CN103462937A - Preparation method of spansules containing large dosage of nicotinic acid - Google Patents
Preparation method of spansules containing large dosage of nicotinic acid Download PDFInfo
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- CN103462937A CN103462937A CN 201310430070 CN201310430070A CN103462937A CN 103462937 A CN103462937 A CN 103462937A CN 201310430070 CN201310430070 CN 201310430070 CN 201310430070 A CN201310430070 A CN 201310430070A CN 103462937 A CN103462937 A CN 103462937A
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims abstract description 171
- 235000001968 nicotinic acid Nutrition 0.000 title claims abstract description 91
- 239000011664 nicotinic acid Substances 0.000 title claims abstract description 91
- 229960003512 nicotinic acid Drugs 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 238000000576 coating method Methods 0.000 claims abstract description 98
- 239000011248 coating agent Substances 0.000 claims abstract description 92
- 239000006187 pill Substances 0.000 claims abstract description 51
- 239000002775 capsule Substances 0.000 claims abstract description 39
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000843 powder Substances 0.000 claims abstract description 29
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- 238000013268 sustained release Methods 0.000 claims description 25
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Abstract
The invention discloses a preparation method of spansules containing large dosage of nicotinic acid, aiming to provide a preparation method of spansules which are high in nicotinic acid content, are ideal in slow-release effect, are simple in production process, and are good in reproducibility. The preparation method of the spansules sequentially comprises the following steps of (1) pretreating original auxiliary materials; (2) mixing the original auxiliary materials and premixed powder together, placing blank pill cores into a coating granulator, adding the premixed powder into a charging hopper, additionally spraying 5% hydroxypropyl methylcellulose solution, and preparing pill cores containing nicotinic acid by a lamination method; (3) preparing a coating liquid, taking 18-20-mesh pill cores containing nicotinic acid, placing into the coating granulator, spraying the coating liquid, meanwhile spraying talcum powder on the pill cores containing nicotinic acid at the speed of 0.6g-1.4g/min, and stopping spraying the talcum powder when spraying of the coating liquid is finished, thereby obtaining the coated medicine pills; (4) mixing the coated medicine pills together after thermal treatment; and (5) filling the capsules according to the percentage content of nicotinic acid in the coated pills. The preparation method of the spansules containing large dosage of nicotinic acid belongs to the technical field of medicine preparation.
Description
Technical field
The invention provides a kind of preparation method of slow releasing capsule, specifically, is a kind of preparation method containing heavy dose of apellagrin sustained-release capsule, belongs to medical preparing technical field.
Background technology
Nicotinic acid is that 4 at present the most frequently used large classes are regulated one of blood fat medicine, in clinical practice over half a century, can effectively improve the lipid metabolism situation of patients with dyslipidemia.Clinical observation confirmed nicotinic acid tune fat determined curative effect and comprehensively, can effectively reduce plasma glycerol three vinegar (TG), high density lipoprotein increasing-cholesterol (HDL-C), also can reduce T-CHOL (TC) and LDL-C (LDL-C), but also there is the effect of unique reduction lipoprotein (a) [Lp (a)].
Because the half-life of nicotinic acid is extremely short, two kinds of side effect of flushing and liver toxicity, often appear in only 25-45min, and heavy dose of nicotinic acid that uses, and give full play to curative effect, must make slow releasing preparation.Though spacetabs type nicotinic acid is not as statins on reduction low-density lipoprotein cholesterol degree of convergence, its character that can improve 20% HDL-C and reduction by 25% triglyceride levels simultaneously makes it in all kinds of fat-reducing medicaments, win special status.
U.S. Kos Pharmaceuticals company develops niacin slow-release tablet the earliest, in July, 1997, in the U.S., go on the market, the promise of commodity Niaspan(prior art by name is flat), adopt matrix type release technology, nicotinic acid is prepared into to the effect that the hydrophilic gel slow releasing tablet reaches slow release.The domestic niacin slow-release tablet of examining and going on the market also has many families at present, and the also patent applied for had.
Chinese patent CN200580017017.7 discloses a kind of for oral niacin sustained release composition, and the slow-released carrier that mainly utilizes hydrophilic polymer and hydrophobic polymer to form maintains the constant release rate of nicotinic acid; Chinese patent CN201010123458.8 discloses and a kind ofly can reduce erubescent niacin preparation, and slow-released carrier used is selected the cellulose or derivatives thereof with good dilatancy and gel-type; Chinese patent CN20078001354.6 discloses a kind of niacin sustained release skeleton preparation that can direct compression, comprises nicotinic acid, delayed release agent and other excipient.Scholar state Fomitopsis officnalic（Vill.:Fr.)Bond.et Sing, Wang Liqing, Li Wenfeng, Wu Haiyan etc. all select hydroxypropyl emthylcellulose as blocker, and the matrix type niacin sustained-release preparation is developed to research.Matrix type release technology belongs to the unit medicine-releasing system, but the major defect of unit release drug-supplying system be easy to produce prominent release and flotation property bad, have potential safety hidden danger.And the delayed release agent described in above-mentioned document all is selected from slow-release material that viscosity is larger as hypromellose, natural gum etc.Caused like this production process wayward, production cost is higher.
Chinese patent CN200510043251.9 discloses a kind of nicotinic acid controlled releasing tablet and preparation method thereof, institute's controlled release tablet is comprised of label and release-controlled film, release-controlled film comprises film clothing material, porogen and plasticizer, and its film clothing material is one or more in cellulose acetate, ethyl cellulose, polyacrylic acid resin, polyamide or ethylene-vinyl acetate copolymer, polrvinyl chloride, polyamide, Merlon; Porogen is one or more in methylcellulose, Polyethylene Glycol, polyvinylpyrrolidone, sucrose, hypromellose, polymethacrylate, phthalic acid cellulose family; Plasticizer is one or more in the third dioctyl phthalate dioctyl ester, diethyl phthalate, mannitol, Oleum Ricini, glycerol.The de-philosophy of Zhou Tong, Chen Jin is selected aqueous dispersion and the alcoholic dispersion of ethyl cellulose; it is coating material that Lee's Yi etc. is selected aqueous acrylic resin dispersion, adopt micropill film control techniques to prepare the niacin sustained release micropill, they all select PEG 4000 or HPMC E5 as porogen.The domestic patents such as CN200810238273.4, CN200810239882.1, CN201210057612.5 have more been announced pharmaceutical composition of a kind of compound slow release preparation and preparation method thereof, wherein slow-released part adopts coating of pellets film control techniques, and the rate of release of medicine is controlled by the micropore coating membrane fully.
Coating of pellets film control techniques belongs to the multiple-unit medicine-releasing system, can improve medicine and gastrointestinal contact area, makes drug absorption complete, thereby improves bioavailability; Individual variation is little, and medicine seldom is subject to the impact that gastric emptying changes in vivo, and absorption in vivo has the good repeatability that obtains; Safe, make the technique of slow releasing preparation in the micropill surface coatings than easily row is reliable at the tablet surface coating, can avoid the coating such as tablet inhomogeneous and cause the danger such as medicine punching leakage, defect in indivedual micropill preparations is unlikely to the drug release behavior generation of whole preparation is had a strong impact on, and for the unit delivery system, safety coefficient is high.
The research discovery, the rounding property of ball core and size, coating solution formula, coating parameter three aspects: affect larger on the formation of the clothing film of niacin sustained release micropill.Aspect sustained release coating liquid prescription, porogen and antiplastering aid cause larger impact to the micropill release characteristics.Existing coating preparation thereof solution commonly used has aqueous dispersion and alcoholic dispersion system.The aqueous dispersion form has the advantages such as solids content is high, viscosity is low, easy operating, the coating time is short, film forming is even, and, without problems such as inflammable and explosive, organic solvent residuals, is conducive to environmental conservation, little to the human injury.Relate to material that in the existing document of aqueous dispersion coating prescription, porogen mostly is good water solubility as HPMC, PVP, PEG and lactose etc., antiplastering aid mostly is Pulvis Talci, both consumptions the number all can cause the fluctuation that the micropill release is larger.
In the niacin sustained release microsphere and its preparation of aqueous dispersion coating, because containing heavy dose of nicotinic acid, the coating liquid measure is large, and wherein the water yield is also larger, so micropill viscosity is large, therefore add heavy dose of Pulvis Talci to make antiplastering aid in the coating solution of being everlasting.Pulvis Talci for the preparation of pharmaceutical solid preparation, prevents the adhesion of slow-release micro-pill as antiplastering aid, and usual amounts is polymer weight 20%～60%.Water insoluble and the ethanol of Pulvis Talci, prior art is that Pulvis Talci is added to coating solution, after continuing to stir into suspension together with other coating materials and adjuvant, directly is sprayed to micropill.And containing heavy dose of talcous coating suspension, even the Pulvis Talci particle diameter is tiny, still inevitable blocking pipe in the sprinkling process, cause production efficiency low; Containing heavy dose of talcous coating suspension, the easy sedimentation of Pulvis Talci, cause the Pulvis Talci of part amount can't be sprayed onto on micropill, causes micropill to criticize a release and large fluctuation occurs simultaneously.
In sum, slow-release micro-pill is one of comparatively ideal slow release formulation of generally acknowledging at present, but find in existing research data, the formation of coating of pellets process underpants film is subject to the character of ball core, coating fluid prescription, technological parameters etc. are the impact of factor in many ways, the extended release coatings film is directly connected to the release characteristics of micropill, the variation of every kind of factor all can cause the variation of micropill release, finally make the repeatability of slow release effect of slow-release micro-pill poor, in actual production process, the qualification rate of product is unstable, increases labour cost.
Summary of the invention
For above-mentioned deficiency, the object of the present invention is to provide a kind of Nicotinic Acid Content high, slow release effect ideal, the preparation method of the apellagrin sustained-release capsule of the simple and favorable reproducibility of production process.
For solving the problems of the technologies described above, technical scheme provided by the invention is such: should, containing the preparation method of heavy dose of apellagrin sustained-release capsule, comprise successively lower step:
1) supplementary material pre-treatment
Take nicotinic acid, microcrystalline Cellulose, lactose and cross 120 mesh sieves, Pulvis Talci is crossed 1250 mesh sieves, and celphere is crossed after the 40-60 mesh sieve standby;
2) preparation is containing nicotinic acid ball core
A) the premix powder is always mixed: nicotinic acid, microcrystalline Cellulose and lactose after step 1) is sieved mix and make the premix powder, standby;
B) lamination pill: the celphere after step 1) is sieved is placed in coating granulator, the premix powder that adds step a) to make in loading hopper, start coating granulator by following major parameter and carry out the lamination pill: air blast 30%～60%, engine speed 50～130rpm, spray into 5% hypromellose solution with spray pump speed 10～50rpm, with speed 10～60rpm, supply the premix powder; Grow to when granularity is 18～24 order and stop whitewashing and supply powder until pill, polishing, dry, and must contain nicotinic acid ball core;
3) prepare coated pill
A) preparation coating solution: take sodium lauryl sulphate and be dissolved in purified water, add especially strange (Eudragit) NE 30D, stir;
B) take granularity 18～24 orders containing nicotinic acid ball core, put in coating granulator, start coating granulator by following major parameter and carry out coating in the centrifugal rotation mode: air blast 40%～80%, engine speed 40～150rpm, 35～90 ° of angle of gun, whiff pressure 0.08～0.15MPa, speed with 5～20g/min sprays into above-mentioned coating solution, spray Pulvis Talci to containing on nicotinic acid ball core with the speed of 0.6g～1.4g/min simultaneously, sprayed coating solution and stopped Pulvis Talci simultaneously, make coated pill;
4) heat treatment, total mixed
By after the coated pills heat treatment, sieve, mix;
5) encapsulated
According to nicotinic acid percentage composition in coated pill, load capsule;
Wherein: in nicotinic acid ball core prescription, the quality of celphere: the quality of nicotinic acid: the quality of microcrystalline Cellulose: the quality of lactose is 1.3～4.0:20～25:0.7～0.75:1.1～1.25;
In coated pill prescription, the quality of nicotinic acid ball core: the quality of strange (Eudragit) NE 30D especially: the quality of sodium lauryl sulphate: talcous quality: the quality of purified water is 21～25:3.0～5.7:0.008～0.014:1.2～1.75:4～6.72.
The above-mentioned preparation method containing heavy dose of apellagrin sustained-release capsule, the preparation method of described celphere is,
Microcrystalline Cellulose is put in coating granulator; start main frame; by following major parameter, operated: air blast 30%～95%, engine speed 50～135rpm, spray pump rotating speed 10～60rpm; whiff pressure 0.05～0.15MPa; spray into 5% hypromellose solution, make celphere, polishing 2 minutes; take the dish out of the pot, dry.
The above-mentioned preparation method containing heavy dose of apellagrin sustained-release capsule, described heat treatment is to dry coated pills 24 hours at 40 ℃.
The above-mentioned preparation method containing heavy dose of apellagrin sustained-release capsule, step 2) described bake out temperature is 60 ℃.
Further, the above-mentioned preparation method containing heavy dose of apellagrin sustained-release capsule, every of described capsule contains nicotinic acid 250mg.
Compared with prior art, technical scheme provided by the invention has following technique effect:
1) the invention provides technical scheme, Pulvis Talci directly is sprayed to slow-release micro-pill with the form of pressed powder, effectively solve the phenomenon of the Pulvis Talci production equipment line clogging that the content height easily causes in coating solution and coating material loss; In the coating process of micropill, use Pulvis Talci simultaneously as antiplastering aid and the porogen of coating material, optimize talcous ratio in coating weightening finish and coating prescription, finally make the whole evenly controlled coating membrane that forms of coating material; Described coating prescription is simple, has not only solved the adhesion problems in the coating of pellets process, also make affect the micropill release in the coating process factor still less, selected raw material is easy to get feasible, production process is simple, cost is low, is beneficial to industrialized great production, has good repeatability;
2) apellagrin sustained-release capsule that prepared by technical scheme provided by the invention is containing heavy dose of nicotinic acid (250mg/ grain), single administration can guarantee the 24 hours interior active drug concentration of body, be convenient to patient's long-term treatment, improve the compliance of medication, and reduced the side effect that the heavy dose of administration of nicotinic acid brings;
3) apellagrin sustained-release capsule that adopts technical scheme provided by the invention to prepare, its slow release principle is mainly the film controlling type slow-release micro-pill, can significantly reduce the preparation differences between batches.
The accompanying drawing explanation
Fig. 1 be slow releasing capsule provided by the invention and prior art promise put down release curve comparison diagram under water condition;
Fig. 2 be slow releasing capsule provided by the invention and prior art promise put down release curve comparison diagram under the pH6.8 condition;
Fig. 3 be slow releasing capsule provided by the invention and prior art promise put down release curve comparison diagram under the pH4.0 condition;
Fig. 4 be slow releasing capsule provided by the invention and prior art promise put down release curve comparison diagram under the pH1.2 condition;
Fig. 5 is that slow releasing capsule own product provided by the invention is criticized a release repeatability comparison curves.
The specific embodiment
Below in conjunction with the specific embodiment; claim of the present invention is described in further detail; but do not form any limitation of the invention, the modification of any limited number of time of making in the claims in the present invention scope, still within claim protection domain of the present invention.
A kind of preparation method containing heavy dose of apellagrin sustained-release capsule provided by the invention, its prescription is as follows:
Nicotinic acid ball core prescription:
| Name of material | Consumption (kg) |
| Celphere | 4.0 |
| Nicotinic acid | 25 |
| Microcrystalline Cellulose | 0.75 |
| Lactose | 1.25 |
| 5% hypromellose E5 | 10 |
The coated pill prescription:
| Name of material | Consumption (kg) |
| Nicotinic acid ball core | 25 |
| Strange NE 30D especially | 5.7 |
| Sodium lauryl sulphate | 0.014 |
| Pulvis Talci | 1.75 |
| Purified water | 6.72 |
Its preparation method comprises the steps: successively
1) supplementary material pre-treatment
Take each raw material by above-mentioned recipe quantity, nicotinic acid, microcrystalline Cellulose, lactose 120 orders that sieve, standby.
Pulvis Talci: directly buy 1250 order Pulvis Talci.
Celphere: 40～60 purpose graininess celphere, purchased from the happy Kanggong of card department.
2) preparation of nicotinic acid ball core
A) the premix powder is always mixed: the nicotinic acid of recipe quantity, microcrystalline Cellulose and lactose are put in automatic lifting hopper mixer, mixed 20 minutes with rotating speed 12rpm, discharging, obtain the premix powder, standby.
B) preparation method of 5% hypromellose slurry: take the hypromellose of 0.5 kg, add 2.5 kg purification boiling water, stir, then add purification cold water (0 ℃) to 10 kg, to stir, get final product.
C) lamination pill: the celphere that takes recipe quantity; put in coating granulator; separately the premix powder mixed is added in solid feed hopper; the 5% hypromellose solution of take is binding agent; start coating granulator by following parameter and carry out the lamination pill: air blast 40%～50%, engine speed 75～110rpm, spouting velocity 10～40rpm; for powder speed 10～60rpm, whiff pressure 0.05～0.15MPa.Stop whitewashing and supply powder when pill grows to 18～24 order size, engine speed is constant, and the spray velocity modulation is 2rpm polishing 6 minutes, takes the dish out of the pot 60 ℃ and dries to moisture≤3.0%.
D) nicotinic acid ball core is always mixed: the nicotinic acid ball core after the drying screening is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
3) coating
The preparation of coating solution: the sodium lauryl sulphate that takes recipe quantity is dissolved in the purified water of recipe quantity, then adds the Eudragit NE 30D of recipe quantity, stirs.
Take 25 kg 18～24 order nicotinic acid ball cores; put in coating granulator; start coating granulator by following parameter and carry out coating: air blast 55%; engine speed 90rpm; 90 ° of angle of gun; whiff pressure 0.12MPa, spray and state coating solution with the speed of 5～20g/min, sprays Pulvis Talci to nicotinic acid ball core with 0.6g～1.4g/min speed simultaneously.Sprayed coating solution and stopped Pulvis Talci simultaneously, polishing 2 minutes, heat treatment again after taking the dish out of the pot, 40 ℃ aging 24 hours, cross 16 mesh sieves and obtain coated pills.
4) total mixed
Coated pills is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
5) fill
According to nicotinic acid percentage composition measurement result in coated pill, load capsule, every capsules is containing nicotinic acid 250mg.
Another kind provided by the invention is containing the preparation method of heavy dose of apellagrin sustained-release capsule, and its prescription is as follows:
Nicotinic acid celphere prescription:
| Name of material | Consumption (kg) |
| Microcrystalline Cellulose | 3.0 |
| 5% hypromellose E5 | (approximately 22) in right amount |
Nicotinic acid ball core prescription:
| Name of material | Consumption (kg) |
| Celphere | 3.0 |
| |
20 |
| Microcrystalline Cellulose | 0.75 |
| Lactose | 1.25 |
| 5 |
8 |
The coated pill prescription:
| Name of material | Consumption (kg) |
| Nicotinic acid ball core | 21 |
| Strange NE 30D especially | 5.5 |
| Sodium lauryl sulphate | 0.01 |
| Pulvis Talci | 1.5 |
| Purified water | 5.4 |
Its preparation method comprises the steps: successively
1) supplementary material pre-treatment
Take each raw material by above-mentioned recipe quantity, nicotinic acid, microcrystalline Cellulose, lactose 120 orders that sieve, standby.
Pulvis Talci: directly buy 1250 order Pulvis Talci.
2) preparation of micropill
A) the premix powder is always mixed: the nicotinic acid of recipe quantity, microcrystalline Cellulose and lactose are put in automatic lifting hopper mixer, mixed 20 minutes with rotating speed 12rpm, discharging, obtain the premix powder, standby.
B) 5% hypromellose slurry: take the hypromellose of 1.5 kg, add the 7.5 kg purified water of boiling, stir, then add cold purified water to 30 kg, stir, get final product.
C) prepare celphere: the microcrystalline Cellulose of getting about 1.5kg is put in coating granulator, starts main frame, by following parameter, is operated.Air blast 30%～95%, engine speed 60～125rpm, spray pump rotating speed 10～50rpm, whiff pressure 0.05～0.15MPa, spray into 5% hypromellose solution, makes sizeable celphere, then engine speed is constant, the spray velocity modulation is 2rpm polishing 2 minutes, takes the dish out of the pot, and dries to moisture≤3.0% for 60 ℃.
D) lamination pill: the celphere that takes recipe quantity; put in coating granulator; separately the premix powder mixed is added in solid feed hopper; the 5% hypromellose solution of take is binding agent; start coating granulator by following parameter and carry out the lamination pill: air blast 40%～60%, engine speed 50～110rpm, spouting velocity 10～35rpm; for powder speed 10～60rpm, whiff pressure 0.05～0.15MPa.Stop whitewashing and supply powder when pill grows to 18～24 order size, engine speed is constant, and the spray velocity modulation is 2rpm polishing 6 minutes, takes the dish out of the pot 60 ℃ and dries to moisture≤3.0%.
E) nicotinic acid ball core is always mixed: the nicotinic acid ball core after the drying screening is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
3) coating
A) preparation of coating solution: the sodium lauryl sulphate that takes recipe quantity is dissolved in the purified water of recipe quantity, then adds the Eudragit NE 30D of recipe quantity, stirs.
B) take 21 kg 18～24 order nicotinic acid ball cores; put in coating granulator; start coating granulator by following parameter and carry out coating: air blast 40%; engine speed 75 rpm; 45 ° of angle of gun; whiff pressure 0.15MPa, spray and state coating solution with the speed of 5～20g/min, sprays Pulvis Talci to nicotinic acid ball core with the speed of 0.6g～1.4g/min simultaneously.Sprayed coating solution and stopped Pulvis Talci simultaneously, polishing 2 minutes, the after-baking that takes the dish out of the pot, 40 ℃ aging 24 hours, cross 16 mesh sieves and obtain coated pills.
4) total mixed
Coated pills is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
5) fill
According to nicotinic acid percentage composition measurement result in coated pill, load capsule, every capsules is containing nicotinic acid 250mg.
Embodiment 3
Another kind provided by the invention is containing the preparation method of heavy dose of apellagrin sustained-release capsule, and its prescription is as follows:
Nicotinic acid celphere prescription
| Name of material | Consumption (kg) |
| Microcrystalline Cellulose | 4.0 |
| 5% hypromellose E5 | (approximately 25) in right amount |
Nicotinic acid ball core prescription:
| Name of material | Consumption (kg) |
| Celphere | 1.3 |
| Nicotinic acid | 25 |
| Microcrystalline Cellulose | 0.7 |
| Lactose | 1.1 |
| 5% hypromellose E5 | (approximately 12) in right amount |
The coated pill prescription:
| Name of material | Consumption (kg) |
| Nicotinic acid ball core | 22 |
| Strange NE 30D especially | 3.2 |
| Sodium lauryl sulphate | 0.008 |
| Pulvis Talci | 1.2 |
| |
4 |
Its preparation method comprises the steps: successively
1) supplementary material pre-treatment
Take each raw material by above-mentioned recipe quantity, nicotinic acid, microcrystalline Cellulose, lactose 120 orders that sieve, standby.
Pulvis Talci is pulverized: Pulvis Talci is pulverized with fluidized bed air flow crusher, standby.
2) preparation of micropill
A) the premix powder is always mixed: the nicotinic acid of recipe quantity, microcrystalline Cellulose and lactose are put in automatic lifting hopper mixer, mixed 20 minutes with rotating speed 12rpm, discharging, obtain the premix powder, standby.
B) 5% hypromellose slurry: take the hypromellose of 1.5 kg, add the 7.5 kg purified water of boiling, stir, then add cold purified water to 30 kg, stir, get final product.
C) celphere processed: the microcrystalline Cellulose of getting about 1.2kg is put in coating granulator, starts main frame, by following parameter, is operated.Air blast 30%～95%, engine speed 60～125rpm, spray pump rotating speed 10～50rpm, whiff pressure 0.05～0.15MPa, spray into 5% hypromellose solution, makes sizeable celphere, then engine speed is constant, the spray velocity modulation is 2rpm polishing 2 minutes, takes the dish out of the pot, and dries to moisture≤3.0% for 60 ℃.
D) lamination pill: the celphere that takes recipe quantity; put in coating granulator; separately the premix powder mixed is added in solid feed hopper; the 5% hypromellose solution of take is binding agent; start coating granulator by following parameter and carry out the lamination pill: air blast 30%～50%, engine speed 70～130rpm, spouting velocity 10～50rpm; for powder speed 10～60rpm, whiff pressure 0.05～0.15MPa.Stop whitewashing and supply powder when pill grows to 18～24 order size, engine speed is constant, and the spray velocity modulation is 2rpm polishing 6 minutes, takes the dish out of the pot 60 ℃ and dries to moisture≤3.0%.
E) nicotinic acid ball core is always mixed: the nicotinic acid ball core after the drying screening is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
3) coating
A) preparation of coating solution: the sodium lauryl sulphate that takes recipe quantity is dissolved in the purified water of recipe quantity, then adds the Eudragit NE 30D of recipe quantity, stirs.
B) take 22 kg 18～24 order nicotinic acid ball cores; put in coating granulator; start coating granulator by following parameter and carry out coating: air blast 80%; engine speed 150 rpm; 65 ° of angle of gun; whiff pressure 0.1MPa, spray and state coating solution with the speed of 5～20g/min, sprays Pulvis Talci to nicotinic acid ball core with 0.6g～1.4g/min speed simultaneously.Sprayed coating solution and stopped Pulvis Talci simultaneously, polishing 2 minutes, the after-baking that takes the dish out of the pot, 40 ℃ aging 24 hours, cross 16 mesh sieves and obtain coated pills.
4) total mixed
Coated pills is put in automatic lifting hopper mixer and mixed 10 minutes with the 12rpm rotating speed, discharging.
5) fill
According to nicotinic acid percentage composition measurement result in coated pill, load capsule, every containing nicotinic acid 250mg.
Technical scheme provided by the invention is controlled its coating effect by optimizing coating prescription, preparation were established and parameter.This coating prescription using Pulvis Talci antiplastering aid and porogen use in coating material simultaneously, is optimized talcous ratio in coating gain in weight and coating prescription simultaneously.In the coating process of micropill, the technological parameter by heavy dose of Pulvis Talci with pressed powder form and optimization directly is sprayed on nicotinic acid ball core, finally makes the whole evenly controlled coating membrane that forms of coating material.Preparation method coating prescription of the present invention is simple, not only solved the adhesion problems in the coating of pellets process, also make affect the micropill release in the coating process factor still less, production process is simple, production cost is low, be beneficial to large production, the slow release effect of final niacin sustained release coated micropill of the present invention is good and repeatability is very good.
For the advantage of technical scheme provided by the invention better is described, below provide stripping (release) the four curve comparable situation of preparation provided by the invention and former triturate.Drug release determination: get formulation samples of the present invention, press drug release determination method (two appendix X D of Chinese Pharmacopoeia version in 2010) and adopt dissolution method (two appendix X C of Chinese Pharmacopoeia version in 2010) the second subtraction unit, respectively with water, pH6.8 buffer solution, pH4.0 buffer solution and pH1.2 buffer solution 900ml are dielectric solvent, rotating speed is per minute 50 to turn, operation in accordance with the law, 2, 4, 6, 8, 12, 16, 20, 24 hours, getting respectively solution 5ml filters, and the instant solvent 5ml that supplements uniform temp in process container, precision measures subsequent filtrate 1ml, put in the 10ml measuring bottle, be diluted to scale with phosphate buffer, according to ultraviolet visible spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2010), measure trap at 263nm wavelength place.Separately get promise flat as reference preparation of former triturate U.S. Kos Pharmaceuticals company, be measured in the same method.Calculate respectively every burst size at different time.
Consult Fig. 1 to Fig. 4, in embodiment 1, the release curve of slow releasing capsule is 1, and in prior art, the flat release curve of promise is 2.
Fig. 1 be the slow releasing capsule that provides of the invention process 1 and prior art promise put down release curve comparison diagram under water condition; Leaching condition: oar method, 1000ml, water, 37 ℃, sedimentation basket.
Fig. 2 be the slow releasing capsule that provides of the invention process 1 and prior art promise put down release curve comparison diagram under the pH6.8 condition; Leaching condition: oar method, 1000ml, pH6.8 buffer solution, 37 ℃, sedimentation basket;
Fig. 3 be the slow releasing capsule that provides of the invention process 1 and prior art promise put down release curve comparison diagram under the pH4.0 condition; Leaching condition: oar method, 1000ml, pH4.5 buffer solution, 37 ℃, sedimentation basket;
Fig. 4 be the slow releasing capsule that provides of the invention process 1 and prior art promise put down release curve comparison diagram under the pH1.2 condition; Leaching condition: oar method, 1000ml, pH 1.2 buffer solution, 37 ℃, sedimentation basket.
The experimental result demonstration, the In Vitro Dissolution curve of preparation of the present invention is consistent with former triturate.
Below provide repeatability of the present invention preparation provided by the invention and criticize a repeatability comparison curves in order better to illustrate.Get three batches of formulation samples provided by the invention, press drug release determination method (two appendix X D of Chinese Pharmacopoeia version in 2010) and adopt dissolution method (two appendix X C of Chinese Pharmacopoeia version in 2010) the second subtraction unit, take water 900ml respectively as solvent, rotating speed is per minute 50 to turn, operation in accordance with the law, 2, 4, 6, 8, 12, 16, 20, 24 hours, getting respectively solution 5ml filters, and the instant solvent 5ml that supplements uniform temp in process container, precision measures subsequent filtrate 1ml, put in the 10ml measuring bottle, be diluted to scale with phosphate buffer, according to ultraviolet visible spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2010), measure trap at 263nm wavelength place, calculate release.Result is consulted Fig. 5, and curve a is first formulation samples, and curve b is the second batch formulation samples, and curve c is the 3rd batch of formulation samples.Experimental result shows, preparation of the present invention batch between repeatability good.
Claims (5)
1. the preparation method containing heavy dose of apellagrin sustained-release capsule, is characterized in that, comprises the steps: successively
1) supplementary material pre-treatment
Take nicotinic acid, microcrystalline Cellulose, lactose and cross 120 mesh sieves, Pulvis Talci is crossed 1250 mesh sieves, and celphere is crossed the 40-60 mesh sieve, standby;
2) preparation is containing nicotinic acid ball core
A) the premix powder is always mixed: nicotinic acid, microcrystalline Cellulose and lactose after step 1) is sieved mix and make the premix powder, standby;
B) lamination pill: the celphere after step 1) is sieved is placed in coating granulator, the premix powder that adds step a) to make in loading hopper, start coating granulator by following major parameter and carry out the lamination pill: air blast 30%～60%, engine speed 50～130rpm, spray into 5% hypromellose solution with spray pump speed 10～50rpm, with speed 10～60rpm, supply the premix powder; Grow to when granularity is 18～24 order and stop whitewashing and supply powder until pill, polishing, dry, and must contain nicotinic acid ball core;
3) prepare coated pill
A) preparation coating solution: take sodium lauryl sulphate and be dissolved in purified water, add especially strange NE 30D, stir;
B) take granularity 18～24 orders containing nicotinic acid ball core, put in coating granulator, start coating granulator by following major parameter and carry out coating in the centrifugal rotation mode: air blast 40%～80%, engine speed 40～150rpm, 35～90 ° of angle of gun, whiff pressure 0.08～0.15MPa, speed with 5～20g/min sprays into above-mentioned coating solution, spray Pulvis Talci to containing on nicotinic acid ball core with the speed of 0.6g～1.4g/min simultaneously, sprayed coating solution and stopped Pulvis Talci simultaneously, make coated pill;
4) heat treatment, total mixed
By after the coated pills heat treatment, sieve, mix;
5) encapsulated
According to nicotinic acid percentage composition in coated pill, load capsule;
Wherein: in nicotinic acid ball core prescription, the quality of celphere: the quality of nicotinic acid: the quality of microcrystalline Cellulose: the quality of lactose is 1.3～4.0:20～25:0.7～0.75:1.1～1.25;
In coated pill prescription, the quality of nicotinic acid ball core: the quality of strange NE 30D especially: the quality of sodium lauryl sulphate: talcous quality: the quality of purified water is 21～25:3.0～5.7:0.008～0.014:1.2～1.75:4～6.72.
2. the preparation method containing heavy dose of apellagrin sustained-release capsule according to claim 1, is characterized in that, the preparation method of described celphere is; microcrystalline Cellulose is put in coating granulator, started main frame, operated by following major parameter: air blast 30%～95%; engine speed 50～135rpm; spray pump rotating speed 10～60rpm, whiff pressure 0.05～0.15MPa, spray into 5% hypromellose solution; make celphere; polishing 2 minutes, take the dish out of the pot, and dries.
3. the preparation method containing heavy dose of apellagrin sustained-release capsule according to claim 1, is characterized in that, described heat treatment is to dry coated pills 24 hours at 40 ℃.
4. the preparation method containing heavy dose of apellagrin sustained-release capsule according to claim 1, is characterized in that, every of described capsule contains nicotinic acid 250mg.
5. the preparation method containing heavy dose of apellagrin sustained-release capsule according to claim 1, is characterized in that step 2) described bake out temperature is 60 ℃.
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Address after: Three road 528300 in Guangdong province Foshan city Shunde District of Ronggui high tech Park Keyuan cross No. 2 Patentee after: SINOPHARM GUANGDONG GLOBAL PHARMACEUTICAL CO., LTD. Address before: 528300 No. 2 West Bridge Road, Ronggui street, Shunde District, Guangdong, Foshan Patentee before: Huanqiu Pharmaceutical Co., Ltd., Guangdong |