending (special-shaped tablets) to promote initial release, also can not make medicine reach effective blood drug concentration rapidly thereby do not add the rapid release part.Subsequently, the release of drug slow can be kept effective blood drug level for a long time, makes the medicine interaction energy keep the long period (greater than 10 hours).
The insoluble gel skeleton solid dispersion sheet of embodiment 3 preparations
Prescription: artificial Moschus: 100g
Ethyl cellulose: 200g
Hydroxypropyl emthylcellulose: 20g
Starch: 20g
Polyethylene Glycol: 10g
Make 1000 altogether
Its production technology is: (1) crosses 80 mesh sieves (granularity is 25.4mm/80) after taking by weighing recipe quantity hydroxypropyl emthylcellulose, starch pulverize separately, equivalent incremental method mix homogeneously,
(2) artificial Moschus and the ethyl cellulose that takes by weighing recipe quantity is dissolved in 50ml 95% ethanol, a few hours are left standstill in airtight shading, add in the mixed accessories in (1), the system soft material, cross 20 mesh sieves (granularity is 25.4mm/20) systems granule, 50 ℃ of dryings 2 hours, 16 mesh sieves (granularity is 25.4mm/16) granulate is crossed in dry back, add the magnesium stearate mix homogeneously, tabletting.
(3) tablet is through being up to the standards, and packing promptly.
These routine characteristics are to adopt solid dispersion technology, and medicine and ethyl cellulose are dissolved or dispersed in the ethanol, add water-soluble substanceses such as hydroxypropyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol as porogen, regulate drug releasing rate.Ethyl cellulose is insoluble framework material, and drug releasing rate is decided by diffusion velocity, and is irrelevant with the dissolution velocity of medicine.Medicine is the saturated solution state in skeleton, discharge from insoluble framework material, reaches slow release medication purpose.
The full sheets of powder of the embodiment 4 insoluble skeletons of preparation
Adopt the present embodiment 4 tablet formulation content of industrial pharmacy existent method preparation as follows:
Prescription: artificial Moschus: 100g
Ethyl cellulose: 80g
Hydroxypropyl emthylcellulose: 20g
Starch: 120g
Microcrystalline Cellulose: 20g
Make 1000 altogether
These routine characteristics adopt direct compression of full-powder, and ethyl cellulose is insoluble framework material, and drug releasing rate is decided by diffusion velocity, and are irrelevant with the dissolution velocity of medicine.Medicine is the saturated solution state in skeleton, discharge from insoluble framework material, reaches slow release medication purpose.
Embodiment 5 preparation Moschus floating in stomach sheets
Prescription: artificial Moschus: 100g
Hydroxypropyl emthylcellulose (K15M): 35g
Hydroxypropyl emthylcellulose (K100M): 65g
Lactose: 120g
Cera Flava: 5g
Magnesium stearate: 5g
Make 1000 altogether.
Its production technology is: (1) takes by weighing the artificial Moschus, hydroxypropyl emthylcellulose, lactose of recipe quantity etc. and pulverizes the back respectively and cross 80 mesh sieves (granularity is 25.4/80), equivalent incremental method mix homogeneously.
(2) with powder in (1) with 95% ethanol system soft material, cross 20 mesh sieves (granularity is 25.4mm/20) system granule, 50 ℃ of dryings 2 hours, dry back 16 mesh sieves (granularity is 25.4mm/16) granulate, adding magnesium stearate mix homogeneously, tabletting.
The preparation that this example is made is the floating in stomach sheet, its characteristics be hydroxypropyl emthylcellulose suction back expand and float on gastric content above, discharge medicine gradually, materials of low density such as adding Cera Flava have improved floating ability, add the lactose soluble component, help release, the rate of release of scalable preparation.Can reach 10～12 hours at gastric transit time, and have the feature of skeleton release, thereby further improve bioavailability of medicament.
Embodiment 6 preparation coating type slow-release micro-pill
Prescription: artificial Moschus: 100g
Hydroxypropyl emthylcellulose: 30g
Ethyl cellulose: 200g
Its production technology is: (1) immediate release section: the artificial Moschus 30g, the lactose 30g that take by weighing recipe quantity are mixed and made into piller, according to dosage are divided into immediate release section and slow-released part, and immediate release section is standby.
(2) slow-released part: take by weighing artificial Moschus 70g, the ethyl cellulose 200g of recipe quantity, with being wrapped in piller in the heart through the fluid bed packaging technique behind the dissolve with ethanol, the control fluidized-bed temperature is between 50 ℃～70 ℃.Make the piller of different coating thicknesses and different rate of releasing drug, its slow-released part drug release rate is slow one-level and discharges, and can obtain ideal slow release or controlled release Moschus micropill.
(3) with (1) and (2) part gained micropill mix homogeneously, the tabletting or the hard capsule of packing into.
Described K4M is superfine (controlled release is used) powdery hydroxypropyl emthylcellulose, and viscosity is 4,000 centipoises; K15M is superfine (controlled release is used) powdery hydroxypropyl emthylcellulose, and viscosity is 15,000 centipoises; K100M is superfine (controlled release is used) powdery hydroxypropyl emthylcellulose, and viscosity is 100,000 centipoises.
Claims (7)
1, slow, the controlled release preparation of a kind of Moschus is characterized in that mainly comprising following effective ingredient:
Moschus 20～200 parts by weight
Hydroxypropyl emthylcellulose and/or ethyl cellulose 10～300 parts by weight
2, slow, the controlled release preparation of Moschus according to claim 1 is characterized in that its effective ingredient comprises immediate release section and slow-released part, and wherein immediate release section is made up of artificial Moschus, hydroxypropyl emthylcellulose, lactose; Slow-released part is made up of artificial Moschus, hydroxypropyl emthylcellulose, hydroxypropyl emthylcellulose, starch.
3, slow, the controlled release preparation of Moschus according to claim 1 and 2 is characterized in that it being Tabules.
4, slow, the controlled release preparation of Moschus according to claim 1 and 2 is characterized in that it being the micropill dosage form.
5, the preparation method of slow, the controlled release preparation tablet of the described Moschus of claim 3, it is characterized in that and to sieve behind Moschus, hydroxypropyl emthylcellulose and/or ethyl cellulose, the adjuvant pulverize separately, equivalent incremental method mix homogeneously, starch slurry is made soft material as binding agent, sieve and make granule, tabletting gets tablet.
6, the preparation method of slow, the controlled release preparation tablet of Moschus according to claim 2 is characterized in that
(1) immediate release section: adjuvants such as artificial Moschus, lactose are crossed 80 mesh sieves respectively, equivalent incremental method mix homogeneously, and 10% starch slurry is made binding agent, crosses 20 mesh sieve system granules, 50 ℃ of aeration-dryings, 16 mesh sieve granulate add the magnesium stearate mixing;
(2) slow-released part: hydroxypropyl emthylcellulose, lactose and artificial Moschus are adopted equivalent incremental method mix homogeneously, and 95% ethanol system granule is crossed 20 mesh sieves, 50 ℃ of aeration-dryings, and 16 mesh sieve granulate add the magnesium stearate mixing.
(3) immediate release section and slow-released part are pressed into double-layer tablet in the prescription ratio.
7, the preparation method of slow, the controlled release preparation micropill of the described Moschus of claim 4 is characterized in that adjuvants such as Moschus and lactose are mixed and made into piller; According to dosage be divided into immediate release section and slow-released part, immediate release section is standby; Slow release group piller adopts the bed spray packaging technique to make the piller of different coating thicknesses and different rate of releasing drug with Moschus with the alcoholic solution of ethyl cellulose respectively, as slow-released part; With immediate release section and slow-released part mixing according to a certain percentage, to pack or the hard capsule of packing into can obtain ideal slow release or controlled release Moschus micropill, its slow-released part rate of releasing drug is slow one-level and discharges.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB02149617XA CN1309376C (en) | 2002-12-12 | 2002-12-12 | Musk slow-controlled release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB02149617XA CN1309376C (en) | 2002-12-12 | 2002-12-12 | Musk slow-controlled release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1422659A true CN1422659A (en) | 2003-06-11 |
| CN1309376C CN1309376C (en) | 2007-04-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB02149617XA Expired - Fee Related CN1309376C (en) | 2002-12-12 | 2002-12-12 | Musk slow-controlled release preparation and preparation method thereof |
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| Country | Link |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109260170A (en) * | 2017-07-18 | 2019-01-25 | 湖南湘易康制药有限公司 | A kind of Cetirizine hydrochloride Tablets and preparation method thereof |
-
2002
- 2002-12-12 CN CNB02149617XA patent/CN1309376C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109260170A (en) * | 2017-07-18 | 2019-01-25 | 湖南湘易康制药有限公司 | A kind of Cetirizine hydrochloride Tablets and preparation method thereof |
| CN109260170B (en) * | 2017-07-18 | 2021-12-31 | 湖南湘易康制药有限公司 | Cetirizine hydrochloride tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1309376C (en) | 2007-04-11 |
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