CN1322866C - Multi-unit slow-release preparation - Google Patents
Multi-unit slow-release preparation Download PDFInfo
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- CN1322866C CN1322866C CNB2005101055110A CN200510105511A CN1322866C CN 1322866 C CN1322866 C CN 1322866C CN B2005101055110 A CNB2005101055110 A CN B2005101055110A CN 200510105511 A CN200510105511 A CN 200510105511A CN 1322866 C CN1322866 C CN 1322866C
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Abstract
The present invention relates to an oral taking multi-unit slow release preparation which can decrease medicine administration times every day. The curative component of the present invention is an erythromycin derivative. The preparation is composed of a plurality of micro pills, wherein the pill core of each micro pill at least contains the erythromycin derivative and at least one organic carboxylate. The pill core of each micro pill is covered by a non-water soluble polymer film through which medicines can penetrate to form one micro pill, wherein the film contains water soluble polymers. The present invention which also contains clarithromycin in practical administration is taken once a day.
Description
Technical field
The invention belongs to pharmaceutical field.A kind of multi-unit sustained-release preparation that can reduce the oral erythromycin derivatives of medicining times every day is disclosed.More particularly, the present invention took clarithromycin multi-unit sustained-release preparation once on the 1st.
Technical background
Erythromycin derivatives comprises clarithromycin (6-erythromycin A), Roxithromycin, azithromycin etc., is the semisynthetic antibiotic property medicine of a class, needs 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, etal.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 accelerate to improve bioavailability by the release in vitro that makes that reduces 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 present invention is just providing a kind of erythromycin derivatives pellet preparations, takes once in 1st, can be controlled at intravital release, simultaneously with the ordinary tablet bioequivalence.
The present invention relates to contain the multiple-unit preparation of the identical or different individual micropill of slow release degree, described micropill is made of monofilm or multilayer film ball core that contains erythromycin derivatives and organic carboxyl acid at least and parcel ball core, can sustained release; At least a non-water-soluble in the film for the polymer of drug osmotic except that containing, at least also contain at least a water-soluble polymer.The amount of erythromycin derivatives is about 50%-75% of ball core weight, preferably contains the erythromycin derivatives of the 60%-that has an appointment about 70% (weight).
Erythromycin derivatives is meant the erythromycin that contains the conventional substituted radical that has substituted the hydrogen atom in hydroxyl or the methyl.The preferred clarithromycin of described erythromycin derivatives, Roxithromycin or azithromycin, and first-selected clarithromycin.Clarithromycin is 6-O-erythromycin A.
The preferred C of described organic carboxyl acid
2-C
20Aliphatic carboxylic acid for example, is selected from 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-, first-selected about 1: about 1: 3 of 1.5-.Organic carboxyl acid obviously is beneficial to the release (accompanying drawing 1) of erythromycin derivatives.
Water-insoluble polymer for drug osmotic in the described film, by a kind of acrylate that is selected from, methacrylate or its mixture, 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).
Water-soluble polymer in the described film 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 (seeing accompanying drawing 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 is to be suitable for oral multi-unit sustained-release preparation, and instructions about how to take medicine are for once-a-day, and it comprises:
The ball core contains have an appointment 250mg clarithromycin and about 14mg--70mg 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--.
The preferred capsule of the present invention, also optional pill/granule or tablet.
According to the general knowledge of pharmaceutical field, generally include the inert core may excipient in the ball core of the present invention, because of the ball core, manufacturing method that adopts different different, as diluent, as microcrystalline Cellulose or Icing Sugar or dextrin or starch; Binding agent such as polyethylene are given a tongue-lashing pyrrolidone, 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.
The slow release rete contains a little caking inhibiters 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 the garden method of rolling.
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 to roll garden packing comminutor (for example Freund type), the spray of fluidized bed type side (for example Glatt GCG type) and common centrifugal coating pan.
Extrude and roll in the method for garden, 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 about substrate concentration-time graph of blood 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
Above-mentioned preparation (T), the 250mg/ grain; Contrast medicine (R): carat celestial (Klacid
Clarithromycin tablet, Italian Abbott Laboratories company limited production, Shanghai Abbott Laboratories company limited packing), the 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
(0～24)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) (ug.h/ml) | AUC (0～∞) (ug.h/ml) | C max (ug/ml) | C 24h (ug/ml) | Relative bioavailability (%) | T max(hour) |
| T R | 7.90 8.22 | 9.52 9.42 | 1.44 1.56 | 0.22 0.14 | 96.11 100 | 4.2* 1.9 |
*: nonparametric is tested, and difference has significance.
Table 2 results of statistical analysis
| Parameter | ANOVA | Two one-side t checks | 90% fiducial limit * |
| AUC (0～24) AUC (0～∞) | P＞0.05 P＞0.05 | The equivalence equivalence | 91.2％-101.8％ 93.4％-107.6％ |
* 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 (8)
1. contain the multiple-unit preparation that the identical or different individual micropill of rate of release is formed, wherein:
A. comprise a kind of erythromycin derivatives and at least a organic carboxyl acid in the ball core at least;
B. have and contain at least a water-insoluble polymer film parcel ball core for drug osmotic;
C. contain at least a water-soluble polymer in the rete,
Wherein, described erythromycin derivatives is selected from clarithromycin, Roxithromycin or azithromycin,
Described organic carboxyl acid is selected from tartaric acid, malic acid, succinic acid, 1,3-propanedicarboxylic acid, citric acid, maleic acid, glutamic acid, in mandelic acid and the fumaric acid one or more,
The described water-insoluble polymer of drug osmotic that supplies only is selected from acrylate, methacrylate or its mixture, or ethyl cellulose,
Described water-soluble polymer is selected from hypromellose, hyprolose, and polyvinylpyrrolidone, at least a in methylcellulose and the Polyethylene Glycol,
The part by weight of described water-soluble polymer total amount and water-insoluble polymer for drug osmotic is 3: 100-30: 100.
2. the described preparation of claim 1, wherein said ball core is with solution and the preparation of suspension lamination method.
3. claim 1 or 2 described preparations, wherein said erythromycin derivatives is a clarithromycin.
4. claim 1 or 2 described preparations, wherein said organic carboxyl acid is a citric acid.
5. claim 1 or 2 described preparations, wherein said water-soluble polymer is a hypromellose.
6. claim 1 or 2 described preparations, the mole ratio of wherein said organic carboxyl acid and erythromycin derivatives is 1: 1-1: 5.
7. claim 1 or 2 described preparations, wherein said water-insoluble be 20 for the polymer of drug osmotic and the part by weight of erythromycin derivatives: 100-50: 100.
8. claim 1 or 2 described preparations, wherein said ball core contains the erythromycin derivatives of 50%-75% (weight).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101055110A CN1322866C (en) | 2004-10-12 | 2005-09-23 | Multi-unit slow-release preparation |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410080837 CN1615825A (en) | 2004-10-12 | 2004-10-12 | Poly unit slow release preparation |
| CN200410080837.8 | 2004-10-12 | ||
| CNB2005101055110A CN1322866C (en) | 2004-10-12 | 2005-09-23 | Multi-unit slow-release preparation |
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|---|---|
| CN1757394A CN1757394A (en) | 2006-04-12 |
| CN1322866C true CN1322866C (en) | 2007-06-27 |
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|---|---|---|---|
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5705190A (en) * | 1995-12-19 | 1998-01-06 | Abbott Laboratories | Controlled release formulation for poorly soluble basic drugs |
| WO2002024174A2 (en) * | 2000-09-22 | 2002-03-28 | Galephar M/F | Sustained release composition containing clarithromycin |
| CN1372935A (en) * | 2002-04-02 | 2002-10-09 | 广州贝氏药业有限公司 | Slowly released clamycin capsule |
| CN1757388A (en) * | 2004-10-10 | 2006-04-12 | 广州贝氏药业有限公司 | Multi-unit slow-releasing preparation |
-
2005
- 2005-09-23 CN CNB2005101055110A patent/CN1322866C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5705190A (en) * | 1995-12-19 | 1998-01-06 | Abbott Laboratories | Controlled release formulation for poorly soluble basic drugs |
| WO2002024174A2 (en) * | 2000-09-22 | 2002-03-28 | Galephar M/F | Sustained release composition containing clarithromycin |
| CN1372935A (en) * | 2002-04-02 | 2002-10-09 | 广州贝氏药业有限公司 | Slowly released clamycin capsule |
| CN1757388A (en) * | 2004-10-10 | 2006-04-12 | 广州贝氏药业有限公司 | Multi-unit slow-releasing preparation |
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| Publication number | Publication date |
|---|---|
| CN1757394A (en) | 2006-04-12 |
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