CN1615825A - Poly unit slow release preparation - Google Patents
Poly unit slow release preparation Download PDFInfo
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- CN1615825A CN1615825A CN 200410080837 CN200410080837A CN1615825A CN 1615825 A CN1615825 A CN 1615825A CN 200410080837 CN200410080837 CN 200410080837 CN 200410080837 A CN200410080837 A CN 200410080837A CN 1615825 A CN1615825 A CN 1615825A
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- erythromycin derivatives
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Abstract
The poly unit slow release preparation can reduce the daily times of taking medicine, has active component erythromycin derivative, and consists of several micro pills with at least a kind of erythromycin derivative and at least one kind of organic carboxylic acid in the micro pill core. Permeable membrane coats the pill core to constitute micro pill, and the permeable membrane contains water insoluble polymer for medicine to permeate, water soluble polymer. The erythromycin derivative is preferably clarithromycin.
Description
Technical field:
The invention belongs to pharmaceutical field.Relate to a kind of multi-unit sustained-release preparation that can reduce the oral erythromycin derivatives of medicining times every day.More particularly, the invention provides the clarithromycin multi-unit sustained-release preparation of taking once in 1st.
Technical background:
Erythromycin derivatives such as clarithromycin (6-erythromycin A), Roxithromycin, azithromycin etc. are the semisynthetic antibiotic property medicines of a class, need administration every day two or three times, a common 10-14 days course of treatment usually.Medicining times too much causes compliance poor.
The slow releasing preparation of developing them can improve drug compliance.It is unit (monolithic) slow releasing tablet that this class slow releasing preparation has now a kind of.Another kind may be multiunit slow releasing preparation, for example contains the slow-release micro-pill of said medicine, and numerous micropills constitute a dosage.Multiunit slow releasing preparation is because its release behavior is the set of each micropill behavior, so safety is higher.Simultaneously, micropill is very little, and usually less than 3mm, it is less that the emptying in gastrointestinal tract is influenced by physiologic factor, and repeatability is better.
But erythromycin derivatives all is slightly water-soluble usually, and for example the dissolubility of clarithromycin in water has only 55mg/l (Nakagawa Y, et al.Chem Pharm Bull 1992; 40 (3): 725-728).Therefore, the release that the slow-release micro-pill of usual method manufacturing may record in external special media is good, but then discharges badly in the body, causes bioavailability low.
In JP60163823, disclose the 6-erythromycin A conventional tablet of a kind of adding citric acid (citric acid), can increase its absolute bioavailability.
At US5, a kind of 6-erythromycin A slow releasing tablet that contains organic carboxylic acid, water-soluble alginate is disclosed in 705,190.
In WO02/24174, disclose a kind of employing and extruded the clarithromycin slow-release micropill of spheronization preparation.Contain the 2-20% citric acid in the micropill, contain the non-soluble polymer of the non-pH dependence of 5-20% in the release membranes.The C of this micropill after human body is oral
MaxClarithromycin ordinary tablet than same dose is low, but can not prove whether bioequivalence of itself and ordinary tablet.
In CN1372935A, disclose a kind of clarithromycin slow-release micropill, contained methacrylate copolymer in its peplos.The amount of regulating methacrylate copolymer can obtain the preparation of different release in vitro degree.But further show the human research, the good micropill basic release in human body of this release in vitro is not come out, compare bioavailability with ordinary tablet very low, and can not make release in vitro accelerate to improve bioavailability by reducing methacrylate copolymer.Even the amount of methacrylate copolymer is very low, release in vitro is very fast, and it still shows as in vivo and discharges irregular and bioavailability is low, does not reach standard-required (seeing below).Possible cause is that methacrylate copolymer is very few, then irregular the and insufficient strength of the peplos of micropill.Use acrylate copolymer and the blended preparation of the micropill of different release in vitro degree that pH relies on instead, though release in vitro is good, in the body performance be not discharge and ordinary tablet to be as good as be exactly that bioavailability is very low.
Summary of the invention:
The invention provides a kind of new erythromycin derivatives pellet preparations, took once in 1st, can be controlled at intravital release, simultaneously with the ordinary tablet bioequivalence.
The present invention is to provide the preparation of forming by the erythromycin derivatives micropill, said preparation contains the identical or different individual micropill of slow release degree, described micropill is by containing pill core and permeable membrane constitutes, the active component erythromycin derivatives and at least a organic carboxyl acid that contain effective dose in the ball core, permeable membrane are monofilm or multilayer films parcel ball core, can sustained release; Contain in the film at least a non-water-soluble for drug osmotic polymer and at least also contain a kind of water-soluble polymer.
Erythromycin derivatives is meant the erythromycin that contains the conventional substituted radical that has substituted the hydrogen atom in hydroxyl or the methyl.Described erythromycin derivatives is selected from clarithromycin, Roxithromycin or azithromycin, preferred clarithromycin.Clarithromycin is 6-O-erythromycin A.
During the ball core constituted, the amount of erythromycin derivatives was the 50%-75% of ball core weight, preferably contains 60%-70%.
The ball core contains at least a organic carboxyl acid in constituting, and described organic carboxyl acid is selected from C
3-C
20Aliphatic carboxylic acid, for example, tartaric acid, malic acid, succinic acid, 1,3-propanedicarboxylic acid, citric acid, maleic acid, glutamic acid, one or more in mandelic acid and the fumaric acid.Citric acid (citric acid) most preferably.
In the mole ratio, the proportion of organic carboxyl acid and erythromycin derivatives is about 1: about 1: 5 of 1-, preferred about 1: about 1: 4 of 1-, most preferred about 1: about 1: 3 of 1.5-.Organic carboxyl acid obviously is beneficial to the release (Fig. 1) of erythromycin derivatives.
Contain at least a non-water-soluble polymer in the permeable membrane and at least also contain a kind of water-soluble polymer, described non-water-soluble polymer, be selected from acrylate, methacrylate or its mixture and ethyl cellulose, dimethylaminoethyl group NE30D for example, ethyl cellulose such as commercially available Surelease, Aquacoat.The ratio of non-soluble polymer and erythromycin derivatives is about 20: about 50: 100 of 100-(weight), most preferably neutral methacrylic acid esters and about 40: 100 of erythromycin derivatives ratio about 25: 100-(weight).Described water-soluble polymer is selected from hypromellose, hyprolose, polyvinylpyrrolidone, at least a in methylcellulose and the Polyethylene Glycol.Preferred hydroxypropyl methylcellulose.Water-soluble polymer and non-soluble polymer ratio are about 3: about 30: 100 of 100-(weight), the part by weight of preferred water soluble polymer total amount and water-insoluble polymer for drug osmotic is about 5: about 30: 100 of 100-, most preferably hydroxypropyl first dimension plain (5-6cps) is about 5 with the non-soluble polymer ratio: about 15: 100 of 100-(weight).The erythromycin derivatives that water-soluble polymer in the film can obviously be beneficial in the ball core discharges (see figure 2).The part by weight of water-soluble polymer total amount and water-insoluble polymer for drug osmotic is about 5: about 30: 100 of 100-
Concrete preferred embodiment of the present invention comprises:
The ball core contains have an appointment 250mg clarithromycin and about 14mg--070mg citric acid (monohydrate);
The rete of parcel ball core contains the hypromellose of about 125mg neutral methacrylic acid esters of the 37.5mg--that has an appointment and the about 31mg of about 1mg--.
Preferably, the ball core contains have an appointment 250mg clarithromycin and the about 47mg citric acid of about 25mg--(monohydrate); Polymer film contains the about 100mg neutral methacrylic acid esters of the 62.5mg-that has an appointment, the hypromellose of the about 15mg of about 3.1mg--.
More than preferred scheme be to be suitable for oral multi-unit sustained-release preparation, instructions about how to take medicine are for once-a-day, the preferred capsule of the present invention, also optional pill/granule or tablet.
Can prepare micropill of the present invention according to the general knowledge of galenic pharmacy, generally include the inert core may excipient in the ball core, because of the ball core, manufacturing method that adopts different different, diluent such as microcrystalline Cellulose or Icing Sugar or dextrin or starch; Binding agent such as polyvinylpyrrolidone, hypromellose, sucrose; Surfactant such as sodium lauryl sulphate; Coloring agent.The ball core that contains erythromycin derivatives can wrap one deck sealing coat before bag slow release rete, contain hypromellose and antitack agent such as Pulvis Talci usually, but this does not influence the release of erythromycin derivatives in the ball core.Its objective is to preventing that polymer in the rete and the active component in the ball core from reacting and make things convenient for the operation of parcel rete.
Slow release infiltration rete contains caking inhibiter such as Pulvis Talci usually, and the parcel operation is carried out smoothly.But this is not to be the special design of control drug release.
Equally, the release membranes rete also can wrap one deck sealing coat outward, contains hypromellose and antitack agent such as Pulvis Talci usually, coloring agent, but this does not influence the release of erythromycin derivatives in the ball core.
According to the known experience of pharmaceutical field [Issac Ghebre-Sellassie chief editor. medicine pill technology .Marcel Dekker company publishes, New York, 1989], the ball core that contains erythromycin derivatives can adopt following several method to make: a. solution and suspension lamination; B. powder lamination method; C. extrude spheronization.
In solution and the suspension lamination method, be with erythromycin derivatives and organic carboxyl acid and surfactant, an amount of binding agent such as hypromellose and solvent, as water, or other the pharmaceutically organic alcohol of acceptable such as lower alcohols, for example Different concentrations of alcohol is under agitation made the solution or the suspension that are fit to concentration.Usually adopt fluid bed, particularly the fluidized bed coating device (for example GlattWurster type and similar device) of bottom spraying is coated in it on inert core may of suitable size.This inert core may mainly contains cane sugar powder or microcrystalline Cellulose or starch, dextrin usually, can make by oneself and also can adopt commercially available product for example Suglets, Celshpere, Nu-Pareil etc. and the commercially available inert core may of other confessions, be circle or similar round, diameter is usually less than 2mm.
In the powder lamination method, be after erythromycin derivatives, organic carboxyl acid and surfactant etc. are mixed, under binding agent such as the help of hypromellose solution, to be coated on the inert core may oven dry then.Typical equipment is round as a ball packing comminutor (for example Freund type), the spray of fluidized bed type side (for example GlattGCG type) and common centrifugal coating pan.
Extrude in the spheronization, be with erythromycin derivatives, organic carboxyl acid and other inert core may excipient such as microcrystalline Cellulose, binding agent hypromelloses etc. are with solvent, moistening agglomerating as water or pharmaceutically acceptable organic solvent such as ethanol etc., by pore extrude, cut-out, high speed scroll and circular ball core, oven dry then.
In the example, the example of having enumerated a representative is to describe the present invention in detail.Be that the present invention who contains the 250mg clarithromycin who took once in 1st represents preparation in this example, its bioavailability and the equivalence of clarithromycin ordinary tablet.Promptly take the invention of same dose and represent preparation AUC once-a-day
0-24And AUC
0-∞With 2 equivalences on the one of the ordinary tablet of taking same dose.
The meaning of following term is among the present invention:
T
MaxTime when being meant the maximum blood drug level that observes.
C
MaxBe meant the maximum blood drug level that observes.
C
24hBe meant the blood drug level of taking medicine and recording back 24 hours the time.
AUC
0-24Be meant with trapezoidal method calculate from 0 point (take medicine before) to the blood pharmaceutical concentration-time curve of taking medicine back 24 hours under area.
AUC
0-∞Be meant with trapezoidal method calculate from 0 point (take medicine before) to the blood pharmaceutical concentration-time curve of taking medicine afterwards ∞ hour under area.
Description of drawings:
Fig. 1 represents: the micropill that adds the micropill of citric acid in the ball core and do not add citric acid is in external release comparison
Fig. 2 represents: add the influence of not commensurability hydroxypropyl methylcellulose to release in the permeable membrane
Erythromycin derivatives pellet preparations of the present invention can realize taking in 1st target once, and bioavailability improves, side effect reduces, also may command medicine rate of release in vivo particularly passes through preferred clarithromycin product, has produced beyond thought effect especially.
The specific embodiment:
Embodiment 1: preparation is described in detail
1.1 preparation contains the ball core of erythromycin derivatives
Clarithromycin, citric acid (monohydrate) and binding agent and surfactant are joined in an amount of alcoholic acid solution of 50% (V/V), fully stir and keep stirring.Inert core may is placed spray apparatus at the bottom of the fluid bed, regulate suitable intake velocity and temperature, above-mentioned suspension is coated on the nuclear core.Gained ball core is dried moisture content and is less than 4%.
Prescription (mg/ grain): clamycin 2 50mg, citric acid (monohydrate) 32mg, hypromellose 35mg, sodium lauryl sulphate 4.4mg, inert core may 75mg.
1.2 ball core bag release membranes
Neutral methacrylic acid esters (Eudragit NE30D), hypromellose, polyethylene glycol 6000 and Pulvis Talci are fully stirred and keep stirring, above-mentioned gained ball core is placed spray apparatus at the bottom of the fluid bed, regulate suitable intake velocity and temperature (30-40 ℃), above-mentioned material is coated on the ball core.The gained micropill dried by the fire 12 hours down at 40 ℃.
Prescription (mg/ grain): neutral methacrylic acid esters 81.3mg (existing) in Eudragit NE30D mode, hypromellose 6.5mg, polyethylene glycol 6000: 2.6mg, Pulvis Talci 84mg.
1.3 filled capsules
Measure the content of clarithromycin in the micropill, be filled to capsule by every 250mg.
The test of embodiment 2 bioavailability
2.1 medicine
The preparation (T) of embodiment 1 method preparation, the 250mg/ grain; Contrast medicine (R): carat celestial (Klacid clarithromycin tablet, Italian Abbott Laboratories company limited production, Shanghai Abbott Laboratories company limited packing), 250mg/ sheet.
Bioequivalence standard: Pharmacopoeia of the People's Republic of China version in 2000 two appendix XIXB pharmaceutical preparation human bioavailability and bioequivalence test direction principle.
2.2 EXPERIMENTAL DESIGN and method
Adopt single-dose binary cycle trial design.20 health volunteers (23.0 ± 2.42 years old mean age) are divided into two groups of A, B at random, 10 every group, intersect oral investigational agent or contrast medicine respectively in I, II stage, intersect take medicine before through all cleanings phase.
I step-by-step test: A organizes the oral contrast medicine of 10 routine experimenters 500mg, and B organizes 10 routine experimenter's oral test medicine 500mg.II step-by-step test: A organizes 10 routine experimenter's oral test medicine 500mg, and B organizes the oral contrast medicine of 10 routine experimenters 500mg.
After the fasting 12 hours, swallow on an empty stomach 8 o'clock mornings of next day 500mg contrast medicine or investigational agent (200ml eliminating cold for resuscitation water is taken medicine).Standard meal is advanced in the unification on the same day of taking medicine.Forbid a large amount of activities during being tried, no smoking, drink and spirituosity, caffeine class beverage, and duration of test is prohibited all non-trial drugs of clothes.
Before administration and after the administration 0.5,1.0,1.5,2.0,2.5,3.0,4.0,5.0,6.0,8.0,10.0,12.0,14.0 and 24 hour, extract forearm vein blood 3.0ml, separation of serum, low temperature (20 ℃) is preserved, and is to be measured.The oral another kind of preparation of a week back intersection is taked venous blood by last method at interval.
With reference to two clarithromycin microbial detection of Pharmacopoeia of the People's Republic of China version in 2000 method, adopt the microorganism cylinder plate method to measure clarithromycin blood drug level, the result represents with ug/ml.
2.3 result and statistical analysis
Calculate AUC with trapezoidal method
(0～4)And AUC
(0～∞), C
MaxAnd T
MaxRepresent with measured value.AUC
(0～24)And AUC
(0～∞)Through 90% fiducial limit is checked and calculated to the laggard capable ANOVA check of number conversion, two one-side t.T
MaxTest with nonparametric.
Table 1 major parameter (mean, n=20)
Preparation AUC
(0～24)AUC
(0～∞)C
MaxC
24hBiological relatively sharp T
Max
(ug.h/ml) (ug.h/ml) (ug/ml) (ug/ml) expenditure (%) (hour)
T 7.90 9.52 1.44 0.22 96.11 4.2*
R 8.22 9.42 1.56 0.14 100 1.9
*: nonparametric is tested, and difference has significance.
Table 2 results of statistical analysis
The two one-side t of parameter A NOVA are checked 90% fiducial limit *
AUC
(0～24)The equivalent 91.2%-101.8% in P＞0.05
AUC
(0～∞)The equivalent 93.4%-107.6% in P＞0.05
* standard is 80%-125%.
2.4 conclusion
This preparation 500mg takes once to take once with ordinary tablet 500mg and compares T
MaxObviously postpone, 24 hours blood drug level is than higher, C
MaxReduce, blood drug level shows that obviously than ordinary tablet height this preparation has slow release effect in the time of 24 hours.Relative bioavailability is 96.11 ± 13.22%, AUC
(0～24)And AUC
(0～∞)Warp is to the laggard capable ANOVA check of number conversion, the check of two one-side t and calculate 90% fiducial limit, all shows this preparation and ordinary tablet bioequivalence.
Adopt own control, the multi-dose oral medicine-feeding test of cross-over design at random, this preparation 1000mg takes once and take twice every day with ordinary tablet 500mg and compare every day, and relative bioavailability is 102.48 ± 17.80%, AUC
(0～24)And AUC
(0～∞)Warp is to the laggard capable ANOVA check of number conversion, the check of two one-side t and calculate 90% fiducial limit, also shows this preparation and ordinary tablet bioequivalence.
Above-mentioned explanation, embodiment and data provide the complete preparation and the purposes of the present composition.Because many specific embodiment are not being violated under character of the present invention and the scope situation and can accomplished, they also should be included in the claim scope of the present invention.
Claims (10)
1. multiple-unit preparation that contains the identical or different pastille micropill of rate of release, wherein micropill is characterized in that by containing pill core and permeable membrane constitutes:
A. contain a kind of erythromycin derivatives and at least a organic carboxyl acid in the ball core;
B. contain at least a water-insoluble polymer and at least a water-soluble polymer in the permeable membrane for drug osmotic.
2. the described preparation of claim 1, wherein said erythromycin derivatives is selected from clarithromycin, Roxithromycin or azithromycin; Wherein said organic carboxyl acid is selected from tartaric acid, malic acid, succinic acid, 1,3-propanedicarboxylic acid, citric acid, maleic acid, glutamic acid, mandelic acid and fumaric acid; Wherein said water-insoluble polymer for drug osmotic is selected from acrylate, methacrylate and ethyl cellulose; Wherein said water-soluble polymer is selected from hypromellose, hyprolose, polyvinylpyrrolidone, methylcellulose and Polyethylene Glycol.
3. the described preparation of claim 2, wherein said erythromycin derivatives is a clarithromycin; Wherein said organic carboxyl acid is a citric acid; Wherein said water-insoluble polymer for drug osmotic is a methacrylate; Wherein said water-soluble polymer is hypromellose and Polyethylene Glycol.
4. any one preparation of claim 1-3, the mole ratio of wherein said organic carboxyl acid and erythromycin derivatives is 1: 1-1: 5.
5. the preparation of claim 4, the mole ratio of wherein said organic carboxyl acid and erythromycin derivatives is 1: 1.5-1: 3
6. any one preparation of claim 1-3, the part by weight of wherein said water-soluble polymer total amount and water-insoluble polymer for drug osmotic is 3: 100-30: 100.
7. any one preparation of claim 1-3, wherein said water-insoluble be 20 for the polymer of drug osmotic and the part by weight of erythromycin derivatives: 100-50: 100.
8. any one preparation of claim 1-3, wherein said ball core contains the erythromycin derivatives of 50%-75% weight.
9. the preparation of claim 8, wherein said ball core contains the erythromycin derivatives of 60%-70% weight.
10. any one preparation of claim 1-3, wherein the ball core contains 250mg clarithromycin and 14mg-70mg citric acid monohydrate; The permeable membrane of parcel ball core contains the hypromellose of 37.5mg-125mg neutral methacrylic acid esters and 1mg-31mg.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410080837 CN1615825A (en) | 2004-10-12 | 2004-10-12 | Poly unit slow release preparation |
| CNB2005101055110A CN1322866C (en) | 2004-10-12 | 2005-09-23 | Multi-unit slow-release preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410080837 CN1615825A (en) | 2004-10-12 | 2004-10-12 | Poly unit slow release preparation |
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| Publication Number | Publication Date |
|---|---|
| CN1615825A true CN1615825A (en) | 2005-05-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410080837 Pending CN1615825A (en) | 2004-10-12 | 2004-10-12 | Poly unit slow release preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100376250C (en) * | 2005-12-30 | 2008-03-26 | 刘展欣 | Clamycin fast release micropill and its preparation method |
| CN101002790B (en) * | 2006-01-20 | 2010-04-14 | 范敏华 | Slow releace tablets of clarithromycin, and its preparing method |
| CN102552172A (en) * | 2012-03-21 | 2012-07-11 | 广州共禾医药科技有限公司 | Roxithromycin controlled-release preparation and preparation method thereof |
-
2004
- 2004-10-12 CN CN 200410080837 patent/CN1615825A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100376250C (en) * | 2005-12-30 | 2008-03-26 | 刘展欣 | Clamycin fast release micropill and its preparation method |
| CN101002790B (en) * | 2006-01-20 | 2010-04-14 | 范敏华 | Slow releace tablets of clarithromycin, and its preparing method |
| CN102552172A (en) * | 2012-03-21 | 2012-07-11 | 广州共禾医药科技有限公司 | Roxithromycin controlled-release preparation and preparation method thereof |
| CN102552172B (en) * | 2012-03-21 | 2013-03-20 | 广州共禾医药科技有限公司 | Roxithromycin controlled-release preparation and preparation method thereof |
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