CN105412016A - Enteric solid preparation containing lycopene or resveratrol or melatonin and preparation method of enteric solid preparation - Google Patents

Enteric solid preparation containing lycopene or resveratrol or melatonin and preparation method of enteric solid preparation Download PDF

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CN105412016A
CN105412016A CN201510713729.8A CN201510713729A CN105412016A CN 105412016 A CN105412016 A CN 105412016A CN 201510713729 A CN201510713729 A CN 201510713729A CN 105412016 A CN105412016 A CN 105412016A
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enteric
solid preparation
water
solid
preparation according
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CN105412016B (en
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顾茂健
郑启兰
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Shanghai xuantai Pharmaceutical Technology Co., Ltd
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Shanghai Xuantai Pharmaceutical Technology Co Ltd
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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
    • 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

Abstract

The invention relates to the field of medicine preparations, in particular to an enteric solid preparation containing lycopene or resveratrol or melatonin and a preparation method of the enteric solid preparation. The enteric solid preparation is prepared from an active ingredient resveratrol, a water-soluble and/or enteric carrier adjuvant and other pharmaceutic adjuvants. The water-soluble carrier adjuvant can serve as a water-soluble solid dispersion carrier. The enteric carrier adjuvant is an enteric polymer and can serve as an enteric solid dispersion carrier or enteric coating material. The enteric solid preparation containing resveratrol has good solubility in the intestinal tract, medicine is fast dissolved and released in the intestinal tract, and therefore absorption of resveratrol is increased, and the bioavailability of the enteric solid preparation is improved. The solid dispersion composition containing resveratrol can be suitable for the application and industrial production of tablets, granules, pellets, capsules, enteric capsules, enteric coating tablets, enteric coating pellets, enteric coating granules and other oral dosage forms.

Description

A kind of enteric solid preparation containing lycopene, resveratrol or melatonin and preparation method thereof
Related application
The application is the applying date is on October 27th, 2010, and denomination of invention is the divisional application of the Chinese invention patent application No.201010528511.2 of " a kind of enteric solid preparation containing lycopene, resveratrol or melatonin and preparation method thereof ".
Technical field
The present invention relates to a kind of containing lycopene, resveratrol and/or the melatonin enteric solid preparation and preparation method thereof as active component.Specifically, enteric solid preparation of the present invention is by being combined solid dispersion and enteric release vehicle, make the above-mentioned preparation containing lycopene, resveratrol and/or melatonin add dissolubility and/or the trap of active component, improve the bioavailability of active component.
Background technology
Along with the development of Fully automated synthesis, combinatorial chemistry and High Throughput Screening Assay, increasing new active medicine is also that insoluble drug pendulum is on the streamline of pharmaceutical engineering simultaneously.Have the marketed drugs being greater than 40% to be insoluble drug according to estimates, and the insoluble drug in pharmaceuticals industry laboratory account for more than 60% of total amount.For the medicine of low solubility high-permeability, it absorbs the low dissolution rate that rate-limiting step is medicine.Tradition conventional tablet is difficult to the bioavailability improving this kind of medicine, and suitable technique and modified form are the keys that such drug products is successfully developed, and therefore technique and dosage form play decisive role for the absorption in the gastrointestinal tract of this kind of medicine.Recent domestic has many for the investigative technique of insoluble drug administration strategy, as micronization technology, nanotechnology, microemulsion technology, molecule inclusion technology, liposome technology, solid dispersion technology, block copolymer micelle etc., wherein solid dispersions technique due to solubilizing effect obviously, favored relatively simple, the cost of technique low to compare in industrial quarters.Current commercialized product, research paper or patent mainly bias toward the dissolubility solving medicine in solid dispersions technique application, increase the absorption in medicine body thus improve the bioavailability of medicine with this.
Chinese patent application CN1981742A discloses the application of HPMCAS as the solid dispersion carrier of insoluble drug, but this application also lists some prior art documents, show when HPMCAS and some insoluble drug make solid dispersion, the raising effect of dissolubility is also bad, as Yakuzaigaku, 53 (4), in 221-228 (1993) T.Yamaguchi make solid dispersion about MAT and HPMCAS or CMEC time, the description of the better effects if of CMEC.
In addition, a kind of release dosage form at once containing solid pharmaceutical dispersions is also disclosed in PCT patent application WO2003/063831, it contains disintegrating agent and the porosigen of solid pharmaceutical dispersions, at least 5wt% of at least 30wt%, but according to the commentary in Chinese patent application CN101057834A, even if the release dosage form at once of this solid pharmaceutical dispersions makes the disintegrate under one's belt of described tablet, but medicine recrystallization will be made because solid dispersion is in Digestive system for a long time, and cause drug solubility to reduce.
Lycopene (Lycopene, molecular formula C 40h 56, molecular weight 536.85, sterling is peony acicular crystal) be a kind of acyclic carotenoid, be that separation and Extraction obtains from Fructus Lycopersici esculenti the earliest, can not synthesize voluntarily in human body, must take in from the external world.In all carotenoid, lycopene has the function of the strongest elimination singlet oxygen and eliminates the function of free radical, and belong to powerful antioxidant, it is 2 times of carotene to the elimination ability of singlet oxygen, 100 times of vitamin E; Lycopene can slow down the oxidation of low density lipoprotein, LDL, reduces the cholesterol in blood plasma, prevents cardiovascular diseases; It can effectively be bred by anticancer, has anti-cancer and cancer-preventing effect, has good therapeutical effect especially to carcinoma of prostate.It has the function of activating immune cell in addition, can enhancing human body immunity power and defying age, has important using value and market prospect widely.
Lycopene is the unsaturated aliphatic alkene with 11 carbon-to-carbon conjugated double bonds and 2 unconjugated double bonds.Lycopene in natural food raw material is configured as main with alltrans, quantity accounts for more than 95% of lycopene total amount, and only having a small amount of is cis-configuration (mainly 5-is suitable, 9-is suitable, the genial 15-cis-configuration of 13-); In mammiferous organ, blood and tissue, lycopene is based on various cis-isomer, and All-cislycopene is soluble in cholic acid microgranule and Chylomicron, is more easily absorbed by the body after oral, and therefore its bioavailability is apparently higher than all-trans lycopene.
Lycopene is by force fat-soluble, and fusing point is 174 DEG C, water-soluble hardly, and the dissolubility in water only has about 0.002 μ g/ml, and dissolubility is low limits the absorption of lycopene in gastrointestinal tract, causes oral administration biaavailability low.In addition, extremely unstable under the effect of lycopene light, heat, oxygen, metal ion in atmosphere, oxidizable degraded and isomerization, thus its function is reduced or lost efficacy.Existing commercially available lycopene formulations mainly loads into the oil suspension of soft capsule, does not solve the lycopene problem that dissolubility is low in the gastrointestinal tract.
At present, the oral solid drug composition patent application of published increase lycopene solubility comprises:
(1) the granted patent CN1125601C of Basf company discloses " pulverulent lycopene preparation, its method for making and its application ", relates to the preparation method of the dispersible pulverulent lycopene preparation of water.
(2) the granted patent CN1173637C of DSM N. V. discloses " preparation of finely divided pulverous carotenoid preparation ", prepares lycopene fine powder soluble in water.
(3) WO03045167 of Israel Lycoret company application discloses " carotenoid formulation ".
(4) Chinese patent ZL200610037859.5 discloses " composition and method of making the same of beta-schardinger dextrin-and HP-β-CD mixed inclusion lycopene ", the method mixing cyclodextrin inclusion compound medicine, makes lycopene solubility increase to 14 μ g/ml.
(5) Chinese patent application CN101439030 discloses " a kind of pharmaceutical composition containing lycopene and preparation method thereof ", the method adopts PLURONICS F87 to prepare solid dispersion as carrier, or they and cyclodextrin are prepared into Ternary complex thing, improve the dissolution of lycopene in solid preparation.
(6) Chinese patent application CN1485028 discloses " Lycopene drop pill ", lycopene oleo-resinous has been made the drop pill of oral solid dispersion to improve its dissolubility with water-soluble base (PEG4000, PEG6000, gelatin, stearic acid).
Although above-mentioned patent application has a general character to add lycopene solubility, because lycopene is a large amount of release fast under one's belt, because absorption area little Yi in stomach causes, lycopene is counter separates out, thus it is still very low to cause bioavailability to utilize; There is the shortcomings such as production cost is high, industrialization difficulty is large in the technique on the other hand as the granted patent CN1125601C patent report of Basf company.
Resveratrol (Resveratrol) belongs to non-flavonoid polyphenolic substance, similar estrogen diethylstilbestrol is white crystalline powder, and chemical name is (E)-5-[2-(4-hydroxyphenyl)-vinyl]-1,3-Benzodiazepines, molecular formula C 14h 12o 3, molecular weight 228.25, fusing point 256-257 DEG C, by force fat-soluble, be insoluble in water, it is reported that saturation solubility is about 30 μ g/ml in water, is soluble in methanol, ethanol, ethyl acetate, acetone and other organic solvent.Resveratrol is plant is a kind of phytoalexin that opposing environmental stimuli produces as ultraviolet, fungus, viral infection or mechanical damage; it is mainly present in 70 various plants such as Rhizoma Polygoni Cuspidati, Fructus Vitis viniferae, Semen arachidis hypogaeae, Fructus Mori, pinaster; content in Fructus Vitis viniferae is particularly abundant, has non-oxidizability, anti-oxidizing activities, protection cardiovascular, anticancer, anti-ageing multinomial health care of waiting for a long time.Resveratrol is to light, heat, oxygen instability, and have cis, trans two kinds of isomerss, the biological activity of resveratrol transisomer is better than cis-isomer, and under irradiation under ultraviolet ray, trans-resveratrol can change into cis-isomer.Oral resveratrol absorbs good, but because tachymetabolism and excretion cause bioavailability low, the elimination half-life is short, and II phase metabolic response mainly occurs, and is two metabolite relevant greatly: resveratrol glucosiduronic acid and sulphuric acid resveratrol through liver and small intestinal rapid metabolization.Research finds, duodenum and jejunum are the main portions of trans-resveratrol oral absorption, be drained through journey outside the intestinal that multidrug-associated protein (Mrp-2) participates in trans-resveratrol, outer row's transport protein P-glycoprotein does not participate in the absorption and transport of trans-resveratrol.
About the document of resveratrol and glycoside compound thereof and patent more, but the overwhelming majority concentrates on extraction, preparation, purposes aspect, seldom relate to and improve bioavailability and improve dissolubility aspect, to find and research improves resveratrol water solublity, and improve it and have very important significance in the absorption of small intestinal.Chinese patent CN100453071C discloses a kind of oral resveratrol multi-phase liposome.Chinese patent CN100493497C discloses a kind of resveratrol Solid Self-microemulsion preparation.Chinese patent application CN1951369A discloses a kind of coated nanoliposomes of resveratrol.Chinese patent application CN101317832A discloses a kind of oral administration nano-drug administration system made due to resveratrol and carrier material wheat gliadin, utilize the dissolution rate and the degree that improve resveratrol in the bio-adhesive properties of carrier material and high degree of dispersion characteristic, increase the absorption of medicine at small intestinal.China publication application CN101292966A discloses a kind of resveratrol and solid dispersion thereof and preparation method thereof, with Poloxamer, high molecular weight polyethylene glycol for carrier, prepares dispersion with solvent method and fusion method, improves medicine water solublity.China granted patent CN1220486C provides hydroxypropyl-beta-cyclodextrin inclusion and the preparation method of resveratrol and glycoside and derivant, improves medicine water solublity and stability.
Although above-mentioned patent application part relates to the method making resveratrol dissolubility improve, but degree that these inventions increase resveratrol dissolubility are still very little, the nanometer formulations such as liposome, Solid Self-microemulsion, Nanoliposome coated also existence and stability poor, to adjuvant with equipment requirements is higher, production cost is high, be difficult to the shortcomings such as suitability for industrialized production.
Melatonin (Melatonin, MT), have another name called melatonin or melatonin, be a kind of neuro-endocrinology hormone with extensive physiology and pharmacological action of the pinus secretion of mammal and the mankind, there is the physiological actions such as adjustment biological clock, tranquilizing soporific and immunomodulating.Melatonin is white crystalline powder, and chemical name is MT, molecular formula C 13h 16n 2o 2, molecular weight 232.27, fusing point 116-118 DEG C, in water, dissolubility is less than 1mg/ml (25 DEG C), belongs to amphiphilic compound, and Determination of oil-water partition coefficient LogP is 1.19, slightly water-soluble, be soluble in hot water and propylene glycol, dissolve in aquiferous ethanol, acid, alkali.The oral MT absolute bioavailability of healthy volunteer only 15% and individual variation is large, its absorption at human body is also very unstable, and first pass effect is obvious, and the MT with dose can have 10-20 difference doubly in Different Individual.After oral MT, MT, through Passive diffusion absorbed into serum, is only combined with plasma albumin, combination rate about 33%, but its combination is very loose and unsaturated.Bibliographical information melatonin oral absorption is separately had to have site specific, at the absorption dose > ileum > duodenum=jejunum=colon > stomach of Rat-rectum.Also there are some researches show that its bioavailability is relevant with dosage, Yeleswarown, Krishnaswamy, MelaughlinLeeG etc. have studied the bioavailability of MT different way of administration.After rat oral gavage, availability is 53.5%; During to Canis familiaris L. gavage MT10mg/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, it contains and is selected from one or more active component in lycopene, resveratrol and melatonin and enteric solubility carrier, and wherein said enteric solubility carrier and described active component are present in preparation with enteric solid dispersion form.
In one embodiment, described active component is resveratrol, and described enteric solubility carrier is HPMC-AS (HPMCAS) and/or Hydroxypropyl Methylcellulose Phathalate (HPMCP).
In still another embodiment, described active component is melatonin, and described enteric solubility carrier is that HPMC-AS (HPMCAS) and/or methacrylic acid/ethyl acrylate copolymer are as EudragitL100-55 and/or Hydroxypropyl Methylcellulose Phathalate (HPMCP).
In still another embodiment, described active component is lycopene, and described enteric solubility carrier is Hydroxypropyl Methylcellulose Phathalate (HPMCP).
On the other hand, the invention provides the preparation method of the described enteric solid preparation containing enteric solid dispersion, it comprises and is dissolved in solvent by described active component and enteric solubility carrier, dry except desolventizing is to obtain enteric solid dispersion.
In one embodiment, the preparation method of described enteric solid preparation to comprise described active component and enteric solubility carrier mixing post-heating to melting, then its lyophilization or hot-melt extruded is obtained enteric solid dispersion.
Another aspect, the invention provides a kind of enteric solid preparation, it contains one or more active component be selected from lycopene, resveratrol and melatonin, and enteric solubility carrier and water-solubility carrier, wherein said water-solubility carrier and described active component are present in preparation with water soluble solid dispersion, and contain the enteric coat layer of enteric solubility carrier at this solid preparation external sheath.
In one embodiment, described active component is lycopene, described water-solubility carrier is Soluplus and/or Pluronic F68 (Poloxamer), and described enteric solubility carrier is HPMC-AS (HPMCAS).
In still another embodiment, the described dissolubility of water soluble solid dispersion active component lycopene in pH6.8 phosphate buffer is not less than 10 μ g/ml, is preferably not less than 20 μ g/ml.
In yet another aspect, the invention provides the preparation method of the described enteric solid preparation containing water soluble solid dispersion, it comprises and is dissolved in solvent by described active component and water-solubility carrier, dry except desolventizing is to obtain water-soluble solid dispersion, and enteric coated further to the water-soluble solid dispersion of gained.
In still another embodiment, described preparation method comprise by described active component and water-solubility carrier mixing post-heating to melting, then its lyophilization or hot-melt extruded are obtained water-soluble solid dispersion, and enteric coated further to the water-soluble solid dispersion of gained.
In still another embodiment, describedly comprise in the enteric solid preparation of enteric solid dispersion or water soluble solid dispersion and can also contain surfactant further, preferred CremophorEL and/or CremophorRH40.
In a preferred embodiment, the weight ratio of described active component gross weight and described surfactant is 1: 2-1: 4.
In still another embodiment, the invention provides the enteric solid preparation containing enteric solubility or water soluble solid dispersion, it also can be selected from following composition containing one or more further: anthocyanidin, curcumin, phylloxanthin, beta-carotene, carotene, Punica granatum L. extract water-insoluble if ellagic acid and ursolic acid, fatsoluble vitamin are as vitamin A, vitamin D, vitamin K and vitamin E.
In yet another aspect, the present invention also provides a kind of health composition, and it contains enteric solid preparation as above.
Detailed Description Of The Invention
Without wishing to be bound to any theory, the present invention combines by adopting solid dispersions technique and location release principle, namely the slightly solubility problem by adopting solid dispersions technique to solve medicine, simultaneously by the selection to carrier material character, namely adopt the enteric solubility carrier that could dissolve in intestinal prepare solid dispersion or be first prepared into water-soluble solid dispersion, then carry out coated enteric coating film with control medicine under one's belt on a small quantity release or do not discharge.Because sorbent surface is long-pending large in intestinal, carrier or clothing film dissolve rapidly, and medicine discharges in a large number and absorbs rapidly, thus improves bioavailability.
According to enteric solid preparation of the present invention, can according to one or more active component required containing being selected from lycopene, resveratrol and melatonin as active component.
Wherein, lycopene molecule formula is C 40h 56, there is the structure shown in following formula,
Lycopene of the present invention comprises the cis-trans-isomer of all lycopenes.
The chemical name of resveratrol is (E)-5-[2-(4-hydroxyphenyl)-vinyl]-Resorcinol, and molecular formula is C 14h 12o 3.
Melatonin chemical name is MT, molecular formula C 13h 16n 2o 2.
All be available commercially for lycopene of the present invention, resveratrol and melatonin.
Except above-mentioned three kinds of active components, the enteric solid preparation comprising enteric or water soluble solid dispersion provided by the invention, the active component that also can be suitable for containing one or more other, such as: anthocyanidin, curcumin, phylloxanthin, beta-carotene, carotene, Punica granatum L. extract water-insoluble if ellagic acid and ursolic acid and fatsoluble vitamin are as vitamin A, vitamin D, vitamin K, vitamin E, preferred anthocyanidin, curcumin, phylloxanthin, beta-carotene, ellagic acid and/or carotene.
When using enteric solubility carrier and described active component to form enteric solid dispersion or enteric coating, described enteric solubility carrier under one's belt for control active component discharges or do not discharge on a small quantity is very favourable.And the application of the water soluble solid dispersion in enteric solid dispersion and enteric coating, makes active constituents of medicine amass in large intestinal at sorbent surface further and is able to discharged in a large number and absorb.
In the present invention, enteric solubility carrier refers to a kind of water-soluble pH dependent form carrier, and its dissolving has pH dependency, could dissolve in human body intestinal juice environment (about pH >=5.5), therefore claims the carrier that could dissolve in human body intestinal juice environment to be enteric solubility carrier.
For improving dissolubility, comprising in the enteric solid preparation of enteric solid dispersion or water soluble solid dispersion and can also contain surfactant further.Surfactant both can be added on also can in the external interpolation of solid dispersal together with other carrier auxiliary material in solid dispersion.Suitable surfactant is selected from the material in one or more following group: sodium lauryl sulphate, Pluronic F68 (Poloxamer), Tweens, spans, polyethylene glycols, polyoxyethylene castor oil class if CremophorEL, polyoxyethylene hydrogenated Oleum Ricini class are as Cremophor40, preferred CremophorEL and/or Cremophor40.Surface-active addition can regulate as required, and a preferred proportion is, the weight ratio of described active component weight and described surfactant is 1: 2-1: 4.
According to one embodiment of the invention, containing the enteric solid dispersion that enteric solubility carrier and active component described in one or more are formed in enteric solid preparation.
As the enteric solubility carrier for described enteric solid dispersion, preferred embodiment is described enteric solubility carrier is that one or more are selected from the enteric polymer in following group: Cellacefate (CAP), Cellulose acetotrimellitate (CAT), cellulose acetate succinate (CAS), methyl cellulose, phthalic acid ethyl hydroxy methocel, Hydroxypropyl Methylcellulose Phathalate (HPMCP), HPMC-AS (HPMCAS), acetic acid maleic acid hydroxypropyl emthylcellulose, trimellitic acid hydroxypropyl emthylcellulose (HPMCT), carboxymethylethylcellulose, poly-butanoic acid polyvinyl phthalic, polyvinyl acetate alcohol phthalic acid ester (PVAP), methacrylic acid/ethyl acrylate copolymer and methacrylic acid/methylmethacrylate copolymer.More preferably enteric solubility carrier is that HPMCAS and/or methacrylic acid/ethyl acrylate copolymer are as EudragitL100-55 and/or HPMCP.
Be not particularly limited for the enteric solubility carrier of enteric solid dispersion preparation and the ratio of active component, can add according to the custom requirements of this area.Preferably, the weight ratio of described active component gross weight and described enteric solubility carrier is 1: 1-1: 20.
From discussing above, the enteric solid preparation comprising enteric solid dispersion of the present invention can make the active component contained discharge on a small quantity under one's belt or not discharge.Preferably, the 45 minute dissolutions of described active component resveratrol in 0.1M hydrochloric acid are not more than 20%, are preferably not more than 10%, and 60 minutes dissolutions in pH6.8 phosphate buffer are respectively not less than 75%, are preferably not less than 80%; The 60 minute dissolutions of melatonin in 0.1M hydrochloric acid are not more than 25%, are preferably not more than 15%, and 30 minutes dissolutions in pH6.8 phosphate buffer are respectively not less than 80%, are preferably not less than 90%.In the present invention, described in comprise enteric solid dispersion enteric solid preparation Dissolution experiments measure according to Chinese Pharmacopoeia annex XD drug release determination second method (for enteric coated preparation), concrete method of testing is see test example 1-3.
As required, the enteric solid preparation comprising enteric solid dispersion of the present invention can also comprise other pharmaceutic adjuvant further to make the dosage forms such as tablet, capsule, granule, powder or micropill.Wherein, other described pharmaceutic adjuvant comprise in diluent, disintegrating agent, lubricant, antioxidant one or more.Described diluent, it can be one or more in microcrystalline Cellulose, starch, pregelatinized Starch, lactose, mannitol, calcium hydrogen phosphate; Disintegrating agent, it can be one or more in low substituted cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone; Lubricant, it can be one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, stearic acid, hydrogenated vegetable oil; And antioxidant, it can be one or more in ascorbic acid, sodium ascorbate, sodium L-ascorbate-2-phosphate, vitamin E, VE succinic acid macrogol ester (TPGS).
According to another embodiment of the present invention, containing one or more active component be selected from lycopene, resveratrol and melatonin in enteric solid preparation, and enteric solubility carrier and water-solubility carrier, wherein said water-solubility carrier and described active component are present in this solid preparation with water soluble solid dispersion, and have the enteric coat layer containing enteric solubility carrier at this solid preparation external sheath.
Wherein, described water-solubility carrier refers to the carrier that can dissolve in water, and it comprises non-pH-dependent and pH dependent form two kinds.Wherein the dissolving of non-pH-dependent carrier is not by the impact of solution ph in environment, all can dissolve in any pH value solution; The pH value of solution in environment is depended in the dissolving of pH dependent form carrier, and when the pH value of solution is greater than this dissolving pH value, carrier could dissolve.Water-soluble solid dispersion of first making the another kind of enteric solid preparation related in the present invention and active component contains the water-solubility carrier preferred water dissolubility non-pH-dependent carrier in the enteric coated formulation of enteric solubility carrier again at this solid preparation external sheath.
In a preferred embodiment, described water solublity non-pH-dependent carrier is that one or more are selected from the material in following group: methylcellulose, hydroxypropyl methylcellulose (HPMC), Pluronic F68 (Poloxamer), polyvinylpyrrolidone (PVP), polyoxyethylene (PEO), copolyvidone (Copovidone), polyvinyl alcohol (PVA), polyethylene glycols, Soluplus, saccharide, mannitol and xylitol, more preferably Poloxamer and/or Soluplus.
Described water-solubility carrier and the ratio of active component are not particularly limited, and can adjust as required.Preferably, the weight ratio of described active component gross weight and described water-solubility carrier is 1: 1-1: 20.
As required, it is for oral administration to make the finished products such as enteric coated enteric coatel tablets, capsule, granule, powder or micropill that described enteric solid preparation also can comprise other pharmaceutic adjuvant.Wherein, other described pharmaceutic adjuvant comprise in diluent, disintegrating agent, lubricant, antioxidant one or more.Described diluent, it can be one or more in microcrystalline Cellulose, starch, pregelatinized Starch, lactose, mannitol, calcium hydrogen phosphate; Disintegrating agent, it can be one or more in low substituted cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone; Lubricant, it can be one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, stearic acid, hydrogenated vegetable oil; And antioxidant, it can be one or more in ascorbic acid, sodium ascorbate, sodium L-ascorbate-2-phosphate, vitamin E, VE succinic acid macrogol ester (TPGS).
For the enteric solubility carrier contained in described enteric coat layer, preferably one or more are selected from the enteric polymer in following group for it: Cellacefate (CAP), Cellulose acetotrimellitate (CAT), cellulose acetate succinate (CAS), methyl cellulose, phthalic acid ethyl hydroxy methocel, Hydroxypropyl Methylcellulose Phathalate (HPMCP), HPMC-AS (HPMCAS), acetic acid maleic acid hydroxypropyl emthylcellulose, trimellitic acid hydroxypropyl emthylcellulose (HPMCT), carboxymethylethylcellulose, poly-butanoic acid polyvinyl phthalic, polyvinyl acetate alcohol phthalic acid ester (PVAP), methacrylic acid/ethyl acrylate copolymer and methacrylic acid/methylmethacrylate copolymer, more preferably HPMCAS.
Can also further containing one or more carriers be selected from plasticizer, antiplastering aid and stabilizing agent in described enteric coat layer.Wherein, plasticizer can be selected from the material in one or more following group: diethyl phthalate (DEP), dibutyl sebacate (DBS), tributyl citrate (TBC), triethyl citrate (TEC), Oleum Ricini, triacetyl glycerine (TA), propylene glycol, glycerol, Polyethylene Glycol, cochin oil, oleic acid, alkenyl succinic anhydride and polylactic acid (PLA), preferred TEC; Antiplastering aid can be selected from the material in one or more following group: Pulvis Talci, micropowder silica gel, glyceryl monostearate, preferably talc powder and micropowder silica gel; Stabilizing agent comprises sodium lauryl sulphate.
Ratio containing various composition in described enteric coat layer is not particularly limited, can adjusts as required.Preferably, described enteric solubility carrier is the 60-90 % by weight of described enteric coat layer solid content; Described plasticizer is the 10-30 % by weight of described enteric coat layer solid content; Described antiplastering aid is the 10-30 % by weight of described enteric coat layer solid content; Described stabilizing agent is the 0.5-5 % by weight of described enteric coat layer solid content weight.More preferably described enteric solubility carrier is the 70-80 % by weight of described enteric coat layer solid content; Described plasticizer is the 10-15 % by weight of described enteric coat layer solid content; Described antiplastering aid is the 15-20 % by weight of described enteric coat layer solid content; Described stabilizing agent is the 3-5 % by weight of described enteric coat layer solid content.
Relative to ingredient weight coated in coatings, preferably described enteric coat layer weight is 10-50 % by weight, is more preferably 15-25 % by weight.
Of the present invention water-soluble/preparation method of enteric solid dispersion can adopt the conventional method preparing solid dispersion, comprise fusion method, solvent method, solvent-fusion method, polishing, solvent-freeze-drying, solvent-spray drying method and hot-melt extruded method etc., specifically can publish see Chemical Industry Press, Zhu Shengshan chief editor " novel pharmaceutical formulation " the 1st edition 26-29 page.
As a preferred embodiment, the invention provides a kind of enteric solid preparation, it contains lycopene as active component, enteric solubility carrier and/or water-solubility carrier; Wherein said enteric solubility carrier and lycopene are present in preparation with enteric solid dispersion form, or described water-solubility carrier and described lycopene are present in this solid preparation with water soluble solid dispersion, and contain the enteric coat layer of enteric solubility carrier at this solid preparation external sheath.This enteric solid preparation can improve water solublity and the stability of lycopene, makes medicine discharge on a small quantity at gastric or not discharge, and discharges in a large number at intestinal, increases lycopene bioavailability.
In a presently preferred embodiment, apart from following specified otherwise, it is suitable for the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein said enteric solubility carrier and lycopene are present in preparation with enteric solid dispersion form, preferred enteric solubility carrier is HPMCP.
According to the enteric solid preparation of this preferred embodiment, when wherein said water-solubility carrier and described lycopene are present in this solid preparation with water soluble solid dispersion, and when this solid preparation external sheath has the enteric coat layer containing enteric solubility carrier, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferably Poloxamer, preferred enteric solubility carrier is HPMCAS, more preferably HPMCASAS-LF.
For improving dissolubility, surfactant can be added in lycopene solid enteric coated preparation.Suitable surfactant comprises sodium lauryl sulphate, Pluronic F68 (Poloxamer), Tweens, spans, polyethylene glycols, polyoxyethylene castor oil class if CremophorEL, polyoxyethylene hydrogenated Oleum Ricini class are as Cremophor40 or its combination, preferred CremophorEL and/or Cremophor40.Surface-active addition can be followed and be regulated according to needs, and a preferred proportion is, the weight ratio of described active component weight and described surfactant is 1: 2-1: 4.
Preferably, the dissolubility of described water soluble solid dispersion active component lycopene after adding surfactant in pH6.8 phosphate buffer is not less than 10 μ g/ml, is preferably not less than 20 μ g/ml.
According to the enteric solid preparation of this preferred embodiment, at lycopene in water-soluble or enteric solid dispersion, the weight ratio of lycopene and described enteric solubility or water-solubility carrier is preferably 1: 1-1: 20, and more preferably 1: 8-1: 16.
Lycopene belongs to aliphatic alkene, there is strong reducing property, oxidizable degraded, in order to improve preparation stability, preferably a certain amount of antioxidant is added, such as, in ascorbic acid, sodium ascorbate, sodium L-ascorbate-2-phosphate, vitamin E, VE succinic acid macrogol ester (TPGS) one or more in prescription.
Described lycopene water solublity/enteric solid dispersion can mix with other pharmaceutic adjuvant, it is for oral administration that further processing is prepared into the finished products such as tablet, capsule, granule, powder, micropill or enteric coated enteric coatel tablets, capsule, granule, powder or micropill, the preferred 1mg-20mg of preparation specification.
Preparation method preferred solvent-the spray drying method of the lycopene solid dispersion of this preferred implementation.Because the fusing point of lycopene is high, it is 174 DEG C, and unstable, occurring to decompose and lycopene generation signs of degradation for easily going out expression vector during solid dispersion by hot-melt extruded legal system, therefore preparing lycopene solid dispersion generally preferred employing solvent-spray drying method.
As a specific embodiment, solvent-spray drying method can choose enteric or water-solubility carrier adjuvant and/or surfactant and lycopene, added solubilized above-mentioned substance and in organic solvent to above-mentioned substance inertia, as dichloromethane or ethyl acetate.Then, stir, dissolve, adopt spray drying method removing organic solvent, further dry 10-30h in vacuum drying oven can be put if necessary, obtain the water solublity/enteric solubility carrier solids dispersion of the present embodiment.
For obtained water-solubility carrier solid dispersion, further to its enteric coating, to obtain enteric solid preparation.
As another preferred embodiment, the invention provides a kind of enteric solid preparation, it contains resveratrol as active component, enteric solubility carrier and/or water-solubility carrier; Wherein said enteric solubility carrier and resveratrol are present in preparation with enteric solid dispersion form, or described water-solubility carrier and resveratrol are present in this solid preparation with water soluble solid dispersion, and there is the enteric coat layer containing enteric solubility carrier at this solid preparation external sheath.This solid preparation can improve water solublity and the stability of resveratrol, makes medicine discharge on a small quantity at gastric or not discharge, and discharges in a large number at intestinal, increases the bioavailability of resveratrol.
In a presently preferred embodiment, apart from following specified otherwise, it is suitable for the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein said enteric solubility carrier and resveratrol are present in preparation with enteric solid dispersion form, preferred enteric solubility carrier is HPMCAS and/or HPMCP.
According to the enteric solid preparation of this preferred embodiment, when wherein said water-solubility carrier and resveratrol are present in this solid preparation with water soluble solid dispersion, and when this solid preparation external sheath has the enteric coat layer containing enteric solubility carrier, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferably Poloxamer, preferred enteric solubility carrier is HPMCAS, more preferably HPMCASAS-LF.
According to the enteric solid preparation of this preferred embodiment, at resveratrol, in water-soluble or enteric solid dispersion, the weight ratio of resveratrol and described enteric solubility or water-solubility carrier is preferably 1: 1-1: 20, and more preferably 1: 2-1: 8.
Resveratrol solid dispersion mixes with other adjuvant, finished products such as being prepared into tablet, capsule, granule, powder, micropill or enteric coated enteric coatel tablets, capsule, granule, powder or micropill can be processed further for oral administration, preparation specification 20mg-500mg.
Preparation method preferred solvent-the spray drying method of the resveratrol solid dispersion of this preferred implementation or hot-melt extruded method.
As a specific embodiment, solvent-spray drying method can choose enteric or water-solubility carrier adjuvant and/or surfactant and resveratrol, added solubilized above-mentioned substance and in organic solvent to above-mentioned substance inertia, as dichloromethane or ethyl acetate.Then stir, dissolve, adopt spray drying method removing organic solvent, further dry 10-30h in vacuum drying oven can be put if necessary, obtain the water solublity/enteric solubility carrier solids dispersion of the present embodiment.
As another specific embodiment, hot-melt extruded method is mixed with carrier by medicine to add in hot-melt extruded machine, medicine and carrier is made to reach molten condition rapidly through heating, again through screw mixes element and shearing elements mixing, shear and material exported with extruding, drug particles is disperseed more equably.
As another preferred embodiment, the invention provides a kind of enteric solid preparation, it contains melatonin as active component, enteric solubility carrier and/or water-solubility carrier; Wherein said enteric solubility carrier and melatonin are present in preparation with enteric solid dispersion form, or described water-solubility carrier and melatonin are present in this solid preparation with water soluble solid dispersion, and there is the enteric coat layer containing enteric solubility carrier at this solid preparation external sheath.
In a presently preferred embodiment, apart from following specified otherwise, it is suitable for the discussion for foregoing embodiments.
According to the enteric solid preparation of this preferred embodiment, when wherein said enteric solubility carrier and melatonin are present in preparation with enteric solid dispersion form, preferred enteric solubility carrier is HPMCAS, EudragitL100-55 and/or HPMCP.
According to the enteric solid preparation of this preferred embodiment, when wherein said water-solubility carrier and described melatonin are present in this solid preparation with water soluble solid dispersion, and when this solid preparation external sheath has the enteric coat layer containing enteric solubility carrier, preferred water-solubility carrier is Soluplus and/or Poloxamer, more preferably Poloxamer, preferred enteric solubility carrier is HPMCAS.
According to the enteric solid preparation of this preferred embodiment, at melatonin in water-soluble or enteric solid dispersion, the weight ratio of melatonin and described enteric solubility or water-solubility carrier is preferably 1: 1-1: 20, and more preferably 1: 2-1: 10.
Melatonin solid dispersion of the present invention mixes with other adjuvant, finished products such as being prepared into tablet, capsule, granule, powder, micropill or enteric coated enteric coatel tablets, capsule, granule, powder or micropill can be processed further for oral administration, control melatonin mainly to discharge in small intestinal, increase the oral absorption of melatonin, improve bioavailability.Preparation specification 1mg-10mg.
Preparation method preferred solvent-the spray drying method of the melatonin solid dispersion of this preferred embodiment or hot-melt extruded method.Concrete grammar can see the preparation method of above-mentioned resveratrol solid dispersion.
Feature of the present invention achieves the solubilising of insoluble drug and the regulation and control of release performance by simple method.The enteric solid dispersion adopting enteric polymer to prepare as carrier or water-solubility carrier prepare water soluble solid dispersion and enteric coated further, make medicine with amorphous state or/and molecularity is present in solid dispersion, can possess enteric feature again simultaneously.Preparation process is simple, automaticity is high, time-saving and efficiency, be a kind of can the technology of industrialized great production.
In addition, whole process solvent-free participation during employing hot-melt extruded method, therefore no solvent residue problem and solvent seasoning process.Torching mark and traditional fusion method are all prepare solid dispersion when material reaches molten condition, but the former passes through the organic assembling of screw mixes element and shearing elements, achieve strong mixing, shear with squeezing action work in coordination with, make medicine evenly, closely disperse in the carrier, improve the dissolution of medicine to a greater degree.By preferred vector, make medicine with amorphous state dispersion in the carrier or molecularity dissolve in the carrier.
Detailed description of the invention
Further illustrate the present invention by the following examples, but be not intended to limit the invention.
Embodiment 1-1
Taking each 10g of HPMCASAS-LF, HPMCPHP-55, KollidoneVA64, Poloxamer188, Soluplus is dissolved in 1000g dichloromethane respectively, add 0.05g vitamin C respectively to above-mentioned solution again and be stirred to whole dissolving, then add lycopene (production of Hui Rui bio tech ltd, Changsha) 1g respectively, form uniform solution.Obtain lycopene solid dispersion with BuchiminispraydryerB-290 spraying dry removing organic solvent, in spray-drying process, temperature of charge controls at 50-55 DEG C.
Embodiment 1-2
Taking Soluplus20g, 16g is respectively dissolved in 1000g dichloromethane respectively, add 0.05g vitamin C respectively to above-mentioned solution again and be stirred to whole dissolving, then add lycopene (production of Hui Rui bio tech ltd, Changsha) 1g respectively, form uniform solution.Obtain lycopene solid dispersion with BuchiminispraydryerB-290 spraying dry removing organic solvent, in spray-drying process, temperature of charge controls at 50-55 DEG C.
Embodiment 1-3
Take each 4g of CremophorRH40, CremophorEL, be dissolved in containing in the ascorbic 1000g dichloromethane solution of 16gSoluplus, 0.05g respectively, add 1g lycopene (production of Hui Rui bio tech ltd, Changsha) respectively to above-mentioned solution again, be stirred to whole dissolving.Obtain lycopene solid dispersion with BuchiminispraydryerB-290 spraying dry removing organic solvent, in spray-drying process, temperature of charge controls at 50-55 DEG C.
Embodiment 1-4
Take each 8g of HPMCPHP-55, Soluplus, be dissolved in the 1000g dichloromethane solution containing 0.05g vitamin C, 2gCremophorRH40 respectively, add 1g lycopene (production of Hui Rui bio tech ltd, Changsha) respectively to above-mentioned solution again, be stirred to whole dissolving.Obtain lycopene solid dispersion with BuchiminispraydryerB-290 spraying dry removing organic solvent, in spray-drying process, temperature of charge controls at 50-55 DEG C.
Embodiment 2-1
Getting HPMCAS (HPMCASAS-LF) 10g and 15g is dissolved in containing in the ascorbic 2 parts of acetone solns of 1g respectively, forms uniform solution; Respectively taking 5g resveratrol is respectively dissolved in above-mentioned solution, obtain white powder respectively with BuchiminispraydryerB-290 spraying dry removing organic solvent and be resveratrol: HPMCASAS-LF is the enteric solid dispersion of 1: 2 and 1: 3, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got respectively in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 2-2
Get HPMCAS (HPMCASAS-LF) 15g, resveratrol 5g, sodium L-ascorbate-2-phosphate 1g, be ground, put in parallel dual-screw extruding machine (Thermo Fischer Scient Inc. MiniLab) loading hopper, Screw Extrusion zone temperatures has been preheated to 230 DEG C, screw speed is 30rpm, material is extruded by head nib, and extrudate room temperature cools, and crosses 180 μm of aperture screen clothes and namely obtain enteric solid dispersion after pulverizing.
The enteric solid dispersion got in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 2-3
Get HPMCAS (HPMCASAS-LF) 25g and 40g and be dissolved in 1g respectively containing in ascorbic 2 parts of acetone solns, form uniform solution; Taking 5g resveratrol is respectively dissolved in above-mentioned solution, obtain white powder respectively with BuchiminispraydryerB-290 spraying dry removing organic solvent and be resveratrol: HPMCASAS-LF is the enteric solid dispersion of 1: 5 and 1: 8, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got respectively in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 2-4
Get hydroxypropylmethyl cellulose phthalate HP-55 (HPMCPHP-55) 25g and 40g, be dissolved in 1g respectively containing in ascorbic 2 parts of acetone solns, form uniform solution; Taking 5g resveratrol is respectively dissolved in above-mentioned solution, white powder and resveratrol is obtained respectively: HPMCPHP-55 is the enteric solid dispersion of 1: 5 and 1: 8 with BuchiminispraydryerB-290 spraying dry removing organic solvent, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got respectively in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 2-5
Get 40gPoloxamer188,1g vitamin C fully to disperse, be dissolved in acetone, form uniform solution, taking 5g resveratrol is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be water soluble solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The water solublity non-pH-dependent solid dispersion got in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), with the enteric coating solution coating (OHARA test-type high-efficiency coating machine) containing HPMCASAS-LF, coating weight gain is 15 % by weight, obtains enteric coated tablet.Wherein in enteric coating solution, HPMCASAS-LF, triethyl citrate (TEC), Pulvis Talci, sodium lauryl sulphate account for 72%, 11%, 15%, 2% of Coating Solution solid content weight respectively.
Embodiment 2-6
Get 40gHPMCE5,1g vitamin C fully to disperse, be dissolved in acetone, form uniform solution, taking 5g resveratrol is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be water soluble solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The water solublity non-pH-dependent solid dispersion got in this example is appropriate, by weight resveratrol: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 0.5, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), with the enteric coating solution coating (OHARA test-type high-efficiency coating machine) containing HPMCASAS-LF, coating weight gain is 15 % by weight, obtains enteric coated tablet.Wherein in enteric coating solution, HPMCASAS-LF, TEC, Pulvis Talci, sodium lauryl sulphate account for 72%, 11%, 15%, 2% of Coating Solution solid content weight respectively.
Embodiment 3-1
Get 10g HPMCAS (HPMCASAS-LF) fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-2
Get 15g HPMCAS (HPMCASAS-LF) fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-3
Get 25g HPMCAS (HPMCASAS-LF) fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-4
Get 25g HPMCAS (HPMCASAS-LF), 5g melatonin, be ground, put in parallel dual-screw extruding machine (Thermo Fischer Scient Inc. MiniLab) loading hopper, Screw Extrusion zone temperatures has been preheated to 150 DEG C, screw speed is 30rpm, and material is extruded with transparent bar by head nib, and access is in stainless steel disc, room temperature cools, and crosses 180 μm of aperture screen clothes and namely obtain solid dispersion after pulverizing.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-5
Get 50g HPMCAS (HPMCASAS-LF) fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-6
Get 25gEudragitL100-55 fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-7
Get 25g hydroxypropylmethyl cellulose phthalate HP-55 (HPMCPHP-55) fully to disperse, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be enteric solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The enteric solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai).
Embodiment 3-8
Get 25gPEG4000 dispersion, be dissolved in acetone, form uniform solution, taking 5g melatonin is dissolved in above-mentioned solution, obtain white powder with BuchiminispraydryerB-290 spraying dry removing organic solvent and be water solublity non-pH-dependent solid dispersion, in spray-drying process, temperature of charge controls at 50-55 DEG C.
The water solublity non-pH-dependent solid dispersion got in this example is appropriate, by weight melatonin: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: the ratio mix homogeneously of 20: 1: 1, tabletted (rotary tablet machine ZP-5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), with the enteric coating solution coating (OHARA test-type high-efficiency coating machine) containing HPMCASAS-LF, coating weight gain is 15 % by weight, obtains enteric coated tablet.Wherein in enteric coating solution, HPMCASAS-LF, TEC, Pulvis Talci, sodium lauryl sulphate account for 72%, 11%, 15%, 2% of Coating Solution solid content weight respectively.
Test example 1
Because lycopene dissolves hardly in 0.1M hydrochloric acid, water, pH6.8 phosphate-buffered liquid medium, first measure the water solubility of its solid dispersion.
Experimental technique is as follows: get excessive lycopene solid dispersion and be placed in 10ml0.1M hydrochloric acid or pH6.8 phosphate buffer, in 37 DEG C of water bath sonicator 30min, filter with 0.45 μm of aperture nylon leaching film filter, subsequent filtrate HPLC (Agilent1200 high performance liquid chromatograph) sample introduction measures.
Content and solubility test method adopt high performance liquid chromatography, and mobile phase is 100% acetonitrile, and determined wavelength is 472nm, flow velocity 2.0ml/min, and column temperature 30 DEG C, chromatographic column is C 18post (150 × 4.6mm, 5 μm), lycopene chromatographic retention is 13min.Employing external standard method calculates.Measurement result is in Table 1-1.
In the enteric solid preparation that table 1-1 is different, lycopene is at the dissolubility (HPLC method mensuration) of pH6.8 phosphate buffer
From the solubility results of table 1-1, solid dispersions technique has solubilization to lycopene, and due to the difference of carrier, solubilizing effect is also different, the solubilization of HPMCASAS-LF to lycopene is poor, and the solubilizing effect of carrier S oluplus, HPMCPHP-55 is better; After adding surfactant, solubilizing effect is more obvious.
Get 2 solid dispersion samples of embodiment 1-4 in table 1-1 respectively, in lycopene: microcrystalline Cellulose: low-substituted hydroxypropyl cellulose: magnesium stearate=5: ratio mixed pressuring plate (the rotary tablet machine ZP-5 of 2: 1: 0.5, Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai), with the enteric coating solution coating (OHARA test-type high-efficiency coating machine) containing HPMCASAS-LF, coating weight gain is 15 % by weight, obtain sample 1 and sample 2, dissolution to be measured.Wherein in enteric coating solution, HPMCASAS-LF, TEC, Pulvis Talci, sodium lauryl sulphate account for 72%, 11%, 15%, 2% of Coating Solution solid content weight respectively.
The present invention adopts the process in leaching of dissolution in vitro experimental simulation medicine in gastrointestinal tract, experimental technique is as follows: measure with reference to Chinese Pharmacopoeia annex 2005 editions XD drug release determination second methods (for enteric coated preparation), dissolution medium is 750ml0.1M hydrochloric acid, rotating speed is 100r/min, temperature is 37 DEG C ± 0.5 DEG C, sampling 5ml when stripping 45 minutes, filtration discards 1ml just filtrate, get subsequent filtrate, HPLC method sample introduction is determined at the dissolution (Agilent1200 high performance liquid chromatograph) of 0.1M hydrochloric acid, and supplement equality of temperature equal-volume dissolution medium rapidly, add 250ml0.2M sodium radio-phosphate,P-32 solution simultaneously, pH to 6.8 ± 0.05 is regulated with 2M sodium hydroxide solution, also equality of temperature same volume pH6.8 phosphate buffer is supplemented rapidly in 60min point in time sampling 5ml, be determined at the dissolution of pH6.8 phosphate buffer.The results are shown in Table 1-2.
The accumulation dissolution of table 1-2 lycopene enteric solid preparation indicates percentage composition (%) measurement result table
Test example 2
The present invention adopts the process in leaching of dissolution in vitro experimental simulation resveratrol in gastrointestinal tract, experimental technique is as follows: measure with reference to Chinese Pharmacopoeia annex XD drug release determination second method (for enteric coated preparation), dissolution medium is 750ml0.1M hydrochloric acid, rotating speed is 100r/min, temperature is 37 DEG C ± 0.5 DEG C, sampling 5ml when stripping 45 minutes, filtration discards 1ml just filtrate, get subsequent filtrate, HPLC method sample introduction is determined at the dissolution (Agilent1200 high performance liquid chromatograph) of 0.1M hydrochloric acid, and supplement equality of temperature equal-volume dissolution medium rapidly, add 250ml0.2M sodium radio-phosphate,P-32 solution simultaneously, regulate pH to 6.8 ± 0.05 with 2M sodium hydroxide solution, respectively at 0.5h, 1h point in time sampling 5ml also supplements equality of temperature same volume pH6.8 phosphate buffer rapidly, be determined at the dissolution of pH6.8 phosphate buffer.The results are shown in Table 2-1.
The content of resveratrol and dissolution determination method adopt high performance liquid chromatography, and mobile phase is 27/73 (v/v) acetonitrile/water, and determined wavelength is 303nm, flow velocity 1.0ml/min, and column temperature 30 DEG C, chromatographic column is C 18post (250 × 4.6mm, 5 μm), resveratrol chromatographic retention is 10.356min.Employing external standard method calculates.
The accumulation dissolution of table 2-1 resveratrol enteric solid preparation indicates percentage composition (%) measurement result table
Dissolution results from table 2-1: it is similar that same vehicle and different preparation method under same ratio and spray drying method and hot melt prepare solubilizing effect, as seen the stripping result of embodiment 2-1 and 2-2; When carrier is HPMCASAS-LF, HPMCPHP-55, Poloxamer188, the enteric solid preparation of resveratrol can control again resveratrol and discharge on a small quantity in acid by solubilising; Medicine and enteric carrier HPMCASAS-LF weight ratio all can reach the effect to resveratrol solubilising well 1: 2 to 1: 8; HPMCE5 has solubilization as carrier but solubilizing effect is not obvious.
The study on the stability determination of related substances result table of table 2-2 resveratrol enteric solid preparation
Investigate data by table 2-2 can find out, enteric solid preparation good stability prepared by resveratrol and carrier HPMCASAS-LF, HPMCPHP-55, Poloxamer188, also show simultaneously resveratrol and carrier HPMCASAS-LF, HPMCPHP-55, Poloxamer188 compatibility all fine.
Test example 3
The present invention adopts the dissolution of dissolution in vitro experimental simulation medicine in gastrointestinal tract, and experimental technique is as follows:
The present invention adopts the process in leaching of dissolution in vitro experimental simulation melatonin in gastrointestinal tract, experimental technique is as follows: measure with reference to Chinese Pharmacopoeia annex XD drug release determination second method (for enteric coated preparation), dissolution medium is 750ml0.1M hydrochloric acid, rotating speed is 100r/min, temperature is 37 DEG C ± 0.5 DEG C, sampling 5ml when stripping 60 minutes, filtration discards 1ml just filtrate, get subsequent filtrate, HPLC method sample introduction is determined at the dissolution (Agilent1200 high performance liquid chromatograph) of 0.1M hydrochloric acid, and supplement equality of temperature equal-volume dissolution medium rapidly, add 250ml0.2M sodium radio-phosphate,P-32 solution simultaneously, regulate pH to 6.8 ± 0.05 with 2M sodium hydroxide solution, respectively at 30 minutes, 60 minutes point sampling 5ml also supplement equality of temperature same volume pH6.8 phosphate buffer rapidly, be determined at the dissolution of pH6.8 phosphate buffer.Experimental result is in Table 3-1.
Table 3-1 melatonin solid dispersion accumulation dissolution indicates percentage composition (%) measurement result table
Dissolution results from table 3-1: it is the same that same vehicle and different preparation method under same ratio (embodiment 3-3 and 3-4) and spray drying method and hot melt prepare solubilizing effect; When carrier is HPMCASAS-LF, EudragitL100-55, HPMCPHP-55, Poloxamer188, the enteric solid preparation of melatonin can control again melatonin and discharge on a small quantity in acid by solubilising; Medicine and enteric carrier HPMCASAS-LF weight ratio all can reach the effect to melatonin solubilising well 1: 2 to 1: 10.
The study on the stability determination of related substances result table of table 3-2 melatonin enteric solid preparation
By table 3-2 investigate data can find out, enteric solid preparation good stability prepared by melatonin and carrier HPMCASAS-LF, HPMCPHP-55, while also show resveratrol and carrier HPMCASAS-LF, HPMCPHP-55 compatibility all fine.
The medicine, carrier auxiliary material and other adjuvant that use in the embodiment of the present invention and test example are all commercially available, wherein lycopene raw material purchased from the product (lot number 100503) of North China pharmaceutical Co. Ltd, resveratrol raw material purchased from the product (lot number 100125) of Hui Rui bio tech ltd, Changsha, melatonin raw material be Huangyan, Zhejiang prolong life that melatonin company limited produces give sample (lot number 100920), EudragitL10055 be Degussa company produce give sample (lot number B060904025), the product HPMCASAS-LF (lot number 9013010) that HPMCASAS-LF produces purchased from Japanese Shin-Etsu Chemial Co., Ltd, the product HPMCPHP-55 (lot number 7091249) that HPMCPHP-55 produces purchased from Japanese Shin-Etsu Chemial Co., Ltd, KollidoneVA64 be BASF AG produce give sample KollidoneVA64, PEG4000 is purchased from the product P EG4000 (lot number T20090312) of Chemical Reagent Co., Ltd., Sinopharm Group, Poloxamer188 be BASF AG produce give sample P oloxamer188 (lot number WPMD507C), Soluplus, CremophorRH40, CremophorEL be BASF AG produce sample of giving (lot number is respectively 20777268E0, 89689075L0, 92273309T0), the product (lot number 080904) that microcrystalline Cellulose is produced purchased from Qufu City, Shandong Province Tian Li pharmaceutic adjuvant company limited, low-substituted hydroxypropyl cellulose is the product (lot number 20100221) that Huzhou Zhanwang Pharmaceutical Co., Ltd. gives, the product (lot number 090401) that magnesium stearate is produced purchased from Anhui Shanhe Medical Accessary Material Co., Ltd., other adjuvant used also is well known by persons skilled in the art.

Claims (24)

1. an enteric solid preparation, it contains resveratrol as active component and enteric solubility carrier, and wherein said enteric solubility carrier and described active component are present in preparation with enteric solid dispersion form.
2. enteric solid preparation according to claim 1, wherein said enteric solubility carrier is that one or more are selected from the enteric polymer in following group: Cellacefate, Cellulose acetotrimellitate, cellulose acetate succinate, methyl cellulose, phthalic acid ethyl hydroxy methocel, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS, acetic acid maleic acid hydroxypropyl emthylcellulose, trimellitic acid hydroxypropyl emthylcellulose, carboxymethylethylcellulose, poly-butanoic acid polyvinyl phthalic, polyvinyl acetate alcohol phthalic acid ester, methacrylic acid/ethyl acrylate copolymer and methacrylic acid/methylmethacrylate copolymer.
3. enteric solid preparation according to claim 1, wherein said enteric solubility carrier is HPMC-AS and/or Hydroxypropyl Methylcellulose Phathalate.
4. enteric solid preparation according to claim 1 and 2, the weight ratio of wherein said active component and described enteric solubility carrier is 1:1-1:20.
5. enteric solid preparation according to claim 1 and 2, the 45 minute dissolutions of wherein said active component resveratrol in 0.1M hydrochloric acid are not more than 20%, preferably be not more than 10%, 60 minutes dissolutions in pH6.8 phosphate buffer are respectively not less than 75%, are preferably not less than 80%.
6. enteric solid preparation according to claim 1, it comprises other pharmaceutic adjuvant further to make tablet, capsule, granule, powder or micropill.
7. enteric solid preparation according to claim 6, other wherein said pharmaceutic adjuvant comprise in diluent, disintegrating agent, lubricant, antioxidant one or more.
8. the preparation method of enteric solid preparation according to claim 1, it comprises and is dissolved in solvent by described active component and enteric solubility carrier, except desolventizing is to obtain enteric solid dispersion.
9. the preparation method of enteric solid preparation according to claim 1, it comprise by described active component and enteric solubility carrier mixing post-heating to melting, then its lyophilization or hot-melt extruded are obtained enteric solid dispersion.
10. an enteric solid preparation, it contains the resveratrol as active component, and enteric solubility carrier and water-solubility carrier, wherein said water-solubility carrier and described active component are present in described preparation with water soluble solid dispersion, and contain the enteric coat layer of enteric solubility carrier at solid preparation external sheath.
11. enteric solid preparation according to claim 10, wherein said water-solubility carrier is that one or more are selected from the material in following group: methylcellulose, hydroxypropyl methylcellulose, Pluronic F68, polyvinylpyrrolidone, polyoxyethylene, copolyvidone, polyvinyl alcohol, polyethylene glycols, Soluplus, saccharide, mannitol and xylitol, preferred Pluronic F68 and/or Soluplus.
12. enteric solid preparation according to claim 10, in wherein said water soluble solid dispersion, the weight ratio of described active component and described water-solubility carrier is 1:1-1:20.
13. enteric solid preparation according to claim 10, wherein said enteric solubility carrier is that one or more are selected from the enteric polymer in following group: Cellacefate, Cellulose acetotrimellitate, cellulose acetate succinate, methyl cellulose, phthalic acid ethyl hydroxy methocel, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS, acetic acid maleic acid hydroxypropyl emthylcellulose, trimellitic acid hydroxypropyl emthylcellulose, carboxymethylethylcellulose, poly-butanoic acid polyvinyl phthalic, polyvinyl acetate alcohol phthalic acid ester, methacrylic acid/ethyl acrylate copolymer and methacrylic acid/methylmethacrylate copolymer, preferred HPMC-AS.
14. enteric solid preparation according to claim 10, wherein said enteric coat layer is also containing one or more carriers be selected from plasticizer, antiplastering aid and stabilizing agent.
15. enteric solid preparation according to claim 14, wherein in enteric coat layer, described enteric solubility carrier is the 60-90 % by weight of described enteric coat layer solid content; Described plasticizer is the 10-30 % by weight of described enteric coat layer solid content; Described antiplastering aid is the 10-30 % by weight of described enteric coat layer solid content; Described stabilizing agent is the 0.5-5 % by weight of described enteric coat layer solid content; Preferably described enteric solubility carrier is the 70-80 % by weight of described enteric coat layer solid content; Described plasticizer is the 10-15 % by weight of described enteric coat layer solid content; Described antiplastering aid is the 15-20 % by weight of described enteric coat layer solid content; Described stabilizing agent is the 3-5 % by weight of described enteric coat layer solid content.
16. enteric solid preparation according to claim 10,14 or 15, the weight ratio of wherein said enteric coat layer weight and its coated composition gross weight is 10-50 % by weight, is preferably 15-25 % by weight.
17. enteric solid preparation according to claim 10, it comprises other pharmaceutic adjuvant further to make tablet, capsule, granule, powder or micropill.
18. enteric solid preparation according to claim 17, other wherein said pharmaceutic adjuvant comprise in diluent, disintegrating agent, lubricant, antioxidant one or more.
The preparation method of 19. enteric solid preparation according to claim 10, it comprises and is dissolved in solvent by described active component and water-solubility carrier, except desolventizing is to obtain water-soluble solid dispersion, and enteric coated further to the water-soluble solid dispersion of gained.
The preparation method of 20. enteric solid preparation according to claim 10, it comprise by described active component and water-solubility carrier mixing post-heating to melting, then its lyophilization or hot-melt extruded are obtained water soluble solid dispersion, and enteric coated further to the water-soluble solid dispersion of gained.
21. enteric solid preparation according to claim 1 or 10, wherein also comprises surfactant, preferred CremophorEL and/or CremophorRH40.
22. enteric solid preparation according to claim 21, the weight ratio of wherein said active component weight and described surfactant is 1:2-1:4.
23. enteric solid preparation according to claim 1 or 10, it is also selected from following composition containing one or more further: anthocyanidin, curcumin, phylloxanthin, carotene, carotene, Punica granatum L. extract water-insoluble and fatsoluble vitamin.
24. 1 kinds of health compositions, it contains the enteric solid preparation according to any one of claim 1-7,10-18 and 21-23.
CN201510713729.8A 2010-10-27 2010-10-27 A kind of enteric solid preparation and preparation method thereof containing lycopene, resveratrol or epiphysin Active CN105412016B (en)

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