CN102716090B - Sustained-release metformin hydrochloride pellets and preparation method thereof - Google Patents
Sustained-release metformin hydrochloride pellets and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparations and discloses sustained-release metformin hydrochloride pellets and a preparation method thereof. The sustained-release metformin hydrochloride pellet comprises a drug-containing pellet core and a sustained-release coating coated on the drug-containing pellet core. The drug-containing pellet core comprises 75 to 100 parts by weight of metformin hydrochloride and 0 to 25 parts by weight of one or more excipients, wherein the sum of the part numbers of metformin hydrochloride and the one or more excipients is 100 or the part numbers are increased or decreased based on a certain ratio, and also comprises one or more surfactants and one or more wetting agents, wherein the weight of the one or more surfactants is 0.1 to 8% of the total weight of metformin hydrochloride and the one or more excipients; and the weight of the one or more wetting agents is 0.1 to 30% of the total weight of metformin hydrochloride and the one or more excipients. Through the preparation method, the sustained-release metformin hydrochloride pellets having low friability, a high yield, small particle sizes and smooth surfaces are obtained and are convenient for further processing. In the invention, the drug-containing pellet cores are coated with the sustained-release coatings to form the sustained-release metformin hydrochloride pellets; and a bioavailability experiment is carried out and proves that the sustained-release metformin hydrochloride pellets has the characteristics of controllable quality and good stability in vitro, and has the characteristic of sustained release in vivo.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of diabecron sustained-release micropill and preparation method thereof.
Technical background
Micropill generally refers to the spherical or class spherical preparation of diameter between 0.5-1.5mm.Micropill is as multiple unit type drug-supplying system, compare as conventional tablet with traditional single dose drug-supplying system, micropill particularly slow-release micro-pill tool has the following advantages: after 1. entering in body, be distributed in rapidly whole gastrointestinal tract, because dosage is dispersed in single micropill, medicine and gastrointestinal contact area increase greatly, thereby have improved bioavailability and reduced some drugs to gastrointestinal zest; 2. micropill is 120-180min generally at 120-640min the gastric emptying time of conventional tablet, so the drug absorption of this system is subject to the impact of food and individual variation less, and absorption dynamics repeatability is better; 3. due to absorption dynamics, be the summation of many junior unit drug release behaviors, the defect of single micropill or breakage can not affect the release conditions of whole preparation, can reduce the prominent risk of releasing, and have higher safety; 4. the micropill of different drug release characteristics can be combined into multiple unit system to reach desirable rate of releasing drug, obtain expection blood concentration to reach curative effect (< < Modern Pharmaceutics > >, 1998; The Chinese Medicine science and technology Multiparticulate Drug Delivery Systems for Controlled Release[J of publishing house] .Tropical Journal of Pharmaceutical Research, 2008,7 (3); Multiparticulate formulation approach to colon specific drug delivery:current perspectives[J] .J Pharm Pharm Sci, 2006.9 (3)).
In recent decades, although the preparation method of micropill has a lot, as spherical container shaping method etc. in coating pan pill method, ebullated bed or fluid bed pill method, centrifugal pill method, melting pill method, vibration spraying pill method, liquid, but, extrude spheronization because its unique advantage has become main process technology (Chinese Journal of Pharmaceuticals prepared by micropill, 1998,29 (8), Multiparticulate Drug Delivery Systems for Controlled Release[J] .Tropical Journal of Pharmaceutical Research, 2008,7 (3); Multiparticulate formulation approach to colon specific drug delivery:current perspectives[J] .J Pharm Pharm Sci, 2006.9 (3)).
Though the preparation of micropill has many similar aspects to the wet granulation process of conventional tablet, as formula mainly contains active component, excipient, wetting agent forms, technique mainly contains mixing, soft material processed, " hold agglomerating, light press loose " soft material be easy to compacting in flakes, but, under same situation, due to extrusion difficulty, the reasons such as shaping of cannot rolling are that micropill is prepared unsuccessfully, so, being suitable for preparing micropill active component must possess to extrude round as a ball characteristic or add and possess in a large number the excipient of extruding round as a ball characteristic and could realize (Chinese Journal of Modern Applied Pharmacy, 2011, 1 (28)).
Diabetes have been considered to the third-largest harm humans health after tumor, cardiovascular and cerebrovascular disease in the whole world " killer ".At present, the patient of the diabetes that the whole world has been made a definite diagnosis is about 1.5 hundred million, it is predicted and will reach 3.0 hundred million in 2025.According to statistics, the sickness rate of diabetes is 3%-5% in the world, and within 50 years old, above sickness rate is for each person 10%.Interrelated data demonstration, there are more than 3,000 ten thousand diabeticss in China, increase every year 150～2,000,000 patients newly, and wherein 11 diabetes mellitus types accounts for more than 90%.Metformin hydrochloride is global best-selling type ii diabetes medicine.The two flesh of hydrochloric acid diformazan is a kind of pair of flesh class antidiabetic medicine, the two flesh hydrochlorates of chemistry 1,1 one dimethyl by name; Molecular formula C
4h
11n
5-HCl; Molecular weight: 165.63; For white crystals or crystalline powder, odorless; Easily molten in water, in methanol, dissolve, slightly soluble in ethanol, insoluble in ether or chloroform; Mp 220-225 ℃; UV233nm; Chemical structural formula is as follows:
There are ordinary tablet/capsule and slow releasing tablet/slow releasing capsule in the oral commercial preparation of metformin hydrochloride at present.Patent CN1589782 has described a kind of diabecron sustained-release granule, with ethyl cellulose, metformin hydrochloride is carried out to slow release layer coating.Patent CN 1568950 has described a kind of diabecron sustained-release capsule, celphere is made to medicine carrying granule with the medicine-feeding of metformin hydrochloride solution, then prepare slow-releasing granules with sustained release coating material.
According to reported in literature, in micropill preparation technology, extrude strip under action of gravity or to be cleaved into diameter be that hole diameter of sieve (perforated) plate 2-3 is doubly during irregular brachyplast (disrumpent feelings ratio) through cutting off, easily be rolled onto ganoid micropill (Chinese Journal of New Drugs, 2001.10 (9)).
Surfactant is a kind of like this material, with " class micelle ", " necklace " or " chain pearl " form, be adsorbed on table (boundary) face of hybrid solid material or mixed material, significantly change attribute (< < surfactant application principle (professional book) the > > of material, Chemical Industry Press, 2003).In pharmaceutics, surfactant mainly as solubilizing agent, emulsifying agent, wetting agent, dispersant, flocculating agent, foaming agent and defoamer, antibacterial and antibacterial, detergent and its have the active component of promotion and absorb, antistatic property, carrier function, (< < pharmaceutics > > slaughters stannum moral to targetings etc., People's Health Publisher 2000.3), the application > > of < < surfactant in pharmacy, People's Health Publisher, 1996.2).Particularly, if the characteristic dissolubility of Orally active composition is less than 1mg/100ml, often in reagent combination, add surfactant, be beneficial to dissolving and absorption (< < pharmaceutics > Cui > Ford of active component, People's Health Publisher, sixth version).In disclosed patent documentation (CN182304A, CN 101574326A, CN 101513403A, CN 101185653A), the object of adding surfactant in its formula is also the bioavailability for solubilising and raising active component.
Coating material is all generally wiring solution-forming or makes liquid dispersion and use.The prescription of coating solution or dispersion liquid generally should contain following basic composition: coating filmogen, plasticizer and solvent (or disperse medium), need add porogen sometimes.Sustained release coating mostly is macromolecule insoluble polymer, and its solvent or disperse medium can be divided into organic solvent and water two classes.Organic solvent exists obvious shortcoming, for example dangerous, has the danger of blast; Air pollution, has potential toxicity; Reclaim difficulty and reclaimer costliness etc.The great advantage of aqueous dispersion is (China Medicine University's journal, 2002,33 (suppl): 290-293) such as solids content is high, viscosity is low, easy to operate, film forming fast, the coating time is short.
The extended release coatings of extensive use is at present mainly ethyl cellulose, acrylic resin, cellulose acetate etc., and these clothing materials all have corresponding aqueous dispersion listing.Wherein, Aquacoat has Aquacoat and Surelease (Sulisi), and aqueous acrylic resin dispersion has Eudragit (especially strange) RS30D, Eudragit (especially strange) RL30D, Eudragit (especially strange) NE30D, Eudragit (especially strange) L30D (< < medicament microcapsule new technique and application > > Chen Qing China People's Health Publisher).
When some permeability slow release or release controlling coating material are made the film of closure, often medicine cannot dissolve, infiltrate from micropill, be everlasting and add in the coating solution of these materials some porogen to increase the permeability of coating membrane, to obtain the coated preparation of required rate of releasing drug.Porogen mostly is some water miscible materials as PVOH class, polyvidone, sucrose, salt and other water soluble film-forming materials are as hypromellose, hyprolose, or even insoluble solid composition is as Pulvis Talci, magnesium stearate, silicon dioxide, (the oral sustained-release preparation > of the < < > Tang Xing People's Health Publisher such as titanium dioxide, < < Modern Pharmaceutics > > Ping Qineng People's Health Publisher).
Conventionally adopt water-soluble material as sealing coat clothing can effectively reduce micropill friability, avoid active component and coating material generation chemical reaction and in coating process, drug migration occur.Wherein, hypromellose because of neutral, incompatibility is few, do not affect drug release behavior, ball core weightening finish 2-3% can form a densification, continuous, complete attributes such as clothing film, becomes the most frequently used sealing coat clothing material (the oral sustained-release preparation > of < < > Tang Xing People's Health Publisher).
Still surfactant is not added at present in micropill formula, improve micropill processing trait and further coating prepare the report of diabecron sustained-release micropill.
Summary of the invention:
The slow-release micro-pill that the object of this invention is to provide a kind of hydrochloric metformin.
Another object of the present invention is to provide the preparation method of the slow-release micro-pill of above-mentioned hydrochloric metformin.
The object of the invention is to realize by following technical proposal:
A diabecron sustained-release micropill, this micropill is by making containing the coated extended release coatings of pill core, wherein:
Formula containing pill core contains following raw material:
Metformin hydrochloride 75-100 weight portion, excipient 0-25 weight portion, sum of the two is 100 weight portions, or the umber of the two zooms in or out on year-on-year basis, surfactant is the 0.1-8% of metformin hydrochloride and excipient weight sum, is preferably 2-6%; Wetting agent is the 0.1-30% of metformin hydrochloride and excipient weight sum.
Described slow-release micro-pill is wherein 0.4～0.8mm containing pill core particle size distribution.
Described slow-release micro-pill is wherein 1.2: 1 to 1: 1 containing pill core draw ratio.
Described slow-release micro-pill is wherein any one or the multiple inactive solid matter allowing on pharmaceutics containing the excipient in pill core.
Described slow-release micro-pill, is wherein selected from one or more in following material containing the surfactant in pill core: Polyethylene Glycol, castor oil derivatives, poloxamer, Polysorbate, span, polyoxyethylene fatty acid ester, dioctyl sodium sulphosuccinate, sodium lauryl sulphate, mono fatty acid glyceride, mono fatty acid diglyceride, phospholipid.
Described slow-release micro-pill, is wherein selected from one or more in following material containing the wetting agent in pill core: water, ethanol, ethyl acetate, dichloromethane, chloroform, PEG400, poly-propanol, glycerol.
Described slow-release micro-pill, wherein the extended release coatings formula containing pill core is comprised of insoluble polymer, plasticizer, disperse medium, wherein, insoluble polymer is selected from one or more in following material: ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, acrylic resin; Plasticizer is selected from one or more in following material: glycerol, propylene glycol, Polyethylene Glycol, triacetyl glycerine, citron acid esters, phthalic acid ester, dibutyl sebacate; Disperse medium is selected from one or more in water, organic solvent.
Described slow-release micro-pill, wherein can also comprise antiplastering aid and/or the porogen of any amount in extended release coatings formula, wherein, described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, silicon dioxide, titanium dioxide; Described porogen is selected from one or more in following material: soluble small molecular material is as sucrose, salt, and water-soluble high-molecular material is as Polyethylene Glycol, polyvidone, hypromellose, hyprolose.
Described slow-release micro-pill, wherein in extended release coatings formula, insoluble polymer consumption is the 5%-50% containing pill core weight, preferably 10%-35%, more preferably 15%-30%; Plasticizer is 0～40% of insoluble polymer consumption, and antiplastering aid is 0～50% of insoluble polymer consumption, and porogen is 0～40% of insoluble polymer consumption, and all the other are disperse medium.
Described slow-release micro-pill, should be containing having added the sealing coat material of buffer action between pill core and coated extended release coatings, wherein, described sealing coat material is selected from one or more in following material: water-soluble high-molecular material is as hyprolose, hypromellose, polyvidone, Polyethylene Glycol, preferably hypromellose; Wherein, the consumption of sealing coat material is the 2-3% containing pill core weight.
The preparation method of described slow-release micro-pill, the method adopts extrudes spheronization preparation containing pill core, or further will apply sealing coat material containing pill core, then by the solution of extended release coatings or dispersion to applied or uncoated sealing coat material containing pill core, carry out spray coating.
Described preparation method, wherein adopting extruder sieve diameter while extruding spheronization preparation containing pill core is 0.1～1.5mm, preferably 0.6mm.
In the present invention, surfactant so long as have the material of surface activity ability, does not have special restriction, preferred high HLB surfactant, and for example HLB value is 8-20, preferably HLB12-16.
In addition, surfactant of the present invention can be for having the surfactant of hydrocarbon chain, hydrocarbon chain can be straight chain, side chain, ring-type, there is no special restriction, adducible nonionic surfactant, the ionic surfactant with hydrocarbon chain for example, natural or synthetic surfactant all can.
In addition, surfactant of the present invention is preferably the carbon number of hydrocarbon chain more than 4, more preferably more than 6, more preferably at more than 8 surfactants, and particularly preferably the carbon number of hydrocarbon chain is more than 10, the surfactant below 20.The example of concrete surfactant is as Polyethylene Glycol, castor oil derivatives, poloxamer, Polysorbate, span, polyoxyethylene fatty acid ester, dioctyl sodium sulphosuccinate or sodium lauryl sulphate, mono fatty acid glyceride, mono fatty acid diglyceride, phospholipid and their mixture, but is not limited to above-mentioned substance.
In the present invention, wetting agent is so long as the liquid under normal temperature condition, there is no special restriction, can be selected from water, ethyl acetate, dichloroethanes, polyalcohols or other solvents pharmaceutically allowing and their mixture, preferred water, more preferably ethanol, more preferably alcohol-water mixture.
In the present invention, the surfactant forming containing pill core can mix with other solid matters, also can add in wetting agent, particularly when surfactant is in a liquid state at ambient temperature, preferred mode is that surfactant is added in wetting agent after mix homogeneously, then mixes with his solid matter.
In the present invention, excipient be on pharmaceutics, allow any one or multiplely there is the excipient of extruding round as a ball characteristic, normally inactive solid matter, one or more in preferred following excipient:
Cellulose and cellulose derivative, such as microcrystalline Cellulose, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, ethylhydroxyethylcellulose, carboxymethyl cellulose, cellulose acetate-butyrate, Cellacefate ester etc.
Monosaccharide and disaccharide or polysaccharide, monosaccharide is glucose, galactose, fructose, amino sugar for example, disaccharidase such as lactose, sucrose etc., polysaccharide such as starch, pregelatinized Starch, alginate, xanthan gum, chondrus ocellatus Holmes polysaccharide, glucosan, hyaluronic acid, chitin, Chitosan etc.Other natural polymer, such as albumin, gelatin, arabic gum etc.
Synthetic polymer, for example esters of acrylic acid is as polymethacrylates, polymethylacrylic acid hydroxy methacrylate, polymethyl methacrylate, polymethylacrylic acid hydroxy methacrylate-common methyl methacrylate, carbomer; Polyamide class is as polypropylene phthalein amine, polymethylene diacrylate amine; Polyethers is poly-dihydroxy benzenes oxygen methylmethane, polyvinyl pyrrolidone, and polyvinyl acetate, polyvinyl alcohol, ethylene oxide and copolymer thereof are as Polyethylene Glycol, and polyesters is polylactic acid, polyglycolic acid, polycaprolactone etc.
Inorganic salts, such as calcium carbonate, silicon dioxide, aluminosilicate magnesium sodium, kieselguhr, kaolin, Pulvis Talci etc.
Other material, wax class such as Brazil wax, Cera Flava, glucose wax, castor wax, paraffin etc.; Such as glycerol palmityl stearate, glyceryl monostearate, glycerol tristearate, stearyl alcohol etc. of stearic acid esters; Lipid such as glyceride, phospholipid etc.
In the present invention, the Morphologic Parameters that contains pill core is to adopt image analysis technology to measure.Image analysis technology is by shooting, to contain the two-dimensional silhouette image of pill core, use computer to distinguish the color of each pixel or gray scale, thereby identification contains the two-dimensional silhouette of pill core and two-dimensional silhouette image is calculated, draw the Morphologic Parameters containing pill core.
In the present invention, containing the Morphologic Parameters of pill core medicament, be to utilize mensuration that the BT1600 image of Baite Instrument Co., Ltd., Dandong carries out containing pill core analytical system, the Morphologic Parameters gathering comprises that, containing pill core draw ratio and two kinds of parameters of the comprehensive morphological factor, wherein preferably major diameter is recently described the geometric properties that contains pill core in the present invention.
In the present invention, the major diameter that contains pill core is 1.5: 1 to 1: 1, and they preferably 1.2: 1 to 1: 1.
In the present invention, containing pill core particle size distribution, be 0.1mm to 2.5mm, preferred 0.5mm to 0.8mm.
Of the present invention containing pill core by mixed processes, extrude operation, round as a ball operation, dry and sorting obtains.
Beneficial effect of the present invention:
The present invention adds surfactant in ball core formula, adopts to extrude spheronization and prepare ball core, can access that friability is low, yield is higher, particle diameter is less, any surface finish containing pill core, such ball core is convenient to further processing.The present invention applies extended release coatings to this containing pill core and makes diabecron sustained-release micropill, and has carried out bioavailability experiment, proves that preparation of the present invention has quality controllable, stable feature in vitro, has the feature of slow release in vivo.
Accompanying drawing explanation
Fig. 1 is the dependency of surfactant weight ratio and the disrumpent feelings ratio of strip in formula.
Fig. 2-1,2-2,2-3 are the ball core microphotograpies of embodiment 3.
Fig. 3-1,3-2,3-3 are the ball core microphotograpies of embodiment 4.
Fig. 4-1,4-2,4-3 are the ball core microphotograpies of embodiment 5.
Fig. 5-1,5-2,5-3 are the ball core microphotograpies of embodiment 6.
Fig. 6-1,6-2,6-3 are the ball core microphotograpies of embodiment 7.
Fig. 7-1,7-2,7-3 are the ball core microphotograpies of embodiment 8.
Fig. 8 is diabecron sustained-release micropill release curve in embodiment 3-8.
Fig. 9 is that beasle dog single oral diabecron sustained-release micropill and Tang fall
mean plasma concentration-time graph.
The specific embodiment
The invention will be further elaborated by the following examples.
Embodiment explanation
Capital equipment: wet mixing pelletizer (HLSH2-6, Beijing Aeronautics Research Inst), extruder (E-35A, Chongqing Ying Ge pharmaceutical machine company limited), spheronizator (R-250, Chongqing Ying Ge pharmaceutical machine company limited); Fluid bed (DPL-IIA, Chongqing Seiko pharmaceutical machine company limited), electric drying oven with forced convection (DHG-9140A, Shanghai Yiheng Scientific Instruments Co., Ltd), image particulate analysis system (BT1600, Baite Instrument Co., Ltd., Dandong), slide gauge (Shanghai constant measurer company limited), sub-sieve (commercially available stainless steel sift).
Formula containing pill core contains following raw material:
Metformin hydrochloride 75-100 weight portion, excipient 0-25 weight portion, sum of the two is 100 weight portions, or the umber of the two zooms in or out on year-on-year basis, surfactant is the 0.1-8% of metformin hydrochloride and excipient weight sum; Wetting agent is the 0.1-30% of metformin hydrochloride and excipient weight sum;
Ball core preparation and device parameter thereof: by formula, take metformin hydrochloride, excipient, surfactant, wetting agent and put in wet mixing pelletizer, stir, be mixed uniform mixed material; Shift this mixed material to extruder, be pressed into strip; Shift this strip to spheronizator, this strip of rolling becomes containing pill core; Shift and should, containing pill core to electric drying oven with forced convection, be solidified into the dry pill core that contains; Sub-sieve sorts the pill core that contains of aimed dia, obtains.The preparation of ball core and device parameter thereof see the following form shown in 1.As applying isolated substance, need further these are applied to isolated substance (wrapping contagion gown) containing pill core.
Table 1: main equipment parameters
Ball core coating (extended release coatings or contagion gown) and device parameter thereof: get this applied or uncoated isolated substance put in right amount in fluid bed containing pill core, open blower fan, heat and make ball core be fluidisation state, when ball core reaches after the temperature of charge of setting, open solution feed pump, when spraying into coating solution and making ball core reach formula weightening finish to require, close feed flow, after dry to coated pill core, close heating, blower fan, obtain.Coating processing apparatus parameter sees the following form shown in 2.
Table 2: coating (extended release coatings or contagion gown) processing apparatus parameter
| Blower fan frequency (HZ) | 20→30 |
| Inlet temperature (℃) | 40→55 |
| Temperature of charge (℃) | 30→45 |
| Atomizing pressure (MPa) | 0.1→0.2 |
| Solution feed pump rotating speed (rpm) | 4→10 |
Containing pill core evaluation index: the draw ratio of choosing (E), the comprehensive morphological factor (eR), containing pill core yield (Yd), friability (Fl) and surface smoothness as containing pill core quality evaluation index.
Wherein: E=is containing pill core major diameter/minor axis (international journal of pharmaceutics146 (1997) 21-29);
ER=surface roughness-[1-(two-dimensional projection's eccentricity/projected length)
2]
-2; (pharmacy and clinical research, 2009,17 (5), A.M.Bouwan et al Power Technology146 (2004))
Fl=is placed in spray apparatus at the bottom of fluid bed containing pill core, and under art for coating condition, fluidisation is 15 minutes, and sieve removes fine powder, calculates the ratio (Chinese Journal of Pharmaceuticals, 1999,30 (8)) containing the pill core loss in weight and original weight.
Yd=target is containing pill core weight/formula material gross weight (< < novel pharmaceutical formulation and new technique > > second edition Lu Bin), wherein, target adopts sieve formula sorting containing pill core, sees the following form shown in 3 in concrete particle size distribution interval.
Table 3: particle size distribution is interval
| Hole diameter of sieve (perforated) plate (mm) | 0.8 | 0.6 | 0.4 |
| Containing pill core value diameter (order) | 20-24 | 24-30 | 30-40 |
Surface smoothness: BT1600 image particulate analysis systematic observation is containing pill wicking surface form.
Embodiment 1: the principal element that impact is shaped containing pill core
In the present embodiment, the in the situation that of selected medicine, set active component dissolubility (vitamin C (0.2g/ml, Yi Rong), sarpogrelate hydrochloride (0.02g/ml, slightly molten)), the wetting time (min) of excipient (microcrystalline Cellulose), wetting agent (20% ethanol), surfactant (polyoxyethylene sorbitan monoleate), soft material, extrude frequency (HZ), hole diameter of sieve (perforated) plate (mm), round as a ball time (min), baking temperature (℃) etc. 9 variablees, the P-B experimental design (N=12) of 2 pseudo-variables (Dummy), investigates the principal element that impact is shaped containing pill core.Wherein, the amount of active component is that active component accounts for the weight ratio of (active component and excipient sum), the amount of excipient is that excipient accounts for the weight ratio of (active component and excipient sum), the amount of wetting agent is the weight ratio of wetting agent and (active component and excipient sum), and the amount of surfactant is the percentage by weight of surfactant and (active component and excipient sum); Active component and excipient sum are 1.Each variable, level and the experimental result thereof of P-B experimental design see the following form shown in 4.
Each variable, level and the experimental result thereof of table 4:P-B experimental design
Conclusion:
1. draw ratio (E) is as follows with the single order regression equation (Final equation terms of coded factors) of each variable:
E=+1.17-2.500*10
-003* A-0.032*B+2.500*10
-003* C+2.500*10
-003* D-5.833*10
-003* M-0.012*F-9.167*10
-003* G-0.046*H-3.433*10
-003* J, experimental result shows, the major variable that affects draw ratio is surfactant, hole diameter of sieve (perforated) plate and round as a ball time.Wherein, surfactant is greater than hole diameter of sieve (perforated) plate and the impact of round as a ball time on draw ratio to the impact of draw ratio, and draw ratio reduces along with surfactant, hole diameter of sieve (perforated) plate increase and round as a ball time lengthening, containing pill core, trends towards spherical.
2. the comprehensive morphological factor (eR) is as follows with the single order regression equation (Final equation terms of coded factors) of each variable:
ER=+0.94-2.500*10
-003* A+0.018*B-8.333*10
-004* C-8.333*10
-004* D+8.333*10
-004* M+2.500*10
-003* F-2.500*10
-003* G+0.019*H+0.011*J, experimental result shows, the major variable that affects the comprehensive morphological factor is surfactant, hole diameter of sieve (perforated) plate and excipient successively, the comprehensive morphological factor, along with surfactant, excipient and hole diameter of sieve (perforated) plate increase and increase, trends towards spherical and smooth surface containing pill core.
3. yield (Yd) is as follows with the single order regression equation (Final equation terms of coded factors) of each variable:
Yd=+0.79+2.500*10
-003* A+0.013*B-8.333*10
-004* C+4.167*10
-003* D-0.014*M-0.027*F+2.500*10
-003* G+0.021*H+8.333*10
-004* J, experimental result shows, the major variable that affects yield is the round as a ball time, extrude frequency and surfactant and hole diameter of sieve (perforated) plate.Wherein, yield and round as a ball time, extrude frequency and be contravariant, be just and become with surfactant, hole diameter of sieve (perforated) plate, extrude higher, the round as a ball time of frequency longer, lower containing the yield of pill core, and amount of surfactant, hole diameter of sieve (perforated) plate are larger, higher containing the yield of pill core.
4. friability (F1) is as follows with the single order regression equation (Final equation terms of coded factors) of each variable:
F1=+0.013-2.500*10
-004* A+1.750*10
-003* B-4.167*10
-004* C-4.167*10
-004* D+2.500*10
-0 04* M+8.333*10
-005* F-3.083*10
-003* G+8.333*10
-003* H-2.583*10
-003* J, experimental result shows, the major variable that affects friability is wetting agent, excipient and surfactant and hole diameter of sieve (perforated) plate, wherein, friability and wetting agent, excipient are contravariant, are just and become with surfactant, hole diameter of sieve (perforated) plate, and wetting agent, figuration dosage are larger, less containing the friability of pill core, and amount of surfactant is larger, hole diameter of sieve (perforated) plate is larger, higher containing the friability of pill core.
5. in summary, under selected formula condition, surfactant has important impact to draw ratio, the comprehensive morphological factor, yield and the friability containing pill core, wherein, with the increase of amount of surfactant, the spherical property of yield, the surface smoothness that contain pill core increase and friability attenuating; The dissolubility of active component and baking temperature have no obvious impact to the formability containing pill core.
Embodiment 2: surfactant is on the impact containing important procedure in pill core processing
In the present embodiment, respectively with vitamin C (Yi Rong), taurine (dissolving), hydrochloric acid bromine ammonia rope (slightly molten) be active component respectively with microcrystalline Cellulose (excipient), 20% ethanol (wetting agent) forms basic components, in every kind of basic components, adding respectively with (active substance+excipient) percentage by weight is 0, 1, 2, 3, 4, 6, 7% surfactant (polyoxyethylene sorbitan monoleate) forms series formula, and (formula 1 active component is vitamin C, 2 active component of filling a prescription are taurine, 3 active component of filling a prescription are hydrochloric acid bromine ammonia rope), according to " preparation method " and " working procedure parameter " in " embodiment explanation ", prepare strip, observe and calculate the shape of strip and the yield in the unit interval, and this strip is dropped to naturally in the square plate of 1 meter, after jog, transfer them in electric drying oven with forced convection dry, with slide gauge, measure the average disrumpent feelings ratio of the dry strip of equivalent, investigation table surface-active agent is on the impact containing important procedure in pill core processing, experimental establishment and experimental result see the following form, wherein, disrumpent feelings ratio is that 2-3 interval is doubly shown in Table 5.
Table 5: experimental establishment and experimental result
Note: the amount of active component is that active component accounts for the weight ratio of (active component and excipient sum);
The amount of excipient is that excipient accounts for the weight ratio of (active component and excipient sum);
The amount of wetting agent is the weight ratio of wetting agent and (active component and excipient sum);
The amount of surfactant is the percentage by weight of surfactant and (active component and excipient sum);
Active component and excipient sum are 1.
Conclusion:
1. there is positive correlation in the character of surfactant and strip, and amount of surfactant increases, strip any surface finish and shinny.
2. there is positive correlation in amount of surfactant and strip output, and, along with amount of surfactant increases, material is extruded more smooth, and in the unit interval, the strip of preparation is also more.
3. the disrumpent feelings ratio of amount of surfactant and strip is relevant and have three catastrophe points (seeing Fig. 1): along with amount of surfactant increases, first catastrophe point (A point) appears in disrumpent feelings ratio, disrumpent feelings larger and variation very little (OA section); Amount of surfactant continue to increase, disrumpent feelings than there is second catastrophe point (B point), now, and disrumpent feelings ratio decline rapidly (AB section); Along with the continuation increase of amount of surfactant, disrumpent feelings than occurring the 3rd catastrophe point (C point), disrumpent feelings than changing steady (BC section); Continuing increases dosage of surfactant, and disrumpent feelings ratio starts again rapid decline (> C section).
In certain interval (BC section), although amount of surfactant changes greatly, but the variation of disrumpent feelings ratio relatively little and disrumpent feelings ratio is stabilized between 2-3,1), working procedure parameter stable and produce continuously and efficient this stable disrumpent feelings ratio is conducive to:, 2), the physical dimension of strip is relatively stable, 3), the mixed material processing characteristics of last operation is relatively stable, 4), guarantee after an operation rolling and obtain higher micropill yield.
Embodiment 3
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
10% Sulisi
80 parts of aqueous dispersions
Note: 10% Sulisi
aqueous dispersion is Aquacoat.
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 6, and micropill character is shown in Fig. 2-1,2-2,2-3.
Table 6: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.1 | 1.07 | 1.12 |
| The comprehensive morphological factor (eR) | 0.96 | 0.98 | 0.94 |
| Friability (Fl) | 0.008 | 0.01 | 0.005 |
| Yield (Yd) | 0.86 | 0.82 | 0.86 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 4
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
10% Sulisi
100 parts of aqueous dispersions
4 parts of hypromelloses
Note: 10% Sulisi
aqueous dispersion is Aquacoat.
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 7, and micropill character is shown in Fig. 3-1,3-2,3-3.
Table 7: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.08 | 1.07 | 1.1 |
| The comprehensive morphological factor (eR) | 0.97 | 0.96 | 0.95 |
| Friability (Fl) | 0.009 | 0.01 | 0.007 |
| Yield (Yd) | 0.81 | 0.83 | 0.86 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 5
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
10% is especially strange
80 parts of aqueous dispersions
Note: especially strange
aqueous dispersion is EUDRAGIT NE 30 D EUDRAGIT NE 30D (2: 1) aqueous dispersion.
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 8, and micropill character is shown in Fig. 4-1,4-2,4-3.
Table 8: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.04 | 1.08 | 1.08 |
| The comprehensive morphological factor (eR) | 0.98 | 0.97 | 0.96 |
| Friability (Fl) | 0.011 | 0.009 | 0.007 |
| Yield (Yd) | 0.81 | 0.84 | 0.85 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 6
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
10% is especially strange
100 parts of aqueous dispersions
4 parts of hypromelloses
Note: especially strange
aqueous dispersion is EUDRAGIT NE 30 D EUDRAGIT NE 30D (2: 1) aqueous dispersion.
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 9, and micropill character is shown in Fig. 5-1,5-2,5-3.
Table 9: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.07 | 1.1 | 1.08 |
| The comprehensive morphological factor (eR) | 0.97 | 0.95 | 0.98 |
| Friability (Fl) | 0.009 | 0.006 | 0.009 |
| Yield (Yd) | 0.82 | 0.84 | 0.84 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 7
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
8 parts of ethyl celluloses
95% 92 parts of ethanol
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 10, and micropill character is shown in Fig. 6-1,6-2,6-3.
Table 10: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.11 | 1.09 | 1.08 |
| The comprehensive morphological factor (eR) | 0.95 | 0.96 | 0.96 |
| Friability (Fl) | 0.005 | 0.007 | 0.006 |
| Yield (Yd) | 0.86 | 0.03 | 0.82 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 8
Contagion gown formula (by containing pill core 100 weight portions):
3 parts of hypromelloses
0.3 part of Macrogol 4000
50 parts, water
Extended release coatings formula (containing bag contagion gown containing pill core 100 weight portion meters):
10 parts of ethyl celluloses
95% 90 parts of ethanol
4 parts of hypromelloses
Preparation technology: prepare three batches of micropills according to " embodiment explanation " and above-mentioned formula, quality evaluation result sees the following form shown in 11, and micropill character is shown in Fig. 7-1,7-2,7-3.
Table 11: ball core quality evaluation
| Evaluation index/batch | The 1st batch | The 2nd batch | The 3rd batch |
| Draw ratio (E) | 1.08 | 1.09 | 1.05 |
| The comprehensive morphological factor (eR) | 0.96 | 0.97 | 0.97 |
| Friability (Fl) | 0.007 | 0.009 | 0.011 |
| Yield (Yd) | 0.83 | 0.85 | 0.82 |
| Surface smoothness | Any surface finish | Any surface finish | Any surface finish |
Embodiment 9
According to Chinese Pharmacopoeia (version was two in 2010) appendix XD " drug release determination method ", XC, " " first method carries out diabecron sustained-release micropill release to " embodiment 3-8 " and detects dissolution method, its release result is as following table 12, and its release curve as shown in Figure 8.
Table 12: diabecron sustained-release micropill release (%)
Embodiment 10
According to " embodiment 6 " formula and method, prepare diabecron sustained-release micropill (, according to < < pharmacological experimental methodology > >--" bioavailability and equivalence evaluation " (Xu Shuyun, People's Health Publisher, the third edition) carry out pharmacokinetic studies in beasle dog single oral dose body.
Article 8, healthy beasle dog (12kg/ only, male and female half and half) random packet, the design of binary cycle cross-over experiment, the clean phase is 1 week.Fasting 12h takes medicine, the free diet of 4h after taking medicine.Before experiment, first beasle dog is performed the operation, at primary minimum shadow vein place thereafter, settle one to be detained pin, then will for test preparation and commercial preparation, (Tang falls
specification: 250mg) fill in epiglottis portion, make beasle dog independently swallow and inject 20mL clear water and send down, after administration 0,0.5,1,2,3,4,5,6,8,10,12,14,24,36 get forelimb venous blood 2～3mL puts in heparinization test tube, centrifugal 5min (5000rpm), separated plasma.Get plasma sample 0.3mL, add acetonitrile solution 0.12mL, vortex mixing 1min, is placed in the centrifugal 5min of high speed centrifuge (10000rpm).Get supernatant direct injected, sample size 20 μ L, record peak area, by external standard method, obtain blood drug level.As shown in Figure 9, presentation of results, for test preparation and commercial preparation bioequivalence for the metformin hydrochloride blood drug level-time graph of two groups of preparations.
Claims (16)
1. a diabecron sustained-release micropill, is characterized in that this micropill is by making containing the coated extended release coatings of pill core, wherein:
Formula containing pill core contains following raw material:
Metformin hydrochloride 75-100 weight portion, excipient 0-25 weight portion, sum of the two is 100 weight portions, or the umber of the two zooms in or out on year-on-year basis, surfactant is the 2-6% of metformin hydrochloride and excipient weight sum; Wetting agent is the 0.1-30% of metformin hydrochloride and excipient weight sum;
Wherein: surfactant is polyoxyethylene castor oil, poloxamer, Polysorbate, span or sodium lauryl sulphate; Wetting agent is water or ethanol.
2. slow-release micro-pill according to claim 1, is characterized in that it contains pill core particle size distribution is 0.4～0.8mm.
3. slow-release micro-pill according to claim 1, is characterized in that it contains pill core draw ratio is 1.2:1 to 1:1.
4. slow-release micro-pill according to claim 1, is characterized in that containing the excipient in pill core be any one or the multiple inactive solid matter allowing on pharmaceutics.
5. slow-release micro-pill according to claim 1, it is characterized in that being formed by insoluble polymer, plasticizer, disperse medium containing the extended release coatings formula of pill core, wherein, insoluble polymer is selected from one or more in following material: ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, acrylic resin; Plasticizer is selected from one or more in following material: glycerol, propylene glycol, Polyethylene Glycol, triacetyl glycerine, citron acid esters, phthalic acid ester, dibutyl sebacate; Disperse medium is selected from one or more in water, organic solvent.
6. slow-release micro-pill according to claim 1, is characterized in that can also comprising in extended release coatings formula antiplastering aid and/or the porogen of any amount, and wherein, described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, silicon dioxide, titanium dioxide; Described porogen is selected from one or more in following material: soluble small molecular material, water-soluble high-molecular material.
7. slow-release micro-pill according to claim 6, is characterized in that soluble small molecular material is sucrose, salt, and water-soluble high-molecular material is Polyethylene Glycol, polyvidone, hypromellose, hyprolose.
8. slow-release micro-pill according to claim 1, is characterized in that in its extended release coatings formula, insoluble polymer consumption is the 5%-50% containing pill core weight; Plasticizer is 0～40% of insoluble polymer consumption, and antiplastering aid is 0～50% of insoluble polymer consumption, and porogen is 0～40% of insoluble polymer consumption, and all the other are disperse medium.
9. slow-release micro-pill according to claim 8, is characterized in that in its extended release coatings formula, insoluble polymer consumption is the 10%-35% containing pill core weight.
10. slow-release micro-pill according to claim 9, is characterized in that in its extended release coatings formula, insoluble polymer consumption is the 15%-30% containing pill core weight.
11. slow-release micro-pill according to claim 1, it is characterized in that this contains the sealing coat material that can also add buffer action between pill core and coated extended release coatings, described sealing coat material is selected from water-soluble high-molecular material, and the consumption of sealing coat material is the 2-3% containing pill core weight.
12. slow-release micro-pill according to claim 11, is characterized in that water-soluble high-molecular material is hyprolose, hypromellose, polyvidone, Polyethylene Glycol.
13. slow-release micro-pill according to claim 12, is characterized in that water-soluble high-molecular material is hypromellose.
14. according to the preparation method of the slow-release micro-pill described in claim 1 or 11, it is characterized in that adopting and extrude spheronization preparation containing pill core, or further will apply sealing coat material containing pill core, then by the solution of extended release coatings or dispersion to applied or uncoated sealing coat material containing pill core, carry out spray coating.
15. preparation methoies according to claim 14, it is characterized in that adopting extruder sieve diameter while extruding spheronization preparation containing pill core is 0.1～1.5mm.
16. preparation methoies according to claim 15, is characterized in that sieve diameter is 0.6mm.
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| CN103040761B (en) * | 2012-12-24 | 2015-04-29 | 广州医药研究总院 | Novel metformin hydrochloride sustained release pellets and preparation method thereof |
| CN103417496A (en) * | 2013-08-26 | 2013-12-04 | 中国人民解放军第150中心医院 | Method for preparing metformin hydrochloride controlled-release pellet preparation |
| CN104434846A (en) * | 2014-11-17 | 2015-03-25 | 中国药科大学 | Metformin hydrochloride enteric-coated sustained-release pellet and preparation method thereof |
| CN110801443A (en) * | 2019-12-03 | 2020-02-18 | 仁和堂药业有限公司 | Metformin hydrochloride sustained-release preparation and quality detection method thereof |
| CN111110648A (en) * | 2020-01-13 | 2020-05-08 | 新发药业有限公司 | Metformin hydrochloride controlled release tablet |
| CN112972411B (en) * | 2021-04-09 | 2022-05-31 | 迪沙药业集团有限公司 | Metformin hydrochloride sustained-release tablet composition |
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