CN105412016B - A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin - Google Patents
A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin Download PDFInfo
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- CN105412016B CN105412016B CN201510713729.8A CN201510713729A CN105412016B CN 105412016 B CN105412016 B CN 105412016B CN 201510713729 A CN201510713729 A CN 201510713729A CN 105412016 B CN105412016 B CN 105412016B
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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Abstract
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin.The enteric solid preparation includes active constituent resveratrol, water solubility and/or enteric solubility carrier auxiliary material and other pharmaceutic adjuvants.Water-solubility carrier auxiliary material can be used as water soluble solid dispersion carrier；Enteric solubility carrier auxiliary material is enteric polymer, can be used as enteric solid dispersion carrier or enteric coating membrane material.The enteric solid preparation of resveratrol has good dissolubility in enteron aisle, so that drug quickly dissolved, discharged in enteron aisle, to increase the absorption of resveratrol, improves its bioavilability.Resveratrol solid dispersion composition of the invention is applicable to the application and industrialized production of the peroral dosage forms such as tablet, granule, pellet, capsule, enteric capsule, enteric coated tablet, enteric coated-pellet, enteric coated granule.
Description
Related application
The application be on October 27th, 2010 applying date, it is entitled that " one kind is containing lycopene, resveratrol or taking off
The divisional application of the Chinese invention patent application No.201010528511.2 of enteric solid preparation of melanocyte and preparation method thereof ".
Technical field
The present invention relates to a kind of enteric solid systems containing lycopene, resveratrol and/or epiphysin as active constituent
Agent and preparation method thereof.Specifically, enteric solid preparation of the invention is by being used in combination solid dispersions and enteric release
Carrier, make the above-mentioned preparation containing lycopene, resveratrol and/or epiphysin increase active constituent solubility and/or
Trap improves the bioavilability of active constituent.
Background technique
With the development of Fully automated synthesis, combinatorial chemistry and High Throughput Screening Assay, more and more new active medicines are same
When be also insoluble drug pendulum on the assembly line of pharmaceutical engineering.Having the marketed drugs greater than 40% according to estimates is slightly solubility medicine
Object, and the insoluble drug in pharmaceuticals industry laboratory accounts for about 60% or more of total amount.For low solubility high-permeability
Drug absorbs the low dissolution rate that rate-limiting step is drug.Traditional conventional tablet is difficult to improve the biological utilisation of this kind of drug
Degree, technique appropriate and modified form are the key that such drug products is successfully developed, therefore technique and dosage form are for this kind of medicine
The absorption of object in the gastrointestinal tract plays decisive role.Investigative technique of the recent domestic for insoluble drug administration strategy
There are many, such as micronization technology, nanotechnology, microemulsion technology, molecule inclusion technology, liposome technology, solid dispersion technology, embedding
Section copolymer micelle etc., wherein solid dispersions technique is since solubilizing effect is obvious, technique is relatively easy, at low cost in industry
Compare and is favored.Current commercialized product, research paper or patent mainly biases toward solution using upper in solid dispersions technique
The solubility of drug, with this, to increase, drug is intracorporal to be absorbed to improve the bioavilability of drug.
Chinese patent application CN 1981742A discloses HPMCAS answering as the solid dispersion carrier of insoluble drug
With, but this application also lists several existing technical literatures, solid point is made as HPMCAS and certain insoluble drugs in display
When granular media, the improvement effect of solubility is simultaneously bad, such as Yakuzaigaku, 53 (4), and T.Yamaguchi in 221-228 (1993)
When solid dispersions are made about MAT and HPMCAS or CMEC, the effect of CMEC preferably describes.
In addition, also disclosed in PCT Patent Application WO 2003/063831 it is a kind of containing solid pharmaceutical dispersions at once
Release dosage form, contains at least solid pharmaceutical dispersions of 30wt%, at least disintegrating agent of 5wt% and porosigen, but root
According to the commentary in Chinese patent application CN 101057834A, though the release dosage form at once of the solid pharmaceutical dispersions make it is described
Tablet is disintegrated under one's belt, but drug will be made to recrystallize since solid dispersions are in digestive juice for a long time, causes drug molten
Xie Du is reduced.
Lycopene (Lycopene, molecular formula C40H56, molecular weight 536.85, sterling is peony acicular crystal) and it is one
The carotenoid of kind non-annularity is that separation and Extraction is made from tomato earliest, cannot voluntarily synthesize in human body, it is necessary to from the external world
Intake.In all carotenoid, lycopene has the function of strongest elimination singlet oxygen and eliminates the function of free radical
Can, belonging to powerful antioxidant, the elimination ability to singlet oxygen is 2 times of carrotene, 100 times of vitamin E；Tomato red
Element can slow down the oxidation of low-density lipoprotein, reduce the cholesterol in blood plasma, prevent cardiovascular disease；It can effectively inhibit cancer
Cell proliferation has anti-cancer and cancer-preventing effect, especially has good therapeutic effect to prostate cancer.In addition it has activated immune
The function of cell can enhance immunity of organisms and anti-aging, have important application value and extensive market prospects.
Lycopene is the unsaturated aliphatic alkene with 11 carbon-to-carbon conjugated double bonds and 2 unconjugated double bonds.Naturally
For lycopene in food material based on alltrans configuration, quantity accounts for 95% or more of lycopene total amount, is only on a small quantity
Cis-configuration (mainly 5- is suitable, 9- is suitable, the genial 15- cis-configuration of 13-)；In the organ, blood and tissue of mammal kind
For Lycopene based on various cis-isomers, All-cislycopene is soluble in cholic acid particle and chylomicron, be easier to after oral by
Absorption of human body, therefore its bioavailability is apparently higher than all-trans lycopene.
Lycopene is fat-soluble strong, and fusing point is 174 DEG C, is practically insoluble in water, and solubility in water only has about 0.002
μ g/ml, solubility lower limit absorption of the lycopene in gastrointestinal tract, causes oral administration biaavailability low.In addition, tomato red
Extremely unstable, oxidizable degradation and isomerization under the action of plain light, heat, oxygen, metal ion in air, so that its function be made to drop
Low or failure.Existing commercially available lycopene formulations are mainly the oil suspension loaded into soft capsule, do not solve lycopene
The low problem of solubility in the gastrointestinal tract.
Currently, the published oral solid drug composition patent application for increasing lycopene solubility includes:
(1) the granted patent CN 1125601C of Basf company disclose " pulverulent lycopene preparation, its preparation method and its answer
With ", it is related to the preparation method of the dispersible pulverulent lycopene preparation of water.
(2) the granted patent CN 1173637C of DSM N. V. is disclosed " preparation of finely divided pulverous carotenoid preparation ", preparation
Lycopene fine powder soluble easily in water.
(3) WO 03045167 of Israel Lycoret company application discloses " carotenoid formulation ".
(4) Chinese patent ZL 200610037859.5 discloses " beta-cyclodextrin and hydroxypropyl-β-cyclodextrin mixed inclusion
Composition of lycopene and preparation method thereof ", this method mix cyclodextrin encapsulated drug, increase lycopene solubility
For 14 μ g/ml.
(5) Chinese patent application CN 101439030 discloses a kind of " pharmaceutical composition and its preparation containing lycopene
Method ", this method prepares solid dispersions as carrier using PLURONICS F87, or they are prepared into ternary with cyclodextrin
Inclusion compound improves dissolution rate of the lycopene in solid pharmaceutical preparation.
(6) Chinese patent application CN 1485028 discloses " Lycopene drop pill ", with water-soluble base (PEG4000,
PEG6000, gelatin, stearic acid) dripping pill of oral solid dispersion has been made to improve its solubility in lycopene oleoresin.
Above-mentioned patent application has a general character although to increase lycopene solubility, but since lycopene is
A large amount of quick releases under one's belt easily cause lycopene is counter to be precipitated, so as to cause bioavilability since absorption area is small in stomach
Using still very low；On the other hand as there are production costs for the technique of the granted patent CN1125601C patent report of Basf company
The disadvantages of height, big industrialization difficulty.
Resveratrol (Resveratrol) belongs to non-flavonoids polyphenolic substance, and structure is similar to estrogen diethylstilbestrol
White crystalline powder, chemical name are (E) -5- [2- (4- hydroxyphenyl)-vinyl]-Resorcinol, molecular formula C14H12O3, point
Son amount 228.25, it is 256-257 DEG C of fusing point, fat-soluble strong, it is insoluble in water, it was reported that saturation solubility is about 30 μ g/ml in water,
It is soluble in methanol, ethyl alcohol, ethyl acetate, acetone and other organic solvent.Resveratrol be plant for resist environmental stimuli such as ultraviolet light,
Fungi, virus infection or mechanical damage and a kind of phytoalexin generated, it is primarily present in polygonum cuspidate, grape, peanut, mulberry
In 70 various plants such as mulberry, pine tree, the content in grape is especially abundant, has inoxidizability, anti-oxidizing activities, the protection heart
The multinomial healthcare function such as blood vessel, anticancer, anti-aging.Resveratrol is unstable to light, heat, oxygen, has cis-, trans- two kinds same point
The bioactivity of isomers, resveratrol transisomer is better than cis-isomer, the trans-resveratrol under ultraviolet light
Cis-isomer can be converted to.Oral resveratrol absorbs well, but since tachymetabolism and excretion lead to bioavilability
It is low, half-life short is eliminated, mainly generation II phase metabolic response, is two big relevant metabolism through liver and small intestine rapid metabolization
Object: resveratrol glucosiduronic acid and sulfuric acid resveratrol.It is inhaled the study found that duodenum and jejunum are that trans-resveratrol is oral
The main portions of receipts, the parenterally that multidrug resistance associated protein (Mrp-2) participates in trans-resveratrol are drained through journey, and outlet transports egg
White P- glycoprotein is not involved in the absorption and transport of trans-resveratrol.
Document and patent in relation to resveratrol and its glycoside compound are more, but the overwhelming majority is concentrated on extracting, preparation, be used
Way aspect is seldom related in terms of improving bioavilability and raising solubility, finds and research improves resveratrol water solubility, and
The absorption that it is improved in small intestine has very important significance.Chinese patent CN 100453071C discloses a kind of resveratrol
Oral multiphasic liposomes.Chinese patent CN 100493497C discloses a kind of resveratrol Solid Self-microemulsion preparation.Chinese patent
Application CN 1951369A discloses a kind of coated nanoliposomes of resveratrol.Chinese patent application CN 101317832A is disclosed
A kind of as made of resveratrol and carrier material wheat gliadin oral administration nano-drug administration system, using in carrier material
Bio-adhesive properties and high degree of dispersion characteristic improve resveratrol dissolution rate and degree, increase drug small intestine suction
It receives.Chinese public patent application CN 101292966A discloses a kind of resveratrol and its solid dispersions and preparation method thereof,
Using Poloxamer, high molecular weight polyethylene glycol as carrier, dispersion is prepared with solvent method and fusion method, it is water-soluble to improve drug.
Chinese granted patent CN 1220486C provide the hydroxypropyl-beta-cyclodextrin inclusion of resveratrol and its glucoside and derivative with
And preparation method, improve drug water solubility and stability.
Although above-mentioned patent application part is related to the method for improving resveratrol solubility, these inventions increase white
The degree of veratryl alcohol solubility remains unchanged very little, and there is also steady for the nanometer formulations such as liposome, Solid Self-microemulsion, Nanoliposome coated
It is qualitative it is poor, higher to auxiliary material and equipment requirement, high production cost, be difficult to the disadvantages of industrialized production.
Epiphysin (Melatonin, MT) also known as melatonin or epiphysin are mammal and the pineal body point of the mankind
A kind of neuro-endocrinology hormone with extensive physiology and pharmacological action secreted, have adjustment biological clock, tranquilizing soporific and
The physiological actions such as immunological regulation.Epiphysin is white crystalline powder, and chemical name is 5-methoxy-N-acetyltryptamine, molecular formula
C13H16N2O2, molecular weight 232.27,116-118 DEG C of fusing point, solubility belongs to amphipathicization less than 1mg/ml (25 DEG C) in water
Object is closed, Determination of oil-water partition coefficient Log P is 1.19, is slightly soluble in water, is soluble in hot water and propylene glycol, dissolves in hydrous ethanol, acid, alkali
In.Healthy volunteer take orally MT absolute bioavailability only 15% and individual difference it is big, it is also very unstable in the absorption of human body,
First pass effect is obvious, can there is 10-20 times of difference in Different Individual with the MT of dose.After oral MT, MT is through Passive diffusion
Absorbed into serum, only in conjunction with plasma albumin, Percentage bound about 33%, but its combination is very loose and unsaturated.Separately there is document report
Road epiphysin oral absorption has site specific, in absorption dose > ileum > duodenum=jejunum=knot of Rat-rectum
Intestines > stomach.Also some researches show that its bioavilability is related with dosage, Yeleswarown, Krishnaswamy, Melaughlin
Lee G etc. has studied the bioavilability of MT different way of administration.After rat oral gavage, availability 53.5%；Give dog stomach-filling
When MT 10mg/kg, availability is almost 100%, but as 1mg/kg, is then down to 16.9%.
Summary of the invention
One aspect of the present invention provides a kind of enteric solid preparation, contains selected from lycopene, resveratrol and takes off black
One of element or a variety of active ingredients and enteric solubility carrier, wherein the enteric solubility carrier and the active constituent are solid with enteric
Body dispersion is present in preparation.
In one embodiment, the active constituent is resveratrol, and the enteric solubility carrier is acetate succinate
Sour hydroxypropyl methyl cellulose (HPMCAS) and/or Hydroxypropyl Methylcellulose Phathalate (HPMCP).
In yet another embodiment, the active constituent is epiphysin, and the enteric solubility carrier is acetate succinate
Sour hydroxypropyl methyl cellulose (HPMCAS) and/or methacrylic acid/ethyl acrylate copolymer such as Eudragit L100-55
And/or Hydroxypropyl Methylcellulose Phathalate (HPMCP).
In yet another embodiment, the active constituent is lycopene, and the enteric solubility carrier is adjacent benzene two
Formic acid hydroxypropyl methyl cellulose (HPMCP).
On the other hand, the present invention provides the preparation method of the enteric solid preparation containing enteric solid dispersion,
Including the active constituent and enteric solubility carrier to be dissolved in solvent, solvent is dried and removed to obtain enteric solid dispersion.
In one embodiment, the preparation method of the enteric solid preparation includes by the active constituent and enteric
Property carrier mix after be heated to melting, then be freeze-dried or the obtained enteric solid dispersion of hot-melt extruded.
Another aspect, the present invention provide a kind of enteric solid preparation, contain selected from lycopene, resveratrol and take off black
One of element or a variety of active ingredients and enteric solubility carrier and water-solubility carrier, wherein the water-solubility carrier with it is described
Active constituent is present in preparation with water soluble solid dispersion, and is contained enteric solubility in the solid pharmaceutical preparation external sheath and carried
The enteric coat layer of body.
In one embodiment, the active constituent is lycopene, and the water-solubility carrier is Soluplus
And/or Pluronic F68 (Poloxamer), the enteric solubility carrier are acetate succinate hydroxypropyl first
Base cellulose (HPMCAS).
In yet another embodiment, the water soluble solid dispersion active constituent lycopene is in pH6.8 phosphate
Solubility in buffer is not less than 10 μ g/ml, preferably not less than 20 μ g/ml.
In yet another aspect, the present invention provides the preparation side of the enteric solid preparation containing water soluble solid dispersion
Method comprising the active constituent and water-solubility carrier are dissolved in solvent, dry and remove solvent to obtain water-soluble solid
Dispersion, and it is further enteric coated to resulting water-soluble solid dispersion.
In yet another embodiment, the preparation method includes mixing the active constituent and water-solubility carrier
After be heated to melting, be then freeze-dried or water-soluble solid dispersion be made in hot-melt extruded, and to resulting water solubility
Solid dispersions are further enteric coated.
In yet another embodiment, the enteric solid comprising enteric solid dispersion or water soluble solid dispersion
Surfactant, preferably Cremophor EL and/or Cremophor RH40 can also further be contained in preparation.
In a preferred embodiment, the active constituent gross weight and the weight ratio of the surfactant are 1: 2-
1∶4。
In yet another embodiment, the present invention provides the enteric solid system containing enteric solubility or water soluble solid dispersion
Agent also further can be selected from following ingredient: anthocyanidin, curcumin, lutein, beta carotene, Hu containing one or more
Radish element, pomegranate extract water-insoluble such as ellagic acid and ursolic acid, liposoluble vitamin such as vitamin A, vitamin D, vitamin K
And vitamin E.
In yet another aspect, the present invention also provides a kind of health compositions, contain enteric solid preparation as described above.
Detailed description of the invention
Without wishing to be bound to any theory, the present invention is mutually tied by using solid dispersions technique with positioning release principle
It closes, i.e., solves the problems, such as the slightly solubility of drug by using solid dispersions technique, while passing through the choosing to carrier material property
It selects, i.e., prepares solid dispersions using the enteric solubility carrier that could be dissolved in intestines or be first prepared into water-soluble solid dispersion,
Cladding enteric clothing film is carried out again to be discharged under one's belt to control drug or do not discharged on a small quantity.Since sorbent surface product is big in intestines, carry
Body or clothing film dissolve rapidly, and drug is largely discharged and absorbed rapidly, to improve bioavilability.
Enteric solid preparation according to the present invention, can be according to requiring containing selected from lycopene, white as active constituent
One of veratryl alcohol and epiphysin or a variety of active ingredients.
Wherein, lycopene molecule formula is C40H56, there is structure shown in following formula,
Lycopene of the invention includes the cis-trans-isomer of all lycopenes.
The chemical name of resveratrol is (E) -5- [2- (4- hydroxyphenyl)-vinyl]-Resorcinol, and molecular formula is
C14H12O3。
Epiphysin chemical name is 5-methoxy-N-acetyltryptamine, molecular formula C13H16N2O2。
It is available commercially for lycopene of the invention, resveratrol and epiphysin.
In addition to above-mentioned three kinds of active components, the enteric solid system provided by the invention comprising enteric or water soluble solid dispersion
Agent, also contain other one or more suitable active components, such as: anthocyanidin, curcumin, lutein, beta carotene,
Carrotene, pomegranate extract water-insoluble such as ellagic acid and ursolic acid and liposoluble vitamin such as vitamin A, vitamin D, dimension life
Plain K, vitamin E, preferably anthocyanidin, curcumin, lutein, beta carotene, ellagic acid and/or carrotene.
When forming enteric solid dispersion or enteric coating using enteric solubility carrier and the active constituent, the intestines
It is highly beneficial that solubleness carrier, which is discharged on a small quantity or do not discharged under one's belt for control active constituent,.And enteric solid disperses
The application of water soluble solid dispersion in body and enteric coating further makes active pharmaceutical ingredient in the big intestines of sorbent surface product
It is able to largely be discharged and absorbed.
In the present invention, enteric solubility carrier refers to a kind of water-soluble pH dependent form carrier, and dissolution has pH dependence, in human body
The carrier that could be dissolved in intestinal juice environment (about pH >=5.5), therefore could dissolve in human body intestinal juice environment is referred to as enteric solubility carrier.
It can be with to improve solubility, in the enteric solid preparation comprising enteric solid dispersion or water soluble solid dispersion
Further contain surfactant.Surfactant can both add in solid dispersions and also with other carrier auxiliary materials one
It rises and is added outside solid dispersions.Suitable surfactant is selected from one or more substances in the following group: dodecyl sulphur
Sour sodium, Pluronic F68 (Poloxamer), Tweens, spans, polyethylene glycols, polyoxyethylene caster
Oils such as Cremophor EL, Crodaret class such as Cremophor 40, preferably Cremophor EL and/or
Cremophor 40.The additive amount of surface-active can be adjusted as needed, and a preferred proportional region is the active constituent
Weight and the weight ratio of the surfactant are 1: 2-1: 4.
An embodiment according to the present invention, in enteric solid preparation containing enteric solubility carrier with it is one or more described
The enteric solid dispersion that active constituent is formed.
As the enteric solubility carrier for the enteric solid dispersion, a preferred embodiment is the enteric
Property carrier be it is one or more selected from the enteric polymer in the following group: Cellacefate (CAP), acetic acid are inclined
Benzenetricarboxylic acid cellulose (CAT), cellulose acetate succinate (CAS), methyl cellulose, phthalic acid ethyl hydroxyl
Methylcellulose, Hydroxypropyl Methylcellulose Phathalate (HPMCP), hydroxypropylmethylcellulose acetate succinate
(HPMCAS), acetic acid maleic acid hydroxypropyl methyl cellulose, trimellitic acid hydroxypropyl methyl cellulose (HPMCT), carboxymethyl second
Base cellulose, poly- butyric acid polyvinyl phthalic, polyvinyl acetate alcohol phthalic acid ester (PVAP), methacrylic acid/the third
Olefin(e) acid methacrylate copolymers and methacrylic acid/methylmethacrylate copolymer.More preferable enteric solubility carrier be HPMCAS and/or
Methacrylic acid/ethyl acrylate copolymer such as Eudragit L100-55 and/or HPMCP.
It is not particularly limited for the enteric solubility carrier of enteric solid dispersion preparation and the ratio of active constituent, Ke Yigen
It is added according to the custom requirements of this field.Preferably, the active constituent total weight and the weight ratio of the enteric solubility carrier are 1:
1-1∶20。
From the foregoing discussion, it should be apparent that the enteric solid preparation comprising enteric solid dispersion of the invention can make containing work
Property ingredient is discharged on a small quantity under one's belt or is not discharged.Preferably, 45 points in 0.1M hydrochloric acid of the active constituent resveratrol
Clock dissolution rate is not more than 20%, preferably no greater than 10%, and 60 minutes dissolution rates in 6.8 phosphate buffer of pH are not respectively low
In 75%, preferably not less than 80%；60 minute dissolution rates of the epiphysin in 0.1M hydrochloric acid are not more than 25%, preferably no greater than
15%, 30 minutes dissolution rates in 6.8 phosphate buffer of pH are respectively not less than 80%, preferably not less than 90%.In the present invention
In, the enteric solid preparation Dissolution experiments comprising enteric solid dispersion are according to Chinese Pharmacopoeia annex XD drug release determination
Second method (being used for enteric coated preparations) measurement, specific test method is referring to test example 1-3.
As needed, the enteric solid preparation comprising enteric solid dispersion of the invention can also further include other
Pharmaceutic adjuvant is to be made the dosage forms such as tablet, capsule, granule, powder or pellet.Wherein, other pharmaceutic adjuvants include
One of diluent, disintegrating agent, lubricant, antioxidant are a variety of.The diluent can be microcrystalline cellulose, form sediment
One of powder, pregelatinized starch, lactose, mannitol, calcium monohydrogen phosphate are a variety of；Disintegrating agent, can be low substituted cellulose,
One of croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone are a variety of；Lubricant, can
To be one of magnesium stearate, talcum powder, superfine silica gel powder, stearic acid, hydrogenated vegetable oil or a variety of；And antioxidant, it can be with
Be ascorbic acid, sodium ascorbate, vitamine C palmitate, vitamin E, in VE succinic acid macrogol ester (TPGS)
It is one or more.
Another embodiment according to the present invention, in enteric solid preparation containing selected from lycopene, resveratrol and
One of epiphysin or a variety of active ingredients and enteric solubility carrier and water-solubility carrier, wherein the water-solubility carrier with
The active constituent is present in the solid pharmaceutical preparation with water soluble solid dispersion, and is had in the solid pharmaceutical preparation external sheath
Enteric coat layer containing enteric solubility carrier.
Wherein, the water-solubility carrier refers to the carrier that can be dissolved in water, it includes that non-pH-dependent and pH are relied on
Two kinds of type.Wherein the dissolution of non-pH-dependent carrier is not influenced by solution ph in environment, the equal energy in any pH value solution
Dissolution；The dissolution of pH dependent form carrier depends on the pH value of solution in environment, when the pH value of solution is greater than the dissolution pH value, carries
Body could dissolve.Water-soluble solid dispersion is first made again in another enteric solid preparation, that is, active constituent involved in the present invention
The preferred water-soluble non-pH of water-solubility carrier in the enteric coated formulation that the solid pharmaceutical preparation external sheath contains enteric solubility carrier
Dependent form carrier.
In one preferred embodiment, the water solubility non-pH-dependent carrier is one or more in the following group
Substance: it is methylcellulose, hypromellose (HPMC), Pluronic F68 (Poloxamer), poly-
Vinylpyrrolidone (PVP), polyoxyethylene (PEO), copolyvidone (Copovidone), polyvinyl alcohol (PVA), polyethylene glycol
Class, Soluplus, carbohydrate, mannitol and xylitol, more preferable Poloxamer and/or Soluplus.
The ratio of the water-solubility carrier and active constituent is not particularly limited, and can according to need adjustment.Preferably,
The active constituent gross weight and the weight ratio of the water-solubility carrier are 1: 1-1: 20.
As needed, the enteric solid preparation may also include other pharmaceutic adjuvants so that enteric coated enteric is made
The finished products such as piece, capsule, granule, powder or pellet are for oral administration.Wherein, other pharmaceutic adjuvants include diluent,
One of disintegrating agent, lubricant, antioxidant are a variety of.The diluent can be microcrystalline cellulose, starch, pre- glue
Change one of starch, lactose, mannitol, calcium monohydrogen phosphate or a variety of；Disintegrating agent can be low substituted cellulose, crosslinking carboxylic
One of sodium carboxymethylcellulose pyce, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone are a variety of；Lubricant can be hard
One of fatty acid magnesium, talcum powder, superfine silica gel powder, stearic acid, hydrogenated vegetable oil are a variety of；And antioxidant, it can be anti-bad
One of hematic acid, sodium ascorbate, vitamine C palmitate, vitamin E, VE succinic acid macrogol ester (TPGS)
Or it is a variety of.
It is preferably one or more in the following group for the enteric solubility carrier contained in the enteric coat layer
Enteric polymer: Cellacefate (CAP), Cellulose acetotrimellitate (CAT), acetate succinate are fine
Tie up element (CAS), methyl cellulose, phthalic acid ethyl hydroxymethyl cellulose, phthalic acid hydroxypropyl first
Base cellulose (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), acetic acid maleic acid hydroxypropyl methyl fiber
Element, gathers trimellitic acid hydroxypropyl methyl cellulose (HPMCT), carboxymethylethylcellulose, poly- butyric acid polyvinyl phthalic
Vinyl acetate alcohol phthalic acid ester (PVAP), methacrylic acid/ethyl acrylate copolymer and methacrylic acid/metering system
Sour methyl terpolymer, more preferable HPMCAS.
In the enteric coat layer can also further containing selected from one of plasticizer, antiplastering aid and stabilizer or
Variety carrier.Wherein, plasticizer can be selected from one or more substances in the following group: diethyl phthalate (DEP), the last of the ten Heavenly stems two
Dibutyl phthalate (DBS), tributyl citrate (TBC), triethyl citrate (TEC), castor oil, triacetyl glycerine (TA), third
Glycol, glycerol, polyethylene glycol, cochin oil, oleic acid, alkenyl succinic anhydride and polylactic acid (PLA), preferably TEC；Antiplastering aid can
Selected from one or more substances in the following group: talcum powder, superfine silica gel powder, glycerin monostearate, preferably talc powder and micro mist
Silica gel；Stabilizer includes lauryl sodium sulfate.
Ratio containing various composition in the enteric coat layer is not particularly limited, can according to need tune
It is whole.Preferably, the enteric solubility carrier is the 60-90 weight % of the enteric coat layer solid content；The plasticizer is
The 10-30 weight % of the enteric coat layer solid content；The antiplastering aid is the 10-30 weight of the enteric coat layer solid content
Measure %；The stabilizer is the 0.5-5 weight % of the enteric coat layer solid content weight.More preferably the enteric solubility carries
Body is the 70-80 weight % of the enteric coat layer solid content；The plasticizer is the 10- of the enteric coat layer solid content
15 weight %；The antiplastering aid is the 15-20 weight % of the enteric coat layer solid content；The stabilizer is the intestines
The 3-5 weight % of molten coatings solid content.
Relative to the ingredient weight coated in coatings, preferably the enteric coating layer weight is 10-50 weight %,
More preferably 15-25 weight %.
The side for commonly preparing solid dispersions can be used in the preparation method of water-soluble/enteric solid dispersion of the invention
Method, including fusion method, solvent method, solvent-fusion method, polishing, solvent-freeze-drying, solvent-spray drying process and hot melt
Extrusion molding etc., for details, reference can be made to Chemical Industry Press to publish, the 1st edition the 26-29 pages of " novel pharmaceutical formulation " of Zhu Shengshan chief editor.
As a preferred embodiment, the present invention provides a kind of enteric solid preparations, make containing lycopene
For active constituent, enteric solubility carrier and/or water-solubility carrier；Wherein the enteric solubility carrier and lycopene are with enteric solid point
Dispersion is present in preparation or the water-solubility carrier exists with the lycopene with water soluble solid dispersion
Contain the enteric coat layer of enteric solubility carrier in the solid pharmaceutical preparation, and in the solid pharmaceutical preparation external sheath.The enteric solid
Preparation can be improved the water solubility and stability of lycopene, and drug is made to discharge or not discharged on a small quantity in stomach, and big in enteron aisle
Amount release, increases lycopene bioavilability.
In a presently preferred embodiment, except there is following specified otherwise, it is applicable in the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein the enteric solubility carrier and lycopene are with enteric
When solid dispersions form is present in preparation, preferred enteric solubility carrier is HPMCP.
According to the enteric solid preparation of this preferred embodiment, when the wherein water-solubility carrier and the lycopene with
Water soluble solid dispersion is present in the solid pharmaceutical preparation, and has in the solid pharmaceutical preparation external sheath containing enteric solubility carrier
Enteric coat layer when, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferable Poloxamer, preferably
Enteric solubility carrier be HPMCAS, more preferable HPMCAS AS-LF.
To improve solubility, surfactant can be added in lycopene solid enteric coated preparations.Suitable surface-active
Agent includes lauryl sodium sulfate, Pluronic F68 (Poloxamer), Tweens, spans, poly- second two
Alcohols, Emulsifier EL-60 class such as Cremophor EL, Crodaret class such as Cremophor 40 or its group
It closes, preferably Cremophor EL and/or Cremophor 40.The additive amount of surface-active can be with according to needing to adjust, one preferably
Proportional region be that the weight ratio of the active constituent weight and the surfactant is 1: 2-1: 4.
Preferably, the water soluble solid dispersion active constituent lycopene is after adding surfactant in pH 6.8
Solubility in phosphate buffer is not less than 10 μ g/ml, preferably not less than 20 μ g/ml.
According to the enteric solid preparation of this preferred embodiment, lycopene is water-soluble or enteric solid dispersion in, kind
Lycopene and the enteric solubility or the weight ratio of water-solubility carrier are preferably 1: 1-1: 20, and more preferable 1: 8-1: 16.
Lycopene belongs to aliphatic olefin, have strong reducing property, oxidizable degradation, in order to improve preparation stability,
A certain amount of antioxidant, such as ascorbic acid, sodium ascorbate, vitamine C palmitate, vitamin are preferably added in prescription
E, one of VE succinic acid macrogol ester (TPGS) or a variety of.
Lycopene water solubility/the enteric solid dispersion can be mixed with other pharmaceutic adjuvants, further processing system
It is standby at tablet, capsule, granule, powder, pellet or enteric coated enteric coatel tablets, capsule, granule, powder or pellet etc. at
Product are for oral administration, the preferred 1mg-20mg of preparation specification.
Preparation method preferred solvent-spray drying process of the lycopene solid dispersions of this preferred embodiment.Due to
The fusing point of lycopene is high, is 174 DEG C, and unstable, carrier easily occurs when preparing solid dispersions with hot-melt extruded method
It decomposes and signs of degradation occurs for lycopene, therefore prepare lycopene solid dispersions and generally preferably use solvent-dry by spraying
Dry method.
As a specific embodiment, solvent-spray drying process can choose enteric or water-solubility carrier auxiliary material and/or
Surfactant and lycopene, are added into dissolvable above-mentioned substance and in the inert organic solvent of above-mentioned substance, and such as two
Chloromethanes or ethyl acetate.Then, it stirs, dissolution, organic solvent is removed using spray drying process, it is dry that vacuum can be set if necessary
10-30h is further dried in dry case to get the water solubility/enteric solubility carrier solids dispersion of the present embodiment.
For obtained water-solubility carrier solid dispersions, further to its enteric coating, to obtain enteric solid system
Agent.
As another preferred embodiment, the present invention provides a kind of enteric solid preparations, make containing resveratrol
For active constituent, enteric solubility carrier and/or water-solubility carrier；Wherein the enteric solubility carrier and resveratrol are with enteric solid point
Dispersion is present in preparation or the water-solubility carrier and resveratrol with water soluble solid dispersion are present in this
In solid pharmaceutical preparation, and there is the enteric coat layer containing enteric solubility carrier in the solid pharmaceutical preparation external sheath.The solid pharmaceutical preparation energy
The water solubility and stability for enough improving resveratrol, make drug discharge or not discharged on a small quantity in stomach, and largely discharge in enteron aisle,
Increase the bioavilability of resveratrol.
In a presently preferred embodiment, except there is following specified otherwise, it is applicable in the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein the enteric solubility carrier and resveratrol are with enteric
When solid dispersions form is present in preparation, preferred enteric solubility carrier is HPMCAS and/or HPMCP.
According to the enteric solid preparation of this preferred embodiment, when the wherein water-solubility carrier and resveratrol are with water-soluble
Solid dispersions form is present in the solid pharmaceutical preparation, and has the intestines containing enteric solubility carrier in the solid pharmaceutical preparation external sheath
When molten coatings, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferable Poloxamer, preferred intestines
Solubleness carrier is HPMCAS, more preferable HPMCAS AS-LF.
According to the enteric solid preparation of this preferred embodiment, resveratrol is water-soluble or enteric solid dispersion in white Chenopodiaceae
Reed alcohol and the enteric solubility or the weight ratio of water-solubility carrier are preferably 1: 1-1: 20, and more preferable 1: 2-1: 8.
Resveratrol solid dispersions are mixed with other auxiliary materials, can be further processed and are prepared into tablet, capsule, particle
The finished products such as agent, powder, pellet or enteric coated enteric coatel tablets, capsule, granule, powder or pellet are for oral administration, preparation rule
Lattice 20mg-500mg.
Preparation method preferred solvent-the spray drying process or hot melt of the resveratrol solid dispersions of this preferred embodiment
Extrusion molding.
As a specific embodiment, solvent-spray drying process can choose enteric or water-solubility carrier auxiliary material and/or
Surfactant and resveratrol, are added into dissolvable above-mentioned substance and in the inert organic solvent of above-mentioned substance, and such as two
Chloromethanes or ethyl acetate.Then it stirs, dissolves, organic solvent is removed using spray drying process, it is dry that vacuum can be set if necessary
10-30h is further dried in dry case to get the water solubility/enteric solubility carrier solids dispersion of the present embodiment.
As another specific embodiment, hot-melt extruded method is to mix drug with carrier to be added in hot-melt extruded machine,
It is heated that drug and carrier is made to be rapidly reached molten condition, then the mixing through screw mixes element and shearing elements, shearing and squeeze
Pressure exports material, disperses drug granule more uniformly.
As another preferred embodiment, the present invention provides a kind of enteric solid preparations, contain epiphysin conduct
Active constituent, enteric solubility carrier and/or water-solubility carrier；Wherein the enteric solubility carrier and epiphysin are with enteric solid dispersion
Form is present in preparation or the water-solubility carrier and epiphysin with water soluble solid dispersion are present in the solid system
In agent, and there is the enteric coat layer containing enteric solubility carrier in the solid pharmaceutical preparation external sheath.
In a presently preferred embodiment, except there is following specified otherwise, it is applicable in the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein the enteric solubility carrier and epiphysin are solid with enteric
When body dispersion is present in preparation, preferred enteric solubility carrier be HPMCAS, Eudragit L100-55 and/or
HPMCP。
According to the enteric solid preparation of this preferred embodiment, when the wherein water-solubility carrier and the epiphysin are with water
Molten solid dispersions form is present in the solid pharmaceutical preparation, and has in the solid pharmaceutical preparation external sheath containing enteric solubility carrier
When enteric coat layer, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferable Poloxamer, preferably
Enteric solubility carrier is HPMCAS.
According to the enteric solid preparation of this preferred embodiment, epiphysin is water-soluble or enteric solid dispersion in, take off black
The plain weight ratio with the enteric solubility or water-solubility carrier is preferably 1: 1-1: 20, and more preferable 1: 2-1: 10.
Epiphysin solid dispersions of the invention are mixed with other auxiliary materials, can be further processed be prepared into tablet, capsule,
The finished products such as granule, powder, pellet or enteric coated enteric coatel tablets, capsule, granule, powder or pellet are for oral administration, control
Epiphysin processed mainly discharges in small intestine, increases the oral absorption of epiphysin, improves bioavilability.Preparation specification 1mg-
10mg。
Preparation method preferred solvent-the spray drying process or hot melt of the epiphysin solid dispersions of this preferred embodiment are squeezed
Method out.Specific method can be found in the preparation method of above-mentioned resveratrol solid dispersions.
It is characteristic of the invention that realizing solubilising and the regulation of release performance of insoluble drug with simple method.Using
Enteric polymer makees the enteric solid dispersion of carrier preparation or water-solubility carrier prepares water soluble solid dispersion and further wraps
Enteric coating is present in drug in solid dispersions with amorphous state or/and molecular state, while can have enteric spy again
Sign.Preparation process is simple, high degree of automation, time-saving and efficiency, be it is a kind of can industrialized production technology.
In addition, using whole process solvent-free participation when hot-melt extruded method, therefore no solvent residue problem and solvent seasoning
Process.Torching mark and traditional fusion method are all that solid dispersions are prepared in the case where material reaches molten condition,
But the former passes through the organic assembling of screw mixes element and shearing elements, realizes strong mixing, shearing and squeezing action
Collaboration, makes drug more evenly, closely disperse in the carrier, to improve the dissolution rate of drug to a greater degree.By preferably carrying
Body, make drug with amorphous state dispersion in the carrier or molecular state dissolution in the carrier.
Specific embodiment
The present invention is further illustrated by the following examples, but is not intended to limit the invention.
Embodiment 1-1
It is each to weigh HPMCAS AS-LF, HPMCP HP-55, Kollidone VA64, Poloxamer188, Soluplus
10g is dissolved in respectively in 1000g methylene chloride, then is separately added into 0.05g vitamin C to above-mentioned solution and is stirred to whole dissolutions, so
After be separately added into lycopene (production of Changsha Hui Rui Biotechnology Co., Ltd) 1g, form uniform solution.With Buchi mini
Spray dryer B-290 spray drying removes organic solvent and obtains lycopene solid dispersions, in spray-drying process, object
Material temperature degree is controlled at 50-55 DEG C.
Embodiment 1-2
Soluplus 20g, 16g are weighed respectively to be dissolved in respectively in 1000g methylene chloride, then are separately added into above-mentioned solution
0.05g vitamin C is stirred to whole dissolutions, is then respectively adding lycopene (production of Changsha Hui Rui Biotechnology Co., Ltd)
1g forms uniform solution.Removing organic solvent, which is spray-dried, with Buchi mini spray dryer B-290 obtains tomato red
Plain solid dispersions, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Embodiment 1-3
Each 4g of Cremophor RH40, Cremophor EL is weighed, is dissolved in being tieed up containing 16g Soluplus, 0.05g respectively
In the 1000g dichloromethane solution of raw element C, then to above-mentioned solution it is separately added into 1g lycopene (favour auspicious biotechnology in Changsha has
The production of limit company), stirring to whole dissolutions.It is spray-dried with Buchi mini spray dryer B-290 and removes organic solvent
Obtain lycopene solid dispersions, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Embodiment 1-4
Each 8g of HPMCP HP-55, Soluplus is weighed, is dissolved in respectively containing 0.05g vitamin C, 2g Cremophor
In the 1000g dichloromethane solution of RH40, then to above-mentioned solution it is separately added into 1g lycopene (favour auspicious biotechnology in Changsha is limited
Company's production), stirring to whole dissolutions.Removing organic solvent is spray-dried with Buchi mini spray dryer B-290 to obtain
To lycopene solid dispersions, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Embodiment 2-1
Succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) 10g and 15g is taken to be dissolved in vitamin C containing 1g respectively
2 parts of acetone solns in, formed uniform solution；5g resveratrol is respectively weighed respectively to be dissolved in above-mentioned solution, uses Buchi
It is resveratrol that mini spray dryer B-290 spray drying, which removes organic solvent and respectively obtains white powder: HPMCAS
The enteric solid dispersion that AS-LF is 1: 2 and 1: 3, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the enteric solid dispersion in this example appropriate respectively, by weight resveratrol: microcrystalline cellulose: low substitution hydroxyl
Propyl cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai
It and pharmaceutical machine Co., Ltd).
Embodiment 2-2
Take succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) 15g, resveratrol 5g, vitamin C palm
Acid esters 1g, is ground, and puts into parallel dual-screw extruding machine (Thermo Fischer Scient Inc. MiniLab) loading hopper, spiral shell
Bar squeezes out zone temperatures and is pre-heated to 230 DEG C, and screw speed 30rpm, material is squeezed out by head die hole, and extrudate room temperature is cold
But, 180 μm of aperture sieves are smashed it through up to enteric solid dispersion.
Take the enteric solid dispersion in this example appropriate, by weight resveratrol: microcrystalline cellulose: low substituted hydroxy-propyl
Cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and
Pharmaceutical machine Co., Ltd).
Embodiment 2-3
Succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) 25g and 40g is taken to be dissolved in 1g respectively containing vitamin C
2 parts of acetone solns in, formed uniform solution；It weighs 5g resveratrol respectively to be dissolved in above-mentioned solution, with Buchi mini
It is resveratrol that spray dryer B-290 spray drying, which removes organic solvent and respectively obtains white powder: HPMCAS AS-
The enteric solid dispersion that LF is 1: 5 and 1: 8, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the enteric solid dispersion in this example appropriate respectively, by weight resveratrol: microcrystalline cellulose: low substitution hydroxyl
Propyl cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai
It and pharmaceutical machine Co., Ltd).
Embodiment 2-4
Hydroxypropyl methylcellulose phthalate HP-55 (HPMCP HP-55) 25g and 40g is taken, 1g is dissolved in respectively and contains
In ascorbic 2 parts of acetone solns, uniform solution is formed；5g resveratrol is weighed respectively to be dissolved in above-mentioned solution, is used
Buchi mini spray dryer B-290 spray drying removes organic solvent and respectively obtains white powder i.e. resveratrol:
The enteric solid dispersion that HPMCP HP-55 is 1: 5 and 1: 8, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the enteric solid dispersion in this example appropriate respectively, by weight resveratrol: microcrystalline cellulose: low substitution hydroxyl
Propyl cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai
It and pharmaceutical machine Co., Ltd).
Embodiment 2-5
It takes that 40g Poloxamer 188,1g vitamin C is fully dispersed, is dissolved in acetone, forms uniform solution, weigh
5g resveratrol is dissolved in above-mentioned solution, is spray-dried with Buchi mini spray dryer B-290 and is removed organic solvent
Obtaining white powder is water soluble solid dispersion, and in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the water-soluble non-pH-dependent solid dispersions in this example appropriate, by weight resveratrol: microcrystalline cellulose:
Low-substituted hydroxypropyl cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine
ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), (OHARA test-type is coated with the enteric coating solution of the AS-LF containing HPMCAS
High-efficiency coating machine), coating weight gain is 15 weight %, obtains enteric coated tablet.Wherein HPMCAS AS-LF in enteric coating solution,
Triethyl citrate (TEC), talcum powder, lauryl sodium sulfate account for respectively Coating Solution solid content weight 72%, 11%,
15%, 2%.
Embodiment 2-6
It takes that 40g HPMC E5,1g vitamin C is fully dispersed, is dissolved in acetone, forms uniform solution, weigh the white Chenopodiaceae of 5g
Reed alcohol is dissolved in above-mentioned solution, is obtained with Buchi mini spray dryer B-290 spray drying removing organic solvent white
Color powder is water soluble solid dispersion, and in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the water-soluble non-pH-dependent solid dispersions in this example appropriate, by weight resveratrol: microcrystalline cellulose:
Low-substituted hydroxypropyl cellulose: magnesium stearate=5: 20: 1: 0.5 ratio is uniformly mixed, tabletted (rotary tablet machine
ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), (OHARA test-type is coated with the enteric coating solution of the AS-LF containing HPMCAS
High-efficiency coating machine), coating weight gain is 15 weight %, obtains enteric coated tablet.Wherein HPMCAS AS-LF in enteric coating solution,
TEC, talcum powder, lauryl sodium sulfate account for 72%, 11%, 15%, the 2% of Coating Solution solid content weight respectively.
Embodiment 3-1
Take that 10g succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) is fully dispersed, is dissolved in acetone, shape
It at uniform solution, weighs 5g epiphysin and is dissolved in above-mentioned solution, done by spraying with Buchi mini spray dryer B-290
It is enteric solid dispersion that dry removing organic solvent, which obtains white powder, and in spray-drying process, temperature of charge is controlled in 50-
55℃。
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-2
Take that 15g succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) is fully dispersed, is dissolved in acetone, shape
It at uniform solution, weighs 5g epiphysin and is dissolved in above-mentioned solution, done by spraying with Buchi mini spray dryer B-290
It is enteric solid dispersion that dry removing organic solvent, which obtains white powder, and in spray-drying process, temperature of charge is controlled in 50-
55℃。
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-3
Take that 25g succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) is fully dispersed, is dissolved in acetone, shape
It at uniform solution, weighs 5g epiphysin and is dissolved in above-mentioned solution, done by spraying with Buchi mini spray dryer B-290
It is enteric solid dispersion that dry removing organic solvent, which obtains white powder, and in spray-drying process, temperature of charge is controlled in 50-
55℃。
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-4
25g succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF), 5g epiphysin are taken, is ground, is put into
Into parallel dual-screw extruding machine (Thermo Fischer Scient Inc. MiniLab) loading hopper, Screw Extrusion zone temperatures are warmed-up
To 150 DEG C, screw speed 30rpm, material is squeezed out by head die hole with transparent bar, and access is in stainless steel disc, room temperature
It is cooling, 180 μm of aperture sieves are smashed it through up to solid dispersions.
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-5
Take that 50g succinic acid hydroxypropyl methylcellulose (HPMCAS AS-LF) is fully dispersed, is dissolved in acetone, shape
It at uniform solution, weighs 5g epiphysin and is dissolved in above-mentioned solution, done by spraying with Buchi mini spray dryer B-290
It is enteric solid dispersion that dry removing organic solvent, which obtains white powder, and in spray-drying process, temperature of charge is controlled in 50-
55℃。
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-6
It takes that 25g Eudragit L100-55 is fully dispersed, is dissolved in acetone, forms uniform solution, weigh 5g epiphysin
It is dissolved in above-mentioned solution, is spray-dried removing organic solvent with Buchi mini spray dryer B-290 and obtains white powder
End is enteric solid dispersion, and in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-7
Take that 25g hydroxypropyl methylcellulose phthalate HP-55 (HPMCP HP-55) is fully dispersed, is dissolved in third
In ketone, uniform solution is formed, 5g epiphysin is weighed and is dissolved in above-mentioned solution, with Buchi mini spray dryer B-290
It is enteric solid dispersion that spray drying, which removes organic solvent and obtains white powder, in spray-drying process, temperature of charge control
System is at 50-55 DEG C.
Take the enteric solid dispersion in this example appropriate, by weight epiphysin: microcrystalline cellulose: low substituted hydroxy-propyl is fine
Dimension element: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5, Shanghai day and pharmacy
Machinery Co., Ltd.).
Embodiment 3-8
Take 25g PEG4000 dispersion, be dissolved in acetone, formed uniform solution, weigh 5g epiphysin be dissolved in it is above-mentioned molten
In liquid, being spray-dried removing organic solvent to obtain white powder with Buchi mini spray dryer B-290 is water solubility
Non-pH-dependent solid dispersions, in spray-drying process, temperature of charge is controlled at 50-55 DEG C.
Take the water-soluble non-pH-dependent solid dispersions in this example appropriate, by weight epiphysin: microcrystalline cellulose: low
Replace hydroxypropyl cellulose: magnesium stearate=5: 20: 1: 1 ratio is uniformly mixed, tabletted (rotary tablet machine ZP-5,
Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), with the enteric coating solution coating of the AS-LF containing HPMCAS, (OHARA test-type is efficient
Seed-coating machine), coating weight gain is 15 weight %, obtains enteric coated tablet.Wherein HPMCAS AS-LF in enteric coating solution, TEC,
Talcum powder, lauryl sodium sulfate account for 72%, 11%, 15%, the 2% of Coating Solution solid content weight respectively.
Test example 1
Since lycopene does not almost dissolve in 0.1M hydrochloric acid, water, 6.8 phosphate-buffered liquid medium of pH, measure first
The water solubility of its solid dispersions.
Experimental method is as follows: excessive lycopene solid dispersions being taken to be placed in 6.8 phosphoric acid of 10ml 0.1M hydrochloric acid or pH
Salt buffer is filtered, subsequent filtrate HPLC (Agilent in 37 DEG C of water bath sonicator 30min with 0.45 μm of aperture nylon leaching film filter
1200 high performance liquid chromatographs) sample introduction measurement.
Content and solubility test method use high performance liquid chromatography, and mobile phase is 100% acetonitrile, and Detection wavelength is
472nm, flow velocity 2.0ml/min, 30 DEG C of column temperature, chromatographic column is C18Column (150 × 4.6mm, 5 μm), when lycopene chromatography retains
Between be 13min.It is calculated using external standard method.Measurement result is shown in Table 1-1.
Solubility (HPLC method of the lycopene in pH6.8 phosphate buffer in table 1-1 different enteric solid preparations
Measurement)
By the solubility results of table 1-1 it is found that solid dispersions technique has solubilization to lycopene, due to carrier
Difference, solubilizing effect is also different, and HPMCAS AS-LF is poor to the solubilization of lycopene, and carrier S oluplus,
The solubilizing effect of HPMCP HP-55 is preferable；Solubilizing effect becomes apparent from after surfactant is added.
2 solid dispersions samples for taking embodiment 1-4 in table 1-1 respectively, by lycopene: microcrystalline cellulose: low to take
For hydroxypropyl cellulose: magnesium stearate=5: 2: 1: 0.5 ratio mixed pressuring plate (rotary tablet machine ZP-5, Shanghai day and system
Medicine Machinery Co., Ltd.), it is coated (OHARA test-type high-efficiency coating machine) with the enteric coating solution of the AS-LF containing HPMCAS, packet
Clothing weight gain is 15 weight %, obtains sample 1 and sample 2, dissolution rate to be measured.Wherein HPMCAS AS-LF in enteric coating solution,
TEC, talcum powder, lauryl sodium sulfate account for 72%, 11%, 15%, the 2% of Coating Solution solid content weight respectively.
Process in leaching of the present invention using dissolution in vitro experiment aids drug in gastrointestinal tract, experimental method are as follows: ginseng
According to 2005 editions the second methods of XD drug release determination of Chinese Pharmacopoeia annex (being used for enteric coated preparations) measurement, dissolution medium is 750ml 0.1M
Hydrochloric acid, revolving speed 100r/min, temperature are 37 DEG C ± 0.5 DEG C, and 5ml is sampled when dissolving out 45 minutes, and filtering discards 1ml initial filter
Liquid takes subsequent filtrate, and HPLC method sample introduction measures the dissolution rate (1200 high performance liquid chromatograph of Agilent) in 0.1M hydrochloric acid, and fast
The speed supplement isometric dissolution medium of equality of temperature, while 250ml 0.2M sodium radio-phosphate,P-32 solution is added, pH is adjusted with 2M sodium hydroxide solution
To 6.8 ± 0.05,6.8 phosphate buffer of equality of temperature same volume pH is supplemented in 60min point in time sampling 5ml and rapidly, and measurement exists
The dissolution rate of 6.8 phosphate buffer of pH.It the results are shown in Table 1-2.
The accumulation dissolution rate of table 1-2 lycopene enteric solid preparation indicates percentage composition (%) measurement result table
Test example 2
Process in leaching of the present invention using dissolution in vitro experiment simulation resveratrol in gastrointestinal tract, experimental method is such as
Under: referring to the second method of Chinese Pharmacopoeia annex XD drug release determination (being used for enteric coated preparations) measurement, dissolution medium is 750ml 0.1M
Hydrochloric acid, revolving speed 100r/min, temperature are 37 DEG C ± 0.5 DEG C, and 5ml is sampled when dissolving out 45 minutes, and filtering discards 1ml initial filter
Liquid takes subsequent filtrate, and HPLC method sample introduction measures the dissolution rate (1200 high performance liquid chromatograph of Agilent) in 0.1M hydrochloric acid, and fast
The speed supplement isometric dissolution medium of equality of temperature, while 250ml 0.2M sodium radio-phosphate,P-32 solution is added, pH is adjusted with 2M sodium hydroxide solution
To 6.8 ± 0.05,6.8 phosphate buffer of equality of temperature same volume pH is supplemented respectively at 0.5h, 1h point in time sampling 5ml and rapidly,
Measure the dissolution rate in pH6.8 phosphate buffer.It the results are shown in Table 2-1.
The content and dissolution determination method of resveratrol use high performance liquid chromatography, and mobile phase is 27/73 (v/v) second
Nitrile/water, Detection wavelength 303nm, flow velocity 1.0ml/min, 30 DEG C of column temperature, chromatographic column is C18Column (250 × 4.6mm, 5 μm) is white
Veratryl alcohol chromatographic retention is 10.356min.It is calculated using external standard method.
The accumulation dissolution rate of table 2-1 resveratrol enteric solid preparation indicates percentage composition (%) measurement result table
From the dissolution results of table 2-1: different preparation method, that is, spray drying processes under same vehicle and same ratio
It prepares that solubilizing effect is similar to hot melt, such as sees the dissolution result of embodiment 2-1 and 2-2；When carrier be HPMCAS AS-LF,
When HPMCP HP-55, Poloxamer 188, the enteric solid preparation of resveratrol solubilized can control resveratrol again and exist
It is discharged on a small quantity in acid；Drug can be properly arrived at dialogue black false hellebore 1: 2 to 1: 8 with enteric carrier HPMCAS AS-LF weight ratio
The effect of alcohol solubilising；HPMC E5 has solubilization as carrier but solubilizing effect is unobvious.
The related substance-measuring result table of study on the stability of table 2-2 resveratrol enteric solid preparation
Investigating data by table 2-2 can be seen that, resveratrol and carrier HPMCAS AS-LF, HPMCP HP-55,
Enteric solid preparation stability prepared by Poloxamer 188 is good, at the same also indicate that resveratrol and carrier HPMCAS AS-LF,
HPMCP HP-55,188 Poloxamer compatibility are fine.
Test example 3
Dissolution rate of the present invention using dissolution in vitro experiment aids drug in gastrointestinal tract, experimental method are as follows:
Process in leaching of the present invention using dissolution in vitro experiment simulation epiphysin in gastrointestinal tract, experimental method are as follows:
Referring to the second method of Chinese Pharmacopoeia annex XD drug release determination (being used for enteric coated preparations) measurement, dissolution medium is 750ml 0.1M salt
Acid, revolving speed 100r/min, temperature are 37 DEG C ± 0.5 DEG C, and 5ml is sampled when dissolving out 60 minutes, and filtering discards 1ml primary filtrate,
Subsequent filtrate is taken, HPLC method sample introduction measures the dissolution rate (1200 high performance liquid chromatograph of Agilent) in 0.1M hydrochloric acid, and rapidly
The isometric dissolution medium of equality of temperature is supplemented, while 250ml 0.2M sodium radio-phosphate,P-32 solution is added, pH is adjusted with 2M sodium hydroxide solution and arrives
6.8 ± 0.05,5ml is sampled respectively at 30 minutes, 60 minutes points and supplements equality of temperature same volume pH6.8 phosphate-buffered rapidly
Liquid measures the dissolution rate in 6.8 phosphate buffer of pH.Experimental result is shown in Table 3-1.
Table 3-1 epiphysin solid dispersions accumulate dissolution rate and indicate percentage composition (%) measurement result table
From the dissolution results of table 3-1: same vehicle and same ratio (embodiment 3-3 preparation different under 3-4)
As method, that is, spray drying process with hot melt prepares solubilizing effect；When carrier is HPMCAS AS-LF, Eudragit L100-
55, when HPMCP HP-55, Poloxamer 188, the enteric solid preparation of epiphysin solubilized can control epiphysin in acid again
In discharge on a small quantity；Drug and enteric carrier HPMCAS AS-LF weight ratio can be properly arrived to epiphysin 1: 2 to 1: 10
The effect of solubilising.
The related substance-measuring result table of study on the stability of table 3-2 epiphysin enteric solid preparation
Investigating data by table 3-2 can be seen that, the enteric of epiphysin and carrier HPMCAS AS-LF, HPMCP HP-55 preparation
Solid pharmaceutical preparation stability is good, while also indicating that resveratrol and carrier HPMCAS AS-LF, HPMCP HP-55 compatibility very
It is good.
Drug used in the embodiment of the present invention and test example, carrier auxiliary material and other auxiliary materials be it is commercially available,
Wherein product (lot number 100503), resveratrol raw material of the lycopene raw material purchased from North China pharmaceutical Co. Ltd are purchased from Chang Shahui
Product (lot number 100125), the epiphysin raw material of auspicious Biotechnology Co., Ltd are raw for Huangyan, Zhejiang macrobiosis epiphysin Co., Ltd
What is produced gives sample (lot number 100920)；Eudragit L100 55 be Degussa company production give sample (lot number
B060904025)；The product HPMCAS AS-LF that HPMCAS AS-LF is purchased from Japanese Shin-Etsu Chemial Co., Ltd's production (is criticized
Number 9013010), HPMCP HP-55 is purchased from the product HPMCP HP-55 (lot number of Japanese Shin-Etsu Chemial Co., Ltd's production
7091249), Kollidone VA64 gives sample Kollidone VA64 for BASF AG's production, and PEG4000 is purchased from traditional Chinese medicines
The product PEG4000 (lot number T20090312) of chemical reagent Co., Ltd of group, Poloxamer188 are BASF AG's production
Giving sample P oloxamer188 (lot number WPMD507C), Soluplus, Cremophor RH40, Cremophor EL is
Sample (lot number is respectively 20777268E0,89689075L0,92273309T0), microcrystalline cellulose are given in BASF AG's production
Purchased from the product (lot number 080904) of Qufu City, Shandong Province Tian Li pharmaceutic adjuvant Co., Ltd production, low-substituted hydroxypropyl cellulose is lake
The product (lot number 20100221) that state prospect pharmaceutcal corporation, Ltd gives, magnesium stearate are purchased from the limited public affairs of Anhui mountains and rivers pharmaceutic adjuvant
The product (lot number 090401) of production is taken charge of, other used auxiliary materials are also known to the skilled in the art.
Claims (11)
1. a kind of enteric solid preparation contains the resveratrol and enteric solubility carrier as active constituent and water-soluble load
Body, wherein the water-solubility carrier and the active constituent are present in the preparation with water soluble solid dispersion, and
Contain the enteric coat layer of enteric solubility carrier in solid pharmaceutical preparation external sheath,
Wherein the water-solubility carrier is Pluronic F68,
In the water soluble solid dispersion, the weight ratio of the active constituent and the water-solubility carrier is 1:1-1:20,
The enteric solubility carrier is hydroxypropylmethylcellulose acetate succinate,
Wherein the enteric coat layer also contains selected from one of plasticizer, antiplastering aid and stabilizer or variety carrier,
In enteric coat layer, the enteric solubility carrier is the 70-80 weight % of the enteric coat layer solid content；Described
Plasticizer is the 10-15 weight % of the enteric coat layer solid content；The antiplastering aid is the enteric coat layer solid content
15-20 weight %；The stabilizer is the 3-5 weight % of the enteric coat layer solid content,
The weight ratio of the enteric coating layer weight and its ingredient gross weight coated is 15-25 weight %.
2. enteric solid preparation according to claim 1 further comprises other pharmaceutic adjuvants so that tablet, capsule is made
Agent, granule, powder or pellet.
3. enteric solid preparation according to claim 2, wherein other pharmaceutic adjuvants include diluent, disintegration
One of agent, lubricant, antioxidant are a variety of.
4. the preparation method of enteric solid preparation according to claim 1 comprising by the active constituent and water-soluble
Property carrier be dissolved in solvent, remove solvent to obtain water-soluble solid dispersion, and to resulting water-soluble solid dispersion into
One step is enteric coated.
5. the preparation method of enteric solid preparation according to claim 1 comprising by the active constituent and water-soluble
Property carrier mix after be heated to melting, then be freeze-dried or the obtained water soluble solid dispersion of hot-melt extruded, and to gained
Water-soluble solid dispersion it is further enteric coated.
6. enteric solid preparation according to claim 1, wherein also including surfactant.
7. enteric solid preparation according to claim 6, wherein surfactant be Cremophor EL and/or
Cremophor RH40。
8. enteric solid preparation according to claim 6, wherein the active constituent weight and the surfactant
Weight ratio is 1:2-1:4.
9. enteric solid preparation according to claim 1 is also further selected from following ingredients containing one or more:
Anthocyanidin, curcumin, lutein, carrotene, pomegranate extract water-insoluble and liposoluble vitamin.
10. enteric solid preparation according to claim 1, also further contains beta carotene.
11. a kind of health composition contains enteric solid preparation described in any one of claim 1-3,6-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510713729.8A CN105412016B (en) | 2010-10-27 | 2010-10-27 | A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin |
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| CN201510713729.8A CN105412016B (en) | 2010-10-27 | 2010-10-27 | A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin |
| CN201010528511.2A CN102451179B (en) | 2010-10-27 | 2010-10-27 | A kind of containing lycopene, enteric solid preparation of resveratrol or melatonin and preparation method thereof |
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| CN201510713729.8A Active CN105412016B (en) | 2010-10-27 | 2010-10-27 | A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin |
| CN201010528511.2A Active CN102451179B (en) | 2010-10-27 | 2010-10-27 | A kind of containing lycopene, enteric solid preparation of resveratrol or melatonin and preparation method thereof |
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| CN102614127B (en) * | 2011-01-28 | 2014-07-30 | 北京万生药业有限责任公司 | Resveratrol nanoscale dispersoid and preparation method thereof |
| RU2549760C2 (en) * | 2013-05-31 | 2015-04-27 | Михаил Юрьевич Сидоренко | Biologically active additive and its production method |
| WO2015071394A1 (en) * | 2013-11-15 | 2015-05-21 | Dsm Ip Assets B.V. | Formulation of sparingly soluble compounds by hot-melt extrusion |
| BR112017000858A2 (en) * | 2014-07-17 | 2017-12-05 | Probiotical Spa | compositions comprising melatonin and flavonoids for use in the treatment of chemotherapy resistant tumors |
| US10342779B2 (en) | 2014-10-13 | 2019-07-09 | Worphmed Srl | Anhydrous liquid melatonin composition |
| CN106075413B (en) * | 2016-06-22 | 2019-12-31 | 扬州一洋制药有限公司 | Coating method suitable for compound azintamide enteric-coated tablets |
| CN109419775B (en) * | 2017-08-25 | 2021-02-09 | 南京生矶坊生物工程有限公司 | Water-soluble lycopene and preparation method and application thereof |
| CN107441504A (en) * | 2017-09-06 | 2017-12-08 | 广州中医药大学 | Lycopene inclusion compound and preparation method thereof and lycopene inclusion compound tablet, capsule and particle |
| CN108968051B (en) * | 2018-08-06 | 2022-07-12 | 大连医诺生物股份有限公司 | Resveratrol sustained-release preparation and preparation method thereof |
| CN109674767A (en) * | 2019-01-18 | 2019-04-26 | 安徽瑞达健康产业有限公司 | A kind of pellet and preparation method thereof containing lycopene |
| CN109745291A (en) * | 2019-03-07 | 2019-05-14 | 康赋葆(深圳)生物医药科技有限公司 | A kind of increase curcumin or the nanocrystalline enteric-coated composition of its analog bioavilability and preparation method thereof |
| CN111317827A (en) * | 2020-04-02 | 2020-06-23 | 江西科技师范大学 | Oral colon-targeted lycopene nano-liposome and preparation method thereof |
| CN112569190B (en) * | 2020-12-31 | 2022-03-01 | 苏州大学 | Oral administration preparation of pulsatilla chinensis saponin B4 and preparation method thereof |
| CN112870173A (en) * | 2021-02-04 | 2021-06-01 | 南京天纵易康生物科技股份有限公司 | Freeze-dried flash-release tablet and preparation method thereof |
| CN116077440A (en) * | 2022-12-03 | 2023-05-09 | 江苏宣泰药业有限公司 | Lutein pharmaceutical composition, preparation method thereof and pharmaceutical preparation |
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| CN101057834A (en) * | 2006-04-20 | 2007-10-24 | 信越化学工业株式会社 | Solid preparation comprising enteric solid dispersion |
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| CN1210026C (en) * | 2002-10-09 | 2005-07-13 | 重庆太极医药研究院 | Melatonin two-layer release-controlled tablet and preparing process thereof |
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| CN100362997C (en) * | 2004-10-14 | 2008-01-23 | 上海医药工业研究院 | Enteric coated table of duloxetine, and preparation method |
| CN101439030A (en) * | 2008-12-18 | 2009-05-27 | 中国药科大学 | Pharmaceutical composition containing lycopene and preparation method thereof |
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- 2010-10-27 CN CN201510713742.3A patent/CN105213316A/en active Pending
- 2010-10-27 CN CN201510713729.8A patent/CN105412016B/en active Active
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| US6117450A (en) * | 1997-04-29 | 2000-09-12 | Jenapharm Gmbh & Co. Kg | Method of making a perorally administered solid drug with controlled effective ingredient delivery |
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| CN101703479A (en) * | 2009-11-20 | 2010-05-12 | 天津市弗兰德医药科技发展有限公司 | Resveratrol pellet and preparation method thereof |
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| CN102451179B (en) | 2015-12-16 |
| CN102451179A (en) | 2012-05-16 |
| CN105213316A (en) | 2016-01-06 |
| HK1222809A1 (en) | 2017-07-14 |
| CN105412016A (en) | 2016-03-23 |
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Address after: Room 205 and 207, 515 huanke Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201210 Patentee after: Shanghai xuantai Pharmaceutical Technology Co., Ltd Address before: 201210 1st floor, building 3, 99 Haike Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee before: SINOTHERAPEUTICS Inc. |