CN107970222A - A kind of oral compound preparation of melbine enteric coatel tablets of vitamin B layer cladding and preparation method thereof - Google Patents
A kind of oral compound preparation of melbine enteric coatel tablets of vitamin B layer cladding and preparation method thereof Download PDFInfo
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- CN107970222A CN107970222A CN201610922082.4A CN201610922082A CN107970222A CN 107970222 A CN107970222 A CN 107970222A CN 201610922082 A CN201610922082 A CN 201610922082A CN 107970222 A CN107970222 A CN 107970222A
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- vitamin
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- melbine
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- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- FEZWOUWWJOYMLT-DSRCUDDDSA-M cobalt;[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,1 Chemical compound [Co].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FEZWOUWWJOYMLT-DSRCUDDDSA-M 0.000 description 1
- 235000006279 cobamamide Nutrition 0.000 description 1
- 239000011789 cobamamide Substances 0.000 description 1
- 229960005452 cobamamide Drugs 0.000 description 1
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002974 pharmacogenomic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 208000009189 tinea favosa Diseases 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of preparation method of the oral compound preparation discharged step by step the present invention relates to different Digestive sites in vivo, and in particular to oral compound preparation of melbine enteric coatel tablets of vitamin B layer cladding and preparation method thereof.
Description
Technical field
The invention belongs to technical field of medicine, is related to the oral administered compound that different Digestive sites in vivo discharge step by step
The preparation method of preparation, and in particular to a kind of oral compound preparation and its system of the melbine enteric coatel tablets of vitamin B layer cladding
Preparation Method.
Background technology
Diabetes are a kind of more and more common diseases of morbidity of the whole world in recent years.Treating this sick common medicine includes diformazan pair
Guanidine (mainly famous with its antihyperglycemic activity), and Metformin hydrochloride (are widely used in non-insulin-dependent glycosuria
Disease).Metformin hydrochloride is widely used in clinic, cheap, and domestic more medical units can produce, and not have patent
Authority system, is the most wide hypoglycemic medicine of current clinical application range.
Alpastic anemia is a kind of disease using whole blood trace elements as main clinical manifestation, and each age group can be sent out
Disease.In recent years, the number of the infected of China's Patients with Aplastic Anemia has rejuvenation and increases year by year.In recent years, hindered using regeneration
The gene expression data base of impenetrability anaemia morbidity,, will using the achievement in research of pharmacogenomics using bioinformatics method
Clinical common 3000 multi-medicament gene expression spectrum signature and the gene expression profile progress characteristic analysis for hindering morbidity again, find
Metformin hydrochloride has the function that to suppress to hinder pathogenesis related genes expression again while promote to resist to hinder related gene expression again, this table
It is bright：Metformin hydrochloride may have the function that to treat alpastic anemia.
State in the treatment in disease, clinic is more and more to use Metformin hydrochloride, because the adverse reaction that the medicine produces
It is slighter.But the prolonged application medicine can cause semicystinol concentration in adverse reaction, including blood to raise.Because cysteine raises
The cerebrovascular disease incidence of disease including coronary heart disease is prompted to improve, so the late result of patient is undesirable.Therefore, reduce
Caused by Metformin hydrochloride cysteine raise, can improve by blood sugar reducing function play protection cardiovascular function the effect of.
Vitamin B12 can reduce melbine this side effect more significantly, but diabetic needs to carry out diet due to conventional
Limitation, it is easy to cause to cannot get enough vitamin B12s from food.
Another adverse reaction of long-term use of Metformin hydrochloride is exactly megaloblastic anemia, its reason is hydrochloric acid
Melbine can suppress the absorption of vitamin B12, and then cause the shortage of hematopoiesis raw material to cause megaloblastic anemia, trigger
Peripheral neuropathy.And give vitamin B12 and treated, then can with early prevention peripheral neuropathy and its triggered four
Acroanesthesia, disorder of limb's activity, limitation of activity and the serious consequence such as can't take care of oneself caused by nervous function declines.
Therefore in order to mitigate the above-mentioned adverse reaction caused by prolonged application Metformin hydrochloride, have diformazan is double
Guanidine and vitamin B12 make prescription there is an urgent need to.
It is currently, there are several by by the scheme of melbine and vitamin B12 combination medicine-feeding：1) by Metformin hydrochloride and
After vitamin B12 mixes at the same time plus tablet or capsule formulation is made in corresponding auxiliary material (such as starch)；2) it is hydrochloride is double
Guanidine and vitamin B12 are respectively prepared single preparation and are packaged in same medicine box, and when in use, patient can successively use successively
Medicine, 3) medication at the same time after mixing separated Metformin hydrochloride and Vitamin B12 preparation.
Analyzed according to medicine generation, vitamin B12 is mainly absorbed in stomach, and Metformin hydrochloride is mainly in intestinal absorption effect
It is good.If pressing above-mentioned three kinds of administrations, discharged after oral melbine hydrocloride in upper digestive tract, without to small intestine site
Positioning release, will be digested in stomach, can not escape enzyme barrier；In addition, two kinds of vitamin B12 and Metformin hydrochloride effectively into
Point absorbing at the same time, melbine can suppress VB12 absorptions, and in pH acidity and there are pepsin condition may generate newly
Material, these result in local drug concentration and bioavilability and reduce.Meanwhile Metformin hydrochloride also produces not intestines and stomach
Good stimulation.In order to make medication safety and reliability, local drug concentration and bioavilability are improved, therefore exist according to different digestion
The pH value and albumen enzymatic property at position are designed, the compound preparation that the different Digestive sites to prepare in vivo discharge step by step
Demand.
The content of the invention
For above-mentioned technical problem, the present invention such as above-mentioned pH value and albumen enzymatic property according to different Digestive sites is set
Meter, the compound preparation that the different Digestive sites to prepare in vivo discharge step by step.
Mainly absorbed in view of vitamin B12 in stomach, and Metformin hydrochloride is mainly good in intestinal absorption effect, and
The ratio of melbine and vitamin B great disparity, if absorbed at the same time, influences the absorption of vitamin B12 in medicament composing prescription, so will
Vitamin B is fabricated to layer and is coated on outside melbine enteric coating layer, so as to fulfill the purpose of the present invention.
In order to make the metformin hydrochloride tablet core stabilization and bioavilability height in compound preparation, design and use enteric coatel tablets system
Agent mode, does not discharge in upper digestive tract but positions and discharge in small intestine site, avoid digesting in stomach, so that enzyme barrier is escaped,
Local drug concentration and bioavilability are improved, while avoids the pessimal stimulation to intestines and stomach.Moreover, the stabilization for preparation
Property consider, be not outside label directly it is enteric coated, but design between label and enteric coating layer make barrier gown layer, with
Obtain stable compound preparation.
From the above mentioned, in a first aspect, the Section 1 technical solution of the present invention provides a kind of preparation of oral compound preparation
Method, the different Digestive sites of the preparation in vivo discharge step by step, and the described method includes the pH value according to different Digestive sites
It is prepared by more layer components that compound preparation is carried out with albumen enzymatic property.
Specifically, Section 2 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Contain two or more effective ingredient in square preparation, and the mass ratio of any two kinds of effective ingredients is 1000：1
More than.
Specifically, Section 3 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Square preparation be vitamin B layer cladding melbine enteric coatel tablets, the vitamin B and melbine in different Digestive sites step by step
Discharge respectively, the preparation method comprises the following steps：
Melbine label is suppressed first, then coats barrier gown layer and enteric coating layer successively outside melbine label,
Obtain melbine enteric coatel tablets；Then in melbine enteric coatel tablets outer cladding vitamin B layer.
Specifically, Section 4 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Square preparation is the melbine enteric coatel tablets of vitamin B layer cladding, and the preparation method comprises the following steps：
1) melbine label forms preparation with following raw materials of every 1000 required weight：
The component in addition to lubricant is mixed, through adding water to pelletize, wet whole grain is dry, after doing whole grain, adds lubricant and mixes
Close, then tabletting obtains melbine label to more than hardness 50kgf；
2) barrier gown layer forms preparation with following raw materials of every 1000 required weight：
Above-mentioned raw materials composition is dissolved in suitable quantity of water, isolation coat is carried out to melbine label made from step 1), is obtained
Obtain isolation coat piece；
3) enteric coating layer forms preparation with following raw materials of every 1000 required weight：
Above-mentioned raw materials composition is dissolved in suitable quantity of water, enteric coating coating is carried out to isolation coat piece made from step 2), is obtained
Obtain enteric coating coating tablet；
4) vitamin B layer forms preparation with following raw materials of every 1000 required weight：
Above-mentioned raw materials composition is dissolved in suitable quantity of water, vitamin B layer bag is carried out to enteric coating coating tablet made from step 3)
Clothing, obtains the melbine enteric coatel tablets of vitamin B layer cladding.
Specifically, Section 5 technical solution of the invention provides the preparation method of oral compound preparation, wherein, in step
1) PVPK30 and HPMCK4M is contained in the described adhesive in, the disintegrant is MCC101, and the filler forms sediment for pregelatinated
Powder, the lubricant include magnesium stearate and superfine silica gel powder；
In step 2-4) in the hypromellose be Methocel E5 Premium, the lubricant includes
PEG 6000 and Talc；The diluent is TiO2, the EUDRAGIT L100-55 is selected from Opadry or outstanding
It is special strange.
Talc, that is, the talcum powder.
The TiO2That is titanium dioxide or titanium dioxide.
The vitamin B is selected from one or more of group consisting of：Vitamin B12, vitamin B1, vitamin B2, dimension
Raw element PP, vitamin B6, vitamin B5, vitamin B7 and Vitamin B9.
Specifically, Section 6 technical solution of the invention provides the preparation method of oral compound preparation, and the method is also
It is included in the light shield layer that vitamin B layer outer cladding contains opacifier component.
Second aspect, by above-mentioned first to five Technologies scheme method, Section 7 technical solution of the invention provides
A kind of oral compound preparation of the stabilization of the melbine enteric coatel tablets of vitamin B layer cladding, including melbine label, isolation
Clothing layer, enteric coating layer and vitamin B layer.
Specifically, Section 8 technical solution of the invention provides oral compound preparation, wherein, melbine label with every
Mass ratio from three layers of clothing layer, enteric coating layer and vitamin B layer summation is 100：13-19；Preferably, barrier gown layer, enteric coating
Layer and the mass ratio of vitamin B layer three are 1：3-6：0.5-2.
Specifically, Section 9 technical solution of the invention provides oral compound preparation, wherein, melbine accounts for whole mouth
The mass percent for taking compound preparation is 60-85%；The mass ratio of melbine and vitamin B is 6000-40000：1.
Inventor, which particularly contemplates, is particularly VB12 property light fugitives in vitamin B complex, when being coated as outermost layer, preferably
Inactivated in degraded.And the patient for taking this compound preparation is conventional medication, the medicine box regular medicine taking of not lucifuge is commonly used.So it is
Patient considers, considers for drug effectiveness is extended, and especially design light shield layer outside vitamin B layer, it is with orally available nonhazardous
The medicinal opacifier raw material of effect is made.
Specifically, Section 10 technical solution of the invention provides the preparation method of oral compound preparation, it is in vitamin B
Layer is outer also to include light shield layer, and the light shield layer includes chemical light shield layer and/or physics anti-light package product；The chemistry light shield layer
Opacifier component be selected from titanium dioxide, sunset yellow, famille rose, indigo, iron oxide red, any of iron oxide yellow or it is a kind of with
On；The double aluminum composite membranes of PVC film, PVC or the double aluminum composite membranes of PVC drier can be selected in the physics anti-light package product.
Specifically, in the oral compound preparation, the label be by Metformin hydrochloride and auxiliary material such as adhesive,
Disintegrant, filler and lubricant and suitable quantity of water form；
The barrier gown layer is made of hypromellose and lubricant and suitable quantity of water；
The enteric coating layer is made of EUDRAGIT L100-55 and lubricant and suitable quantity of water；With
The vitamin B layer is made of vitamin B and hypromellose and diluent and lubricant with suitable quantity of water.
When vitamin B is preferably vitamin B12, the oral compound preparation of Pass through above-mentioned technical proposal acquisition, can make
Vitamin B12 is mainly absorbed in stomach, and Metformin hydrochloride mainly in intestinal absorption, is able to play hydrochloride pair to greatest extent
The positive therapeutic effect of guanidine, including anti-diabetic and treatment alpastic anemia, while reduce to greatest extent bad anti-with its
Relevant symptom is answered, prevents megaloblastic anemia caused by katz syndrome, prevents and treats Diabetic Peripheral
Neuropathy, and effectively prevent Homocysteine caused by semicystinol concentration rise in blood.
The present invention is designed according to the pH value and albumen enzymatic property of different Digestive sites, and the difference to prepare in vivo disappears
Change the compound preparation that discharges step by step of position, so that by several difference in functionality or the drug regimen that should not be compressed in a sheet body
Into an entirety, reduce the medication amount of patient's medication, and some drugs can be overcome can not to be stored jointly in preparation
The problem of, add the stability of compound formulation.
By setting the multiple coatings with difference in functionality, the compound preparation such as figure of tablet is obtained, can be distinguished
In human stomach, intestines different parts be disintegrated, discharge and absorbed, substantially increase local drug concentration and bioavilability.And
And compound formulation stable quality of the present invention, it disclosure satisfy that all kinds of demands of Clinical practice.
Embodiment
It should be understood that the technical solution that is described is simply to illustrate that citing, not limits herein, specific protection domain is to weigh
Subject to profit requires.
Any numerical value drawn herein is included from lower limit to upper limit value.For example, if concentration range is described as 0.01%-
50%, it is meant that the numerical value such as 0.2%-40%, 10%-30% or 1%-3% is all clearly enumerated in this specification.These
It is only the example being specifically mentioned, the possible combinations of values of the whole between minimum and peak is considered in the application
In clearly state.
Furthermore, it will be understood that word used herein and term are only used for description purpose, and it is non-limiting.Now define such as
Under：
Definition
Term " vitamin B " used herein, " VB " include but not limited to vitamin B12 (including cobamamide, first cobalt
Amine, cyanocobalamin, cobalamin), further include vitamin B1 (also known as thiamine, anti beriberi vitamin), vitamin B2 (riboflavin),
Nicotinic acid (also known as niacin or nicotinic acid, nicotinic acid), vitamin B6 (also known as pyridoxol, adermin),
Vitamin B5 (pantothenic acid, also known as pantothenic acid), vitamin B7 (also known as biotin, biotin), Vitamin B9 (also known as folic acid) and its
Its vitamin B complex member.Vitamin B7 indication：For dermatitis, eczema, atrophic glossitis, hyperesthesia, courbature, burnout,
Apocleisis and anemia, alopecia), effect includes：Help fat, glycogen and amino acid is normally synthesized in human body and generation
Thank；Promote the normal operation and growth of sweat gland, nerve fiber, marrow, male gonad, skin and hair, mitigate eczema, dermatitis disease
Shape；Prevent white hair and alopecia, help to treat bald；Relax myalgia；Promotion urea synthesizing is synthesized with excretion, purine and oil
The biosynthesis of acid；For treating not normal artery sclerosis, apoplexy, lipid metabolism, hypertension, coronary heart disease and blood circulation disorder
Disease.The effect of vitamin B1 includes：Internal glycometabolism is adjusted, ensures the staple food starch that daily intakes and carbohydrate in human body
It is converted into energy and is utilized.Also multi-vitamins can be selected, indication includes：Peripheral neuritis, insomnia, uneasiness；Mitigate anti-
Cancer medicine and radiotherapy cause Nausea and vomiting or vomiting of pregnancy etc., for malnutrition, apocleisis, athlete's foot, bark favus and shortage
Vitamin B etc..
Term " appropriate " used herein refers to the scope that those skilled in the art can rule of thumb judge, such as small in medicine
In examination.
Term " auxiliary material " used herein includes the medicament of filling effect, adhesive effect, calving disaggregation and lubricating action, tool
Body includes term used herein " filler ", " adhesive ", " disintegrant " and " lubricant ", and other figurations commonly used in the art
Agent.
Term " lubricant " used herein is the concept of a broad sense in pharmacy, is glidant, antiplastering aid and (narrow
Justice) lubricant general name, wherein：1. glidant (Glidants) be between reducing particle frictional force so as to improving powder flowbility
Material；2. antiplastering aid (Antiadherent) is the material for preventing supplementary material to be adhered to punch head surface；(3. narrow sense) lubricant
It is the material for reducing frictional force between tablet and punch die hole wall, this is lubricant truly.Therefore, a kind of preferably profit
Lubrication prescription should have concurrently it is above-mentioned help stream, anti-stick and three kinds of effects of lubrication, but in current existing lubricant, still without this ideal
Lubricant, they often have a preferable performance at some or certain two aspects, but other effects are then relatively poor.According to habit
Used sorting technique, generally will all be referred to as lubricant with a kind of any of the above described auxiliary material of effect.Lubricant citing includes：Firmly
Fatty acid magnesium；Superfine silica gel powder；Talcum powder；Hydrogenated vegetable oil；Polyethylene glycols and magnesium laurylsulfate, etc..
Term " light shield layer " used herein, " shading oxidant layer " are interchangeable, including those skilled in the art can use
Chemical light shield layer and/or physics anti-light package product.The opacifier component of the chemistry light shield layer is selected from titanium dioxide, sunset
Any of yellow, carmine, indigo, iron oxide red, iron oxide yellow or more than one.Titanium dioxide both may be used as opacifier
It is also used as diluent.The physics anti-light package product can be selected：The double aluminum composite membranes of PVC film, PVC, with the double aluminium of PVC drier
The packaged forms such as composite membrane, it is preferred that using the double aluminum composite membrane packagings of PVC drier.
Term " Metformin hydrochloride " used herein and " melbine " are used interchangeably.
Term " carrying out full inspection by quality standard " used herein, standard is performed with reference to national drug test stone.
Term " EUDRAGIT L100-55 " used herein, is the component of enteric coating, it can be with art
Language " acrylic resin " is general, including and is not limited to methacrylic acid and ethyl acrylate (1:1) copolymer, methacrylic acid
Resin, ethyl acrylate list polymers etc..With aqueous dispersion or the those skilled in the art such as organic solution coating solution can be replaced with
Known form uses.
For the purpose of citing, specific embodiments of the present invention described in detail below：
In a first aspect, the Section 1 technical solution of the present invention provides a kind of preparation method of oral compound preparation, it is described
The different Digestive sites of preparation in vivo discharge step by step, and the described method includes the pH value and protease according to different Digestive sites
It is prepared by more layer components that matter carries out compound preparation.
Specifically, Section 2 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Contain two or more effective ingredient in square preparation, and the mass ratio of any two kinds of effective ingredients is 1000：1
More than, preferably 2000：More than 1, and then preferably 6000：More than 1.The mass ratio of any two kinds of effective ingredients is preferably
1000-15000：1；And then preferably 2000-13000：1；And then preferably 5000-12000：1；Further 9000-11000：
1.The mass ratio of any two kinds of effective ingredients can be 1500：1；2000：1；2500：1；3000：1；3500：1；
4000：1；4500：1；5000：1；5500：1；6000：1；6500：1；7000：1；8000：1；9000：1；11000：1；12000：
1；13000：1；14000：1；15000：1.
Specifically, Section 3 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Square preparation be vitamin B layer cladding melbine enteric coatel tablets, the vitamin B and melbine in different Digestive sites step by step
Discharge respectively, the preparation method comprises the following steps：
Melbine label is suppressed first, then coats barrier gown layer and enteric coating layer successively outside melbine label,
Obtain melbine enteric coatel tablets；Then in melbine enteric coatel tablets outer cladding vitamin B layer, oral compound preparation is obtained；
The raw material of wherein described diformin tablet core includes melbine, adhesive, disintegrant, filler, lubricant；Institute
Stating the raw material of barrier gown layer includes hypromellose and lubricant；The raw material of the enteric coating layer include methacrylic acid-
Ethyl acrylate copolymer and lubricant；The raw material of the vitamin B layer includes vitamin B, hypromellose, lubricant
And diluent.
Specifically, Section 4 technical solution of the invention provides the preparation method of oral compound preparation, described oral multiple
Square preparation is the melbine enteric coatel tablets of vitamin B layer cladding, and the preparation method comprises the following steps：
1) melbine label forms preparation with following raw materials of every 1000 required weight：
In every 1000 tablets of medicines, melbine is chosen as 250-305g；Adhesive is chosen as 30-40g；Disintegrant is chosen as
25-35g；Filler is chosen as 15-25g；Lubricant is chosen as 1-3g；
The component in addition to lubricant is mixed, through adding water to pelletize, wet whole grain is dry, after doing whole grain, adds lubricant and mixes
Close, then tabletting obtains melbine label to more than hardness 50kgf, such as 55kgf；
2) barrier gown layer forms preparation with following raw materials of every 1000 required weight：
In every 1000 tablets of medicines, hypromellose is chosen as 6-8g；Lubricant is chosen as 1.2-2g；
Above-mentioned raw materials composition is dissolved in suitable quantity of water, isolation coat is carried out to melbine label made from step 1), is obtained
Isolation coat piece is obtained, by percentage to the quality, its melbine label mass weight gain 1.5- obtained relative to step 1)
3.5%, preferably 2-3%, preferably 2.5%；
3) enteric coating layer forms preparation with following raw materials of every 1000 required weight：
In every 1000 tablets of medicines, EUDRAGIT L100-55 is chosen as 25-30g；Lubricant is chosen as 7-
10g；
Above-mentioned raw materials composition is dissolved in suitable quantity of water, enteric coating coating is carried out to isolation coat piece made from step 2), is obtained
Enteric coating coating tablet is obtained, by percentage to the quality, its melbine label mass weight gain 8-12% obtained relative to step 1),
It is preferred that 11%；
4) vitamin B layer forms preparation with following raw materials of every 1000 required weight：
In every 1000 tablets of medicines, hypromellose is chosen as 6-8g；Lubricant is chosen as 1.2-2g；Vitamin B can
Elect 0.02-1g, preferably 0.02-0.1g, further preferably 0.02-0.05g, more preferably 0.02-0.04g as；Diluent is chosen as 0.5-
3g；
Above-mentioned raw materials composition is dissolved in suitable quantity of water, vitamin B layer bag is carried out to enteric coating coating tablet made from step 3)
Clothing, obtains the melbine enteric coatel tablets of vitamin B layer cladding, by percentage to the quality, its diformazan obtained relative to step 1)
Biguanides label mass weight gain 1-4%, preferably preferably 2-3%, 2.5%-2.9%.
Specifically, Section 5 technical solution of the invention provides the preparation method of oral compound preparation, wherein, in step
1) PVPK30 and HPMCK4M is contained in the described adhesive in, the disintegrant is MCC101, and the filler forms sediment for pregelatinated
Powder, the lubricant include magnesium stearate and superfine silica gel powder；
In step 2-4) in the hypromellose be Methocel E5 Premium, the lubricant includes
PEG 6000 and Talc；The diluent is TiO2, the EUDRAGIT L100-55 is selected from Opadry or outstanding
It is special strange；The vitamin B is selected from group consisting of for one or more：Vitamin B12, vitamin B1, vitamin B2, dimension life
Plain PP, vitamin B6, vitamin B5, vitamin B7 and Vitamin B9.
Alternatively, additionally provided in this technical solution and carry out a step 4 again after step 4) ') do and be coated.This coating
Composition is applicable to, according to the available chemistry of conditions of patients or biological agent, include but not limited to preventative medicament, therapeutic medicine
Agent, trophism medicament, can be directed to the primary or complication of patient, can be other vitamins specifically, in particular other
Vitamin B.It can bring to artery sclerosis, apoplexy, lipid metabolism are not normal, the disease of hypertension, coronary heart disease and blood circulation disorder
The auxiliary therapeutic action of disease, and relieving insomnia, uneasiness, mitigate Nausea and vomiting, improve malnutritive, apocleisis and other effects.
Alternatively, in step 4) and step 4 ') between can carry out step 2 ') make barrier gown layer.
Alternatively, in the preparation method for the oral compound preparation that this technical solution provides, the adhesive in step 1)
The quality parts ratio of PVPK30 and HPMCK4M is 1：0.5-2, preferably 8：5；The methacrylic acid-acrylic acid in step 3)
Methacrylate copolymers are EUDRAGITL30D-55.
PVPK30 of the present invention, HPMCK4M, MCC101, Methocel E5 Premium, PEG 6000, Opadry or
Utech (EUDRAGITL) (such as EUDRAGITL30D-55) is commercially available pharmaceutic adjuvant.
Specifically, Section 6 technical solution of the invention provides the preparation method of oral compound preparation, and the method is also
It is included in the light shield layer that vitamin B layer outer cladding contains opacifier component.
Second aspect, by above-mentioned first to five Technologies scheme method, Section 7 technical solution of the invention provides
A kind of oral compound preparation of the stabilization of the melbine enteric coatel tablets of vitamin B layer cladding, including melbine label, isolation
Clothing layer, enteric coating layer and vitamin B layer.
Alternatively, additionally provided in this technical solution and coat one layer of coatings again outside vitamin B layer.This coatings forms
It is applicable to, according to the available chemistry of conditions of patients or biological agent, include but not limited to preventative medicament, therapeutic medicament, battalion
Nourish one's nature medicament, the primary or complication of patient can be directed to, can be other vitamins specifically, be in particular that other dimensions are given birth to
Plain B.It can bring to artery sclerosis, apoplexy, lipid metabolism are not normal, the disease of hypertension, coronary heart disease and blood circulation disorder
Auxiliary therapeutic action, and relieving insomnia, uneasiness, mitigate Nausea and vomiting, improve malnutritive, apocleisis and other effects.
Alternatively, there are barrier gown layer between B layers of said vitamin and coatings outside it.
Specifically, Section 8 technical solution of the invention provides oral compound preparation, wherein, melbine label with every
Mass ratio from three layers of clothing layer, enteric coating layer and vitamin B layer summation is 100：13-19, and then preferably 100：15-17, more into
One step preferably 100：16；Preferably, the mass ratio of barrier gown layer, enteric coating layer and vitamin B layer three is 1：3-6：0.5-
2, and then preferably 1：4-5：0.8-1.5, further preferably 1.2：5.5：1.4.
Specifically, Section 9 technical solution of the invention provides oral compound preparation, wherein, melbine accounts for whole mouth
The mass percent for taking compound preparation is 60-85%, optional 60-65%, and then preferred 61-63%；Melbine and vitamin B
Mass ratio be 6000-40000：1, it is preferably 7000-20000：1, more preferably 8000-15000：1, more preferably 9000-
12000：1.
Inventor, which particularly contemplates, is particularly VB12 property light fugitives in vitamin B complex, when being coated as outermost layer, preferably
Inactivated in degraded.And the patient for taking this compound preparation is conventional medication, the medicine box regular medicine taking of not lucifuge is commonly used.So it is
Patient considers, considers for drug effectiveness is extended, and especially design light shield layer outside vitamin B layer, it is with orally available nonhazardous
The opacifier of effect is made.
Specifically, Section 10 technical solution of the invention provides the preparation method of oral compound preparation, it is in vitamin B
Layer is outer also to include light shield layer, and the light shield layer includes chemical light shield layer and/or physics anti-light package product；The chemistry light shield layer
Opacifier component be selected from titanium dioxide, sunset yellow, famille rose, indigo, iron oxide red, any of iron oxide yellow or it is a kind of with
On；The double aluminum composite membranes of PVC film, PVC or the double aluminum composite membranes of PVC drier can be selected in the physics anti-light package product.
Embodiment
The present invention will more specifically described by the following examples.Although the following examples further provide
The detailed description of embodiment of the present invention, they should be regarded only as illustrative, and not limit in any way by appended right
It is required that the present invention limited.Those skilled in the art can carry out the modification of various modes in the technological concept of the present invention and change
Into.
Preparation example 1
1st, compound medicine is always formulated
2nd, technological process
Melbine label is suppressed first, then coats barrier gown layer and enteric coating layer successively outside melbine label,
Obtain melbine enteric coatel tablets；Again in melbine enteric coatel tablets outer cladding vitamin B layer, oral compound preparation is obtained.
2.1 prepare melbine label
1) melbine label formula
Piece weight is 350mg, every 250mg containing melbine.Experimental lots are 200,000 (i.e. 70kg).
2) tabletting flow and operation
1. claim sample：Each material (except magnesium stearate, superfine silica gel powder) is weighed by proportioning, as material caking needed 60 mesh sieves；
2. mix：Above-mentioned 1. material is put in High Speed Stirring Machine and is mixed 5-10 minutes；
3. pelletize：After above-mentioned 2. material mixes, while add appropriate waterside stirring granulation, to be presented to hold agglomerating, one by i.e. broken
Particle；
4. wet whole grain：16 mesh sieve whole grains are carried out to above-mentioned 3. wet granular with oscillating granulator；
5. dry：Above-mentioned 4. whole good wet granular is dried to LOD in baking oven<2%；
6. dry whole grain：20 mesh sieve whole grains are carried out to the particle after above-mentioned 5. drying with oscillating granulator；
7. mix：Magnesium stearate and superfine silica gel powder are added in above-mentioned 6. whole good dry particl by proportioning, in mixer
Mix 1-3min.
8. tabletting：By the above-mentioned particle 7. mixed in the shallow arc punching press rounding pieces of 10mm, piece weight 350mg (± 5%), hardness
Control is in more than 50kgf.
2.2 bag barrier gown layers
1) barrier gown coating formula of liquid
2) barrier gown liquid is prepared
1. MethocelE5 Premium and PEG6000 are dissolved separately in 7-12 times (preferably 9 times) amount water, then mix
Close uniform.
2. Talc is added in 3-5 times (preferably 4 times) amount water and homogenize scattered 10 minutes.
3. will 2. be incorporated to 1., and remaining water washing container is incorporated to, after stirring evenly, up to barrier gown liquid.
3) bag barrier gown layer
The above-mentioned melbine label claimed is put into O ' HaraLabcoatI high-efficiency coating pots, uses infusion pump
Watson505U bag barrier gown layers.Control 58-60 DEG C of inlet air temperature, air quantity 110m3/ h, pot rotating speed 3-7rpm, revolution speed 5-
9rpm, average hydrojet speed 8.4g/min, 31-35 DEG C of temperature of charge, atomizing pressure 0.2MPa, covering of the fan pressure 0.2MPa, outlet air
36-39 DEG C of temperature, negative pressure -0.2cmH2O.After having wrapped barrier gown, make label in coating pan dry 8-15 points under the conditions of low pot speed
Clock.
2.3 enteric-coating layer
1) enteric coating coating formula of liquid
The above-mentioned label for wrapping barrier gown is continued enteric coated according to the following formulation.
2) enteric coating liquid is prepared
After 1. PEG6000 is dissolved in 3-5 times (preferably 4 times) amount water, the Talc with adding the water modulation of 3-5 times (preferably 4 times) amount
Talc suspension homogenizes 10 minutes together.
2. suspension is slowly poured into the EUDRAGITL30D-55 diluted that stirred 1., stir evenly, up to intestines
Molten clothing coating solution.
3) enteric-coating layer
Above-mentioned isolation coat piece is put into coating pan as described above, continues bag enteric using infusion pump as described above
Clothing.Silica gel infusion bore 3.1mm, controls 58-60 DEG C of inlet air temperature, air quantity 110m3/ h, pot rotating speed 4-7rpm, revolution speed 6-
10rpm, average hydrojet speed 7.7g/min, 27-30 DEG C of temperature of charge, atomizing pressure 0.18MPa, covering of the fan pressure 0.18MPa, goes out
34-37 DEG C of air temperature, negative pressure -0.2cmH2O。
After having wrapped enteric coating, label is set to be dried 8-15 minutes under the conditions of low pot speed in coating pan.
2.4 VB12 layers of bags
1) VB12 layers of coating formula of liquid
It is 26.5 μ g (± 5%) that every diformin tablet, which should contain VB12, because medicine-feeding can lose, therefore according to the following formulation 1.1
VB12 layers of amount bag again, another VB12 raw materials need lucifuge to operate and store.
2) VB12 layers of liquid are prepared
1. MethocelE5 Premium and PEG6000 are dissolved separately in 5-20 times to measure in water, then it is uniformly mixed.
②Talc、TiO2Add in 3-5 times (preferably 4 times) amount water and homogenize scattered 10 minutes with VB12.
3. will 2. be incorporated to 1., and remaining water washing container is incorporated to, after stirring evenly, up to VB12 layers of liquid.
3) VB12 layers are wrapped
Above-mentioned melbine enteric coatel tablets are put into coating pan as described above, continue to wrap using infusion pump as described above
VB12 layers.Silica gel infusion bore 3.1mm, controls 58-60 DEG C of inlet air temperature, air quantity 100m3/ h, pot rotating speed 4-7rpm, pump turn
Fast 7rpm, average hydrojet speed 6.3g/min, 28-35 DEG C of temperature of charge, atomizing pressure 0.2MPa, covering of the fan pressure 0.2MPa, goes out
35-38 DEG C of air temperature, negative pressure -0.3cmH2O。
After having wrapped, label is set to be dried 8-15 minutes under the conditions of low pot speed in coating pan.
3rd, intermediate control point
Particle preparation：Pellet moisture (it is required that：LOD<3%) and particle in melbine content (it is required that：250mg ± 5%).
Tabletting：The actual piece weight of monitoring (it is required that：350mg ± 5%), monitoring tablet hardness (it is required that：>5kgf)；Measure label
Middle melbine actual content (it is required that：250mg ± 5%).
Enteric coating is wrapped：Measure and discharged in the acid-resistant strength and buffer solution of melbine enteric coatel tablets, qualified subsequent packet VB12 layers.
VB12 layers are wrapped：Full inspection is carried out by quality standard.Compliance rate 99.8%.
It is packaged in the double aluminum composite membranes of PVC drier and is preserved in shady place.
Preparation example 2
Step 2.1 into the formula of step 2.3 and step and step 2.4 coating process with preparation example 1.Simply wrap
Clothing is not to contain only VB12, but includes VB12 and VB7.
2.4 VB12+VB7 layers of bags
1) VB12+VB7 layers of coating formula of liquid
It is 26.5 μ g (± 5%) that every diformin tablet, which should contain VB12, and VB7 is 26.5 μ g (± 5%), because medicine-feeding can be damaged
Lose, therefore 1.1 times of VB12+VB7 layers of amount bags according to the following formulation, another VB12 are both needed to lucifuge operation and storage with VB7 raw materials.
2) VB12+VB7 layers of liquid are prepared
Step the same 2.4 2), simply 2. middle addition is VB12+VB7.
3rd, intermediate control point
Particle preparation：Pellet moisture (it is required that：LOD<3%) and particle in melbine content (it is required that：250mg ± 5%).
Tabletting：The actual piece weight of monitoring (it is required that：350mg ± 5%), monitoring tablet hardness (it is required that：>5kgf)；
Measure label in melbine actual content (it is required that：250mg ± 5%).
Enteric coating is wrapped：Measure and discharged in the acid-resistant strength and buffer solution of melbine enteric coatel tablets, qualified subsequent packet VB12+
VB7 layers.
VB12+VB7 layers are wrapped：Full inspection is carried out by quality standard.As a result compliance rate 99.7%.
It is packaged in the double aluminum composite membranes of PVC drier and is preserved in shady place.
Preparation example 3
Step 2.1 to step 2.4 formula and step with preparation example 1, simply in addition wrap VB7 VB12 layer coating are outer
Layer.
2.5 VB7 layers of bags
1) VB7 layers of coating formula of liquid
It is 26.5 μ g (± 5%) that every diformin tablet, which should contain VB7, because medicine-feeding can lose, therefore according to the following formulation 1.1 times
VB7 layers of amount bag, another VB7 raw materials are both needed to lucifuge operation and storage.
2) VB7 layers of liquid are prepared
Step the same 2.4 2), simply 2. middle addition is VB7.
3) VB7 layers are wrapped
Step condition and equipment are the same.
VB7 layers are wrapped：Full inspection is carried out by quality standard.Compliance rate 99.8%.
It is packaged in the double aluminum composite membranes of PVC drier and is preserved in shady place.
Preparation example 4
Above-mentioned 1 gained tablet of preparation example is coated into shading oxidant layer：
1) shading oxidant layer coating solution formula
2) shading oxidant layer liquid is prepared
1. MethocelE5 Premium and PEG6000 are dissolved separately in 5-20 times to measure in water, then it is uniformly mixed.
2. titanium dioxide, Talc are added in 3-5 times (preferably 4 times) amount water and homogenize scattered 10 minutes.
3. will 2. be incorporated to 1., and remaining water washing container is incorporated to, after stirring evenly, up to shading oxidant layer liquid.
3) bag shading oxidant layer
Above-mentioned 1 gained tablet of preparation example is taken out from the double aluminum composite membranes of PVC drier of encapsulation, input such as preparation example 1
The coating pan, uses the infusion pump bag light shield layer described in preparation example 1.Silica gel infusion bore 3.1mm, controls inlet air temperature
58-60 DEG C, air quantity 100m3/ h, pot rotating speed 4-6rpm, revolution speed 7rpm, average hydrojet speed 6.7g/min, temperature of charge 28-
33 DEG C, atomizing pressure 0.18MPa, covering of the fan pressure 0.2MPa, 33-37 DEG C of leaving air temp, negative pressure -0.3cmH2O.After having wrapped, make piece
Core drying 8-15 minutes under the conditions of low pot speed in coating pan.
The experiment of content and release
Investigation project and method：
Content and release ultraviolet spectrometry brightness method.
Release refers to the release in simulate the gastric juice (0.lmol/L hydrochloric acid).
1st, as a result preparation example 1 see the table below compared with 4 tablet：
1 preparation example 1 of table and 4 compound formulation data
| Preparation example 1 | Preparation example 1 | Preparation example 4 | Preparation example 4 | |
| Time | Content (%) | Release (%) | Content (%) | Release (%) |
| 0 day | 99.3 | 0.1 | 99.8 | 0.1 |
| 5 days | 98.5 | 0.2 | 99.7 | 0.2 |
| 10 days | 97.9 | 0.2 | 99.6 | 0.1 |
| 15 days | 97.2 | 0.1 | 99.6 | 0.2 |
2nd, ibid, the measure distinguished 2 and 3 compound formulation of preparation example
2 preparation example 2 of table and 3 compound formulation data
Claims (10)
1. a kind of preparation method of oral compound preparation, the different Digestive sites of the preparation in vivo discharge step by step, the side
It is prepared by more layer components that method includes carrying out compound preparation according to the pH value and albumen enzymatic property of different Digestive sites.
2. the preparation method of the oral compound preparation described in claim 1, two kinds or two kinds are contained in the oral compound preparation
Above effective ingredient, and the mass ratio of any two kinds of effective ingredients is 1000：More than 1.
3. the preparation method of the oral compound preparation described in claim 1, the oral compound preparation is vitamin B layer cladding
Melbine enteric coatel tablets, the vitamin B and melbine discharge respectively step by step in different Digestive sites, the preparation method bag
Include the following steps：
Melbine label is suppressed first, then coats barrier gown layer and enteric coating layer successively outside melbine label, is obtained
Melbine enteric coatel tablets；Then in melbine enteric coatel tablets outer cladding vitamin B layer.
4. the preparation method of the oral compound preparation described in claim 3, the oral compound preparation is vitamin B layer cladding
Melbine enteric coatel tablets, the preparation method comprise the following steps：
1) melbine label forms preparation with following raw materials of every 1000 required weight：
The component in addition to lubricant is mixed, through adding water to pelletize, wet whole grain is dry, after doing whole grain, adds mix lubricant, then
Tabletting obtains melbine label to more than hardness 50kgf；
2) barrier gown layer forms preparation with following raw materials of every 1000 required weight：
By above-mentioned raw materials composition be dissolved in suitable quantity of water, to made from step 1) melbine label carry out isolation coat, obtain every
From coating tablet；
3) enteric coating layer forms preparation with following raw materials of every 1000 required weight：
Above-mentioned raw materials composition is dissolved in suitable quantity of water, enteric coating coating is carried out to isolation coat piece made from step 2), obtains intestines
Molten clothing coating tablet；
4) vitamin B layer forms preparation with following raw materials of every 1000 required weight：
Above-mentioned raw materials composition is dissolved in suitable quantity of water, vitamin B layer coating is carried out to enteric coating coating tablet made from step 3), is obtained
Obtain the melbine enteric coatel tablets of vitamin B layer cladding.
5. the preparation method of the oral compound preparation described in claim 4, wherein, contain in the described adhesive in step 1)
PVPK30 and HPMCK4M, the disintegrant are MCC101, and the filler is pregelatinized starch, and the lubricant includes tristearin
Sour magnesium and superfine silica gel powder；
In step 2-4) in the hypromellose be Methocel E5 Premium, the lubricant includes PEG
6000 and Talc；The diluent is TiO2, the EUDRAGIT L100-55 is selected from Opadry or especially
Very；The vitamin B is selected from the one or more of group consisting of：Vitamin B12, vitamin B1, vitamin B2, vitamin
PP, vitamin B6, vitamin B5, vitamin B7 and Vitamin B9.
6. the preparation method of claim 1-3 any one of them oral compound preparations, the method are additionally included in vitamin B layer
Outer cladding contains the light shield layer of opacifier component.
7. with the oral compound preparation prepared by claim 1-5 any one of them preparation methods, it is characterised in that with from interior
Melbine label, barrier gown layer, enteric coating layer and vitamin B layer are included to outer order.
8. the oral compound preparation described in claim 7, wherein, melbine label is given birth to barrier gown layer, enteric coating layer and dimension
The mass ratio of three layers of summation of plain B layers is 100：13-19；The mass ratio of barrier gown layer, enteric coating layer and vitamin B layer three is
1：3-6：0.5-2.
9. the oral compound preparation described in claim 7, wherein, melbine accounts for the mass percent of whole oral compound preparation
For 60-85%；The mass ratio of melbine and vitamin B is 6000-40000：1.
10. the preparation method of the oral compound preparation described in claim 6, the light shield layer includes chemical light shield layer and/or thing
Manage anti-light package product；The opacifier component of the chemistry light shield layer is selected from titanium dioxide, sunset yellow, famille rose, indigo, iron oxide
Any of red, iron oxide yellow or more than one；The physics anti-light package product be selected from the double aluminum composite membranes of PVC film, PVC or
Any of double aluminum composite membranes of PVC drier.
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| CN201610922082.4A CN107970222B (en) | 2016-10-21 | 2016-10-21 | Oral compound preparation of metformin enteric-coated tablet coated with vitamin B layer and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002867A2 (en) * | 2007-06-26 | 2008-12-31 | Nutrition 21, Inc. | Multiple unit dosage form having a therapeutic agents in combination with a nutritional supplement |
| CN101990428A (en) * | 2008-04-10 | 2011-03-23 | 韩兀生物制药株式会社 | Pharmaceutical formulation |
| CN104840480A (en) * | 2015-05-27 | 2015-08-19 | 深圳奥萨制药有限公司 | New use of dimethyldiguanide/folic acid/vitamin B12 pharmaceutical composition |
-
2016
- 2016-10-21 CN CN201610922082.4A patent/CN107970222B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002867A2 (en) * | 2007-06-26 | 2008-12-31 | Nutrition 21, Inc. | Multiple unit dosage form having a therapeutic agents in combination with a nutritional supplement |
| CN101990428A (en) * | 2008-04-10 | 2011-03-23 | 韩兀生物制药株式会社 | Pharmaceutical formulation |
| CN104840480A (en) * | 2015-05-27 | 2015-08-19 | 深圳奥萨制药有限公司 | New use of dimethyldiguanide/folic acid/vitamin B12 pharmaceutical composition |
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