CN100336501C - Cuyantong slow-releasing round-particle composition and preparation method - Google Patents
Cuyantong slow-releasing round-particle composition and preparation method Download PDFInfo
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Abstract
The present invention discloses a Cuyantong slow-releasing round-particle composition and a preparation method thereof. The preparation method provides plurality of oral pharmacy formulas, a three-layer different release mechanism and a preparation method that the medicines simultaneously exist in a complete round particle, and preparations which are suitable for capsules are filled. The present invention has the following preparation method: 1, the external layer of the round particle adopts a Cuyantong quick-releasing initial dose; 2, the middle layer of the round particle is an enteric coatel film coated layer which has the action of blocking gastric acid, and the medicine on the internal layer can disintegrate and dissolve; 3, the internal layer of the round particle adopts a majority of maintenance doses, and the rounded particle is a naked rounded particle which is combined by effective components, excipients, forming adhesive agents of the rounded particle, interfacial active agents, etc. 4, the preparation method of the preparation has the advantages that the design of a 'delayed release' mechanism and a 'initial dose' mechanism is simultaneously contained in a rounded particle, and accordingly, slow-releasing functions can be obtained and treating effects are displayed by selecting uniform rounded particles which are made from special slow-releasing materials. The present invention has the following dose calculation formula: Dt=Di+Dm, wherein Dt is the integral dose of each rounded particle; Di is the initial dose of each rounded particle, and Dm is the maintenance dose of each rounded particle.
Description
Technical field
The present invention relates to a kind of medicine and form and method for making, refer to rantudil slow-releasing medicine and preparation method especially.
Background technology
Rantudil (acemetacin) is a kind of on-steroidal anti-inflammatory medicine (NSAID), powerful antiinflammatory, analgesic, analgesic effect are arranged, clinical report shows that this product is good in the various rheumatoid effects of treatment, and patient's better tolerance, intestinal emit side effect low, are fit to be used for the various rheumatism of long-term treatment, arthritis as B.Hazleman and R.M.Bernstein in Curr.Med.Res.Opin. the 13rd the 2nd phase of volume this medicine of the 119th～126 page of report in 1993.It is the premedicant (prodrug) of indomethacin (indomethacin), cures mainly rheumatic arthritis, osteoarthritis (osteoarthritis), ankylosing spondylosis, gout, muscle inflammation, tenosynovitis, bursitis.The structural formula of rantudil is [1-(4-chlorobenzene first anilide)-5-methoxyl group-2-methyl-indol-3-yl-second acyloxy grp] acetic acid [1-(4-Chlorobenzoyl)-5-methoxy-2-methyl--indol-3-yl-acetoxy] acetic acid, is ethyl glycolate (glycolicacid ester) derivant of indomethacin (indomethacin).
Deutsche Bundespatent the 2nd, 234, No. 651 and United States Patent (USP) disclose the method for preparation rantudil for the 3rd, 910, No. 952.United States Patent (USP) the 4th, 900 is addressed slow-releasing round shaped grain prescription for No. 557, and it comprises the enteric round shaped grain that can keep out gastric acid and the initial dose of mixture of powders, is filled into capsule.The enteric round shaped grain contains rantudil, excipient, binding agent, collapses powder etc.The optimum of initial dose is 1/3 accumulated dose.
Known slow releasing capsule (Rantudil
Retard capsules) formed by enteric irregular particle and powder, its shortcoming is because powder is different with particulate density, powder and granule are subjected to vibration to be easy to generate segregation phenomenon when capsule charge, cause powder and enteric coated particles to charge into capsule, therefore inhomogeneous the or lamination of filling easily takes place with certainty ratio.
Summary of the invention
Rantudil of the present invention (acemetacin) slow-releasing round shaped grain constituent, be that a kind of speed that contains is put layer (initial dose), an enteric film clothing layer, nade-shaped circle grain layer (maintenance dose) the 3 layers of difference of etc.ing and disengaged the round shaped grain of mechanism, this composition system filling is in suitable capsular preparation simultaneously.
As shown in Figure 1, rantudil slow-releasing round shaped grain constituent of the present invention, the round shaped grain skin contains the rapid release composition of rantudil, can produce initial dose.The round shaped grain middle level is a kind of enteric film clothing layer, has the effect of keeping out gastric acid, collapses to loose when making the internal layer medicine arrive enteral to reach the effect of dissolving again, thereby delays the release of medicine.The round shaped grain internal layer is the nade-shaped circle grain that is become the branch combination by effective ingredient, excipient, round shaped grain forming adhesives, interfacial agent etc., in order to produce the purpose of maintenance dose.Via the particular method of manufacture of this preparation, make the round shaped grain of a grain, contain simultaneously " delay to disengage " mechanism and " initial dose " design of mechanism,, can reach the function of slow release, and bring into play curative effect to make uniform round shaped grain through special slow release material and technology.
Rantudil slow-releasing round shaped grain constituent of the present invention, be for oral integrally formed round shaped grain constituent, according to particular method of manufacture of the present invention, allow every round shaped grain constituent contain outer speed and put 3 layers on layer (initial dose), middle level enteric film clothing layer, internal layer nade-shaped circle grain layer (maintenance dose) etc., the material of this each layer of constituent is described below respectively;
1. internal layer nade-shaped circle grain layer, its material comprises
(A) effective ingredient: rantudil content accounts for 20～35% of gross weight.
(B) excipient: available lactose (lactose), sorbitol (sorbitol) or its content of mannitol (mannitol) account for 40～55% of gross weight.
(C) round shaped grain shaping adhesive: available microcrystalline Cellulose and sodium carboxymethyl cellulose (microcrystalline cellulose/carboxymethylcellulose sodium such as Avicel
RC591), microcrystalline Cellulose is (as microcrystalline cellulose Avicel
) or its content of microcrystalline Cellulose/low-substituted hydroxypropyl cellulose (microcrystalline cellulose/low substitutionhydroxypropyl cellulose) account for 1～10% of gross weight.
(D) interfacial agent: available sodium lauryl sulphate (sodium lauryl sulfate), polyoxyethylene sorbitan monoleate (polysorbate 80) etc., its content accounts for 0.1～5% of gross weight.
2. the effect of middle level enteric film clothing layer is to keep out the effect of emitting acid, makes the internal layer medicine arrive small intestinal by stomach, utilizes the environment of its pH 5～7, collapse loose molten from after, after intestinal absorption, bring into play drug effect; Its material comprises:
(A) the film clothing forms agent: available acetic acid phthalic acid cellulose (CAP), methacrylic acid copolymer (methacrylic acid copolymer), the third hydroxy-methyl cellulose phthalic acid ester (HPMCP) etc., its content accounts for 1～15% of gross weight.And the commercially available product of methacrylic acid copolymer (methacrylic acid copolymer) have excellent in the base (Eudragit) series products, rantudil slow-releasing round shaped grain constituent of the present invention can adopt Eudragit
L100, Eudragit
S 100, Eudragit
Commodity such as L30 D-55.
(B) plasticiser: available glyceryl triacetate (triacetin), triethyl citrate (triethyl citrate), second vinegar monoglyceride (acetylated monoglyceride) etc., its content accounts for 0.1～10% of gross weight, and the commodity of second vinegar monoglyceride are Myvacet 9～40.
(C) antitack agent: available Pulvis Talci, magnesium stearate etc., its content accounts for 0.1～10% of gross weight.
(D) solvent: available dichloromethane (methylene chloride), ethanol, isopropyl alcohol, acetone, water and with the mixture of water etc.
3. the effect that outer speed is put layer provides the initial dose of effective ingredient rantudil, and its material comprises:
(A) polymer binder: third hydroxy-methyl cellulose (HPMC) or polyvidon (PVP), work as solvent with 95% ethanol and Purified Water (1: 1), its content accounts for 0.1～10% of gross weight.
(B) plasticiser: Polyethylene Glycol (PEG) content accounts for 0.1～10% of gross weight.
(C) effective ingredient: rantudil content accounts for 5～15% of gross weight.
(D) antiseize paste: Pulvis Talci content accounts for 0.1～10% of gross weight.
Microcrystalline Cellulose (microcrystalline cellulose) wherein, low third hydroxylated cellulose (the low substitution hydroxypropyl cellulose that replaces, L-HPC), the third hydroxy-methyl cellulose phthalic acid ester (hydroxypropyl methylcellulose phthalate), or sodium carboxymethyl cellulose materials such as (sodium carboxymethyl cellulose), can optionally select the name of an article of difference for use, ratio allotment according to difference, and the name of an article of difference has the characteristic of its difference, for example microcrystalline Cellulose and sodium carboxymethyl cellulose (Avicel
RC591) because of containing sodium carboxymethyl cellulose, so than microcrystalline Cellulose (Avicel
) have a better bonding force.
Low third hydroxylated cellulose (low substitution hydroxypropyl cellulose) that replaces also can use LH11, LH21, LH30, LH31, LH32, LH40, LH41.Polyvidon (PVP) or Polyethylene Glycol (PEG) all can be selected the molecular weight of difference for use, as Polyethylene Glycol (PEG6000), and polyvidon K-90 (PVP K-90).Third hydroxy-methyl cellulose (HPMC) can select for use different viscosities as 3～15 centipoises.
The Eudragit of base in excellent
L30 D-55 is produced by Luo Mu (Rohm) company, for a kind of enteric film clothing forms agent, contains the emulsion hydrosol of percentage by weight 30% methacrylic acid copolymer, promptly can dissolve in the solution of pH more than 5.5.The commodity of third hydroxy-methyl cellulose (HPMC) have Pharmacoat
606, Pharmacoat
615.
The particular method of manufacture of rantudil slow-releasing round shaped grain constituent of the present invention, the preparation of internal layer nade-shaped circle grain layer: with effective ingredient rantudil, excipient lactose class, round shaped grain forming adhesives microcrystalline Cellulose and raw materials such as sodium carboxymethyl cellulose class, interfacial agent sodium lauryl sulphate class close through mixing, practicing, pelletize, round, and drying process, and screen it;
The preparation of middle level enteric film clothing layer: will contain the suspension that the enteric film clothing forms raw materials such as agent acetic acid phthalic acid cellulose family, antitack agent Pulvis Talci and plasticiser glyceryl triacetate class, spraying coats nade-shaped circle grain, carries out enteric film clothing operation;
Outer speed is put the preparation of layer: the slurry that the polymer binder third hydroxy-methyl cellulose class, plasticiser polyethylene glycols and solvent are combined, spray at enteric film clothing layer, and the conspergative that effective ingredient rantudil and antiseize paste combine carried out the spreading operation, the enteric round shaped grain is coated speed put a layer main constituent, the reuse slurry coats goes up protective layer, makes the slow release round shaped grain at last through sieving drying; Above-mentioned slow release round shaped grain is filled into hard capsule.
Integrally formed slow-releasing round shaped grain is molten from the mechanism that absorbs
(A) this capsule formulation is a kind of round shaped grain medicine prescription of slow release, putting layer rantudil in gastrointestinal tract speed can promptly be absorbed, then utilize higher pH (more than 5.5) that the enteric round shaped grain is dissolved, rantudil is molten from absorbing to liver at intestinal, through liver hydrolysis metabolism is to arrive site of action after active metabolite indomethacin (indomethacin) enters systemic circulation, produces the anti-inflammatory analgesic effect.
(B) invention of this preparation has following advantage:
(a) because all containing, each all measures the quick-acting round shaped grains made from main constituent rantudil that delay of definite proportion, so can quantitatively discharge effective safe dose in the different periods.
(b) because this dosage form was taken once in per 12 hours, only need take 2 every day, can increase patient's compliance and convenience.
(c) vibration of blood level (Fluctuation) is little, and steady statue in the very fast arrival blood plasma.
(d) the intestines and stomach side effect is little.
Description of drawings
Fig. 1 is a rantudil slow-releasing round shaped grain constituent of the present invention, comprises that speed puts layer, enteric film clothing layer, nade-shaped circle grain layer.
Fig. 2 is the flow chart of the preparation embodiment of the invention 1.
Fig. 3 takes the embodiment of the invention 1 medicine and known slow releasing capsule (Rantudil by 16 health volunteers
Retard capsules), measured steady statue, multiple dosetest rantudil plasma concentration---time profile diagram.
Fig. 4 takes the embodiment of the invention 1 medicine and known slow releasing capsule (Rantudil by 16 health volunteers
Retard capsules), measured steady statue, multiple dosetest indomethacin plasma concentration---time profile diagram.
The specific embodiment
Example 1:
1. the prescription of rantudil (acemetacin) pharmacy round shaped grain
(A) internal layer nade-shaped circle grain:
Rantudil 650 grams
Lactose 1074 grams
Microcrystalline Cellulose and sodium carboxymethyl cellulose 72 grams
(Avicel
RC 591)
Sodium lauryl sulphate (sodium lauryl sulfate) 4 grams
Purified water 360 grams
(B) middle level enteric film clothing layer:
Dichloromethane (methylene chloride) 2800 grams
Ethanol (95%) 1400 gram
Glyceryl triacetate (triacetin) 36 grams
Acetic acid phthalic acid cellulose 144 grams
(cellulose acetate phthalate)
Pulvis Talci 20 grams
(C) outer speed is put layer:
(a) slurry:
Ethanol (95%) 245 gram
Purified water 245 grams
Polyethylene Glycol (PEG 6000) 5 grams
Third hydroxy-methyl cellulose, 6 centipoises, 20 grams
(Pharmacoat
606)
(b) main constituent epipasxtic
Rantudil 250 grams
Pulvis Talci 12.5 grams
2. the method for preparing this prescription:
See also shown in Figure 2ly, be the flow chart of preparation method of the present invention:
A. the preparation of internal layer nade-shaped circle grain layer:
(a) earlier rantudil, lactose, microcrystalline Cellulose and sodium carboxymethyl cellulose (Avicel
RC591); cross screen cloth respectively No. 40; mix homogeneously in mixer; add 1.1% lauryl sodium sulfate aqueous solution, 364 grams again; mixing and rubbing are to flexible wet block, and wet mixture process Squeezinggranulator, (the aperture openings diameter is by 0.8mm to 1.2mm for its cylindrical shape porous screen cloth then; depend on the needs) be squeezed into the about 0.8mm to 1.2mm of diameter (depending on the needs) strip shaped grain, about 1.0 centimeters to 3.0 centimeters of length.
(b) just (rolling machine of about 600rpm～1200rpm), it is twisted into diameter is the uniform round shaped grain of 0.8～1.5 mm particle size, between about 2 minutes to 10 minutes of round as a ball time in high speed rotating again this wet strip shaped grain to be put into dress circular friction face plate.
(c) round as a ball round shaped grain is put into drying baker, in 40 ℃～48 ℃ dryings and ripening at least 10 hours, (moisture Control in the round shaped grain is in 5%).
(d) re-use screen cloth 16 and No. 40, sieve is got the round shaped grain of suitable particle diameter, as the base material of middle level enteric film clothing layer.
B. the preparation of middle level enteric film clothing layer:
Earlier acetic acid phthalic acid cellulose (CAP), glyceryl triacetate (triacetin), Pulvis Talci (talc), dichloromethane (methylene chloride) and ethanol in suitable rustless steel container, it is standby to stir into fully uniform suspension mucus with blender.Put into heart fluidized granulator far away (CF-360NS) preparing the dry round shaped grain of finishing then, whole acetic acid phthalic acid celluloses (CAP) suspension mucus is sprayed into, the enteric round shaped grain is coated fully, with the enteric round shaped grain in 45 ℃ of dryings and ripening at least 10 hours.
C. outer speed is put the preparation of layer:
(a) round shaped grain behind the last casing is put into CF-360NS, (about 250rpm～300rpm), spray into and use third hydroxy-methyl cellulose (HPMC 606) in advance, Polyethylene Glycol (PEG 6000), the mucus of ethanol and the preparation of water mixed dissolution in the rotating disk high speed rotating.
(b) etc. the appearance of casing round shaped grain begins to use the powder quantitatively distributor with rantudil and the uniform spreading of Pulvis Talci mixed-powder, till complete spreading of mixed-powder and adhesion when moistening.
(c) put into drying baker preparing integrally formed round shaped grain, in 40 ℃～48 ℃ dryings and ripening at least 10 hours, (moisture Control in the round shaped grain is in 5%).
D. the round shaped grain of method for preparing quantitative (about 230mg) filling is made the capsule formulation of weight homogeneous in suitable capsulae vacuus, take it with oral form.
3. medicine soundness test:
The soundness test of table 1 medicine
| Ai Simeite slow releasing capsule Acemet Retard Capsule 90mg is bottled, box-packed | Lot number TS 446 | ||||
| Pilot project: 1. outward appearance: green No. two transparent sheath and water white transparency body capsule filling yellow particle 2. rantudil content: 90.0～110.0% | |||||
| Through the time | Bottled | Box-packed | |||
| 25℃-RH60％ | 40℃ -RH75％ | 25℃-RH60％ | 40℃-RH75％ | ||
| During beginning | 101.1％ | ||||
| 1 month | -------- | 100.9％ | -------- | 100.7％ | |
| 2 months | -------- | 100.5％ | -------- | 101.0％ | |
| 3 months | 100.7％ | 100.4％ | 100.6％ | 100.1％ | |
| 6 months | 100.2％ | 100.2％ | 100.4％ | 99.9％ | |
| 9 months | 99.6％ | -------- | 99.4％ | -------- | |
Table 1 shows this product medicine soundness test data result, 40 ℃ of accelerated tests, and relative humidity 75% is through after six months, and is no matter bottled and box-packed all very stable, 25 ℃ of long term tests, relative humidity 60% is also very stable through nine months.
4. dissolution method
Table 2 dissolution method
| Time (branch) | % is molten from 0.1N HCl | % is molten from pH4.5 | % is molten from pH6.8 |
| 10 20 30 45 60 90 120 | 0.3 0.3 0.5 0.5 0.4 0.4 0.4 | 2.8 5.1 5.2 7.0 8.7 10.3 12.3 | 40.8 73.1 86.0 92.6 94.3 94.8 94.5 |
The dissolution method of the embodiment of the invention 1 is the basket method according to American Pharmacopeia 24 editions, soaks the buffer that solvent is respectively 0.1NHCl, pH4.5, pH6.8, and table 2 shows the embodiment of the invention 1 dissolution method data, and this product is that pH is dependent as can be known.
5. drug disposition dynamics test (In Vivo Test)
Table 3 medicine dynamics parameter value
| Human bioavailability | Rantudil | Indomethacin | ||||||
| Known slow releasing capsule 90mg | Ai Simeite slow releasing capsule 90mg | Known slow releasing capsule 90mg | Ai Simeite slow releasing capsule 90mg | |||||
| Meansigma methods | SD | Meansigma methods | SD | Meansigma methods | SD | Meansigma methods | SD | |
| AUCo -＞τ，ss (ng/ml×hr) | 1545 | 507 | 1484 | 453 | 9540 | 2914 | 9224 | 2562 |
| C max，ss (ng/ml) | 588 | 287 | 585 | 283 | 1658 | 573 | 1547 | 391 |
| T max，ss (hr) | 5.19 | 1.14 | 5.22 | 0.71 | 5.53 | 1.07 | 5.47 | 0.83 |
This test is 16 health volunteers, takes the test drug and the known slow releasing capsule (Rantudil of contrast medicine of the embodiment of the invention 1
Retard capsules) tests in the bioequivalence of steady statue; The experimenter extracted 20 blood samples to be for experiment the plasma sample LC/MS/MS method quantitative analysis rantudil and the indomethacin concentration of really imitating in take 8 dosage medicines after the meal on time in 120 hours.
In order to determine the relative human bioavailability of two Medicine prescriptions,---time profile diagram and Fig. 4 indomethacin plasma concentration---time profile diagram by Fig. 3 rantudil plasma concentration can obtain table 3 medicine dynamics parameter value: the gross area (AUC under the individual interval curve of taking medicine of one of steady statue
O-＞τ, ss), the blood level peak (C of steady statue
Max, ss), steady statue arrives peak concentration time (Tmax in the blood, ss) data, statistic analysis result proves that 90 percent credibility interval (90%Confidence Interval) of each parameter is all between 80.0%～125%, so this result of the test proof embodiment of the invention 1 has the human body equality with the contrast medicine.
Example 2:
1. the integrally formed prescription of rantudil (acemetacin) pharmacy round shaped grain
(A) internal layer nade-shaped circle grain layer:
Rantudil 650 grams
Mannitol 1074 grams
Microcrystalline Cellulose (Avicel
) 54 grams
Sodium carboxymethyl cellulose 18 grams
(sodium carboxymethyl cellulose)
Polyoxyethylene sorbitan monoleate (polysorbate 80) 4 grams
Purified water 360 grams
(B) middle level enteric film clothing layer:
Base (Eudragit in excellent
L 30 D-55) 660 grams
Pulvis Talci 100 grams
Triethyl citrate (triethyl citrate) 20 grams
The strict health defoamer of silicon (silicon antifoam) 2 grams
Purified water 828 grams
(C) outer speed is put layer:
(a) slurry:
Polyvidon K-90 (PVP) 10 grams
Ethanol (95%) 250 gram
Purified water 250 grams
(b) main constituent epipasxtic
Rantudil 250 grams
Pulvis Talci 25 grams
2. the method for preparing this prescription
Content is identical with the preparation method of example 1
Example 3:
1. the prescription of rantudil (acemetacin) pharmacy round shaped grain
(A) internal layer nade-shaped circle grain layer:
Rantudil 650 grams
Lactose 1074 grams
Microcrystalline Cellulose 54 grams
(microcrystalline cellulose)
The low third hydroxylated cellulose LH, 3 54 grams that replace
Purified water 500 grams
(B) middle level enteric film clothing layer:
The third hydroxy-methyl cellulose phthalic acid ester, 200 grams
(hydroxypropyl methylcellulose phthalate)
Second vinegar monoglyceride (Myvacet 9～40) 40 grams
Pulvis Talci 40 grams
Ethanol (95%) 820 gram
Dichloromethane (methylene chloride) 890 grams
(C) outer speed is put layer:
(a) slurry:
Ethanol (95%) 245 gram
Purified water 245 grams
Third hydroxy-methyl cellulose, 15 centipoises, 13 grams
(Pharmacoat
615)
(b) main constituent epipasxtic:
Rantudil 250 grams
Pulvis Talci 25 grams
2. the method for preparing this prescription:
Content is identical with the preparation method of example 1
Claims (8)
1, a kind of rantudil slow-releasing round shaped grain constituent, it comprises that internal layer nade-shaped circle grain layer, middle level enteric film clothing layer, outer speed puts layer;
A. internal layer is to be combined by compositions such as main constituent rantudil, excipient, round shaped grain forming adhesives and interfacial agents; And rantudil content accounts for 20～35% of gross weight, excipient content account for gross weight 40%～55% between, round shaped grain forming adhesives content accounts for 1%～10% of gross weight, the interfacial activity agent content accounts for 0.1%～5% of gross weight;
B. the middle level is to form agent, antitack agent, plasticiser and solvent by the enteric film clothing to spray the enteric layers that forms on the internal layer nade-shaped circle grain, the enteric film clothing forms agent content and accounts for 1～15% of gross weight, antitack agent content accounts for 0.1～10% of gross weight, and plasticiser content accounts for 0.1～10% of gross weight;
C. the outer slurry that is combined by polymer binder, plasticiser and solvent sprays at the middle level enteric layer, the conspergative that combines of spreading effective ingredient rantudil and antiseize paste again, the outer instant layer that forms, wherein rantudil content accounts for 5～15% of gross weight, the high molecular bonding agent content accounts for 0.1～10% of gross weight, plasticiser content accounts for 0.1～10% of gross weight, and antiseize paste content accounts for 0.1～10% of gross weight.
2, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: the round shaped grain forming adhesives of described internal layer nade-shaped circle grain is to be selected from the low mixture that replaces third hydroxylated cellulose or microcrystalline Cellulose and sodium carboxymethyl cellulose.
3, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: the interfacial agent of described internal layer nade-shaped circle grain layer constituent can be selected sodium lauryl sulphate, polyoxyethylene sorbitan monoleate for use.
4, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: the plasticiser of described middle level enteric film clothing layer constituent, can select glyceryl triacetate, triethyl citrate, second vinegar monoglyceride for use.
5, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: described enteric film clothing material can be used acetic acid phthalic acid cellulose, methacrylic acid copolymer, the third hydroxy-methyl cellulose phthalic acid ester.
6, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: the slurry that described outer speed is put layer can be selected third hydroxy-methyl cellulose for use, its viscosity 3～15 centipoises, polyvidon K-90.
7, according to the described rantudil slow-releasing of claim 1 round shaped grain constituent, it is characterized in that: the capsule formulation of weight homogeneous is made in described round shaped grain filling in suitable capsulae vacuus.
8, the preparation method of the described rantudil slow-releasing of claim 1 round shaped grain constituent, this method comprises the steps:
The preparation of internal layer nade-shaped circle grain layer: with effective ingredient rantudil, excipient lactose class, round shaped grain forming adhesives microcrystalline Cellulose and sodium carboxymethyl cellulose class, interfacial agent sodium lauryl sulphate class raw material close through mixing, practicing, pelletize, round, and drying process, and screen it;
The preparation of middle level enteric film clothing layer: will contain the suspension that the enteric film clothing forms agent acetic acid phthalic acid cellulose family, antitack agent Pulvis Talci and plasticiser glyceryl triacetate class raw material, spraying coats nade-shaped circle grain, carries out enteric film clothing operation;
Outer speed is put the preparation of layer: the slurry that the polymer binder third hydroxy-methyl cellulose class, plasticiser polyethylene glycols and solvent are combined, spray at enteric film clothing layer, and the conspergative that effective ingredient rantudil and antiseize paste combine carried out the spreading operation, the enteric round shaped grain is coated speed put a layer main constituent, the reuse slurry coats goes up protective layer, makes the slow release round shaped grain at last through sieving drying; Above-mentioned slow release round shaped grain is filled into hard capsule.
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| CN85102343A (en) * | 1984-08-30 | 1986-10-29 | 特罗本维克有限公司和科隆分公司 | The method for preparing pellet-formulation |
| US4900557A (en) * | 1984-08-30 | 1990-02-13 | Troponwerke Gmbh & Co. Kg | Pellet formulation |
| EP0647448A1 (en) * | 1993-10-07 | 1995-04-12 | Euroceltique S.A. | Orally administrable opioid formulations having extended duration of effect |
| CN1215322A (en) * | 1996-04-05 | 1999-04-28 | 沃尼尔·朗伯公司 | Process for encapsulation of caplets in a capsule and solid dosage forms obtainlable by such process |
| CN1270029A (en) * | 1999-01-18 | 2000-10-18 | 格吕伦塔尔有限公司 | Thebaic analgesic with controllable releasement of active content |
| CN1270028A (en) * | 1999-01-18 | 2000-10-18 | 格吕伦塔尔有限公司 | Analgesic with controlled releasement of active content |
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| CN1579369A (en) | 2005-02-16 |
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