CN1211928A - Method for enhancing solubility of substantially water-insoluble compounds - Google Patents

Method for enhancing solubility of substantially water-insoluble compounds Download PDF

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Publication number
CN1211928A
CN1211928A CN 97192577 CN97192577A CN1211928A CN 1211928 A CN1211928 A CN 1211928A CN 97192577 CN97192577 CN 97192577 CN 97192577 A CN97192577 A CN 97192577A CN 1211928 A CN1211928 A CN 1211928A
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Prior art keywords
water
dissolubility
soluble polymer
polymer
solubility
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D·H·多纳贝迪安
L·马林
E·M·A·克拉克
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Union Carbide Chemicals and Plastics Technology LLC
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Union Carbide Chemicals and Plastics Technology LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

Abstract

Methods for enhancing the water-solubility of substantially water-insoluble compounds which is lower than 1000ppmw are disclosed by combining such compounds with a water-soluble polymer, e.g., polyalkylene oxide polymer or a cellulose ether, having a molecular weight of from about 50,000 to 7,000,000 grams/per gram in an amount effective to enhance the water-solubility of the compound in an acidic environment, e.g., pH less than about 5. Compositions comprising the compounds having enhanced water solubility are also disclosed.

Description

Improve the method for water-fast substantially compound dissolution degree
Invention field
The present invention relates to improve the method for the water solubility of water-fast substantially chemical compound, this method comprises mixes described chemical compound with some water-soluble polymer.
Background of invention
Many hydrophobic drugs are owing to their low aqueous solubility has limited dissolubility and rate of dissolution.So just rate of dissolution has limited the bioavailability of many drugs of low aqueous solubility, and rate of dissolution is controlled by dissolved surface area.So, adopted and reduced granularity and improve bioavailability of medicament, for example griseofulvin people such as (, antibiotic chemotherapy 12,232,1962) Atkinson, sulfafurazole people such as (, pharmaceutical science magazine, 4,704,1965) Fincher.Yet, unless to preparation (people such as Yamamato, the pharmaceutical science magazine of micronized medicine, 65,1484,1976) control carefully, otherwise will be owing to assembling (people such as Lin, pharmaceutical science magazine, 57,2143,1968), agglomeration (people such as Finholt, Med.Norsk.Farm.Selskap., 28,17,1966) or the absorption of air effect cause low powder wettability that effective surface area is reduced, and therefore bioavailability also can't improve.
For the above reasons, the technology that relates to solvent deposition method, lyophilization, solvate forming method, the micelle forming method that has used surfactant and solid dispersion method all is used to improve drug bioavailability (people such as Jun, J.Kor.Pharm.Sci.20,1120,1990).The notion of solid dispersion method is to be proposed by Sekiguchi and Obi (chemicals circular, 9,866,1961).They find under study for action, after the eutectic mixture oral administration administration of drugs of low aqueous solubility-sulfathiazole and physiology inertia water-solubility carrier-urea than giving sulfathiazole separately or having higher absorbability and drainage property.Other water-soluble solvent that uses in solid dispersion method comprises Polyethylene Glycol (" PEG ") (people such as Simonelli, pharmaceutical science magazine, 65,3,355,1976 and Chin.Arch.Pharm.Res.2 (1), 49,1979), polyvinylpyrrolidone (the Kollidon  polyvinylpyrrolidone in the pharmaceutical industries, Volker Buhler, BASF, Ludwigshafen, 88,1993) and cyclodextrin (people such as ElBarma, Pharmazie 30,788, and 1993).Above-mentioned material has relatively low molecular weight usually, for example is lower than about 80,000 gram/mole, and in sour environment for example pH be lower than at about 5 o'clock and do not reach enough effectiveness.
Therefore, press for the method that can in sour environment particularly, improve water-fast substantially compound water soluble.The improved compositions that needs dissolubility to improve, said composition can be with the form administration of solid and liquid.
Summary of the invention
The invention provides the water miscible modification method of the water-fast substantially chemical compound of raising.This method comprises: making the heavy average molecular weight of water-fast substantially chemical compound and effective dose is about 50,000-about 7,000, the molar water-soluble polymer of 000g/ mixes with the water miscible effective dose that can improve chemical compound in the sour environment (for example pH is lower than about 5).
In view of superiority of the present invention, the water solublity of water-fast substantially chemical compound can improve about 10%-about 500% or more here at least.So, when adopting method of the present invention to increase the water solublity of water-fast substantially medicine such as ibuprofen and tolbutamide, treat the required ibuprofen of patient or the amount of tolbutamide though reduced, the sanatory effective dose that is provided does not reduce.Outside ending,, the release characteristics of chemical compound in solution can be transferred to required speed by the water-soluble polymer selecting to suit or the molecular weight ranges of mixed polymer.
The present invention also provides and has contained and the mutually blended water-fast substantially compound compositions of water-soluble polymer.Detailed Description Of The Invention
To being applicable to the specific not strict qualification of water-fast substantially chemical compound of the present invention.Usually, this compounds will have and be lower than 1,000 parts per million part (" ppmw "), preferably is lower than the water solubility of about 600ppmw.Here, term " water solubility " expression chemical compound or polymer are dissolved in the amount in the distilled water (pH=7.0) under 25 ℃ and 1 atmospheric pressure, except as otherwise noted.Typical water-insoluble compound comprises: for example, medicine promptly has the chemical compound of medicine, treatment or diagnostic effect to mammal; And other chemical compound, for example, antimicrobial, Biocide, printing ink, coloring agent, antiseptic, additive etc.
The certain drug kind that can be used for the inventive method and compositions comprises; For example, cause the miscarriage medicine, sleeping pill, tranquilizer, tranquilizer, antiinflammatory, antihistaminic, anti-tussive agents, anticonvulsant, muscle relaxant, antineoplastic agent (for example medicine of those treatment malignant tumor formation), local anesthetic, the medicament of Kang Pajinsenshi disease, part or skin reagent, diuretic (preparation that for example contains potassium such as potassium iodide), the medicine of treatment mental sickness (for example medicine that contains lithium of the mad depression of making an uproar of those treatments), spasmolytic, antiulcerative, the preparation (comprising antifungal agent such as metronidazole) that contains multiple treatment cause of disease build infected material, antiparasitic and other antimicrobial drug, antibiotic, antibacterial, antiseptic, antimalarial, the cardiovascular pharmaceutical formulation (for example androgenic estrogen and gestagen) that contains hormone, rare steroid (for example estradiol), sympathomimetic, Hypoylycemic agents, nutrient, the preparation (for example Chymotrypsin) that contains the various active type enzyme, analgesic (for example aspirin) and medicament (comprising nematicide) and other veterinary with other type action use medicine, contraceptive (for example spermicide), antiviral, vitamin, vasodilation, antacid, kerolytic agent, the diarrhea medicine, anti-alopecia agent, the glaucoma medicine, the xerophthalmia compositions, wound healing agent etc.
Substantially water insoluble and be applicable to that medicine example of the present invention comprises: ibuprofen, ketoprofen, chlortalidone, sulfadimidine, papaverine, sulfameter, hydrochlorothiazide, bendroflumethiazide, oneself urinates vinegar sulphur, diazepam, glipizide, nifedipine, griseofulvin, acetaminophen, indomethacin, chlorpropamide, phenoxybenzamine, sulfathiazole, nitrazepam, furosemide, phenytoin, hydroflumethiazide (hydroflumethazide), tolbutamide, thiakylperazine maleate, dizoxin, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, chlormadinone acetate, acetaminophen, salicylic acid, methotrexate, acetylsulfamethoxazole, erythromycin, progestogen, estrogen, gestagen (progestational), corticosteroid etc.
The preferred agents that is applicable to the inventive method is selected from ibuprofen, tolbutamide, sulfathiazole and hydroflumethiazide and their mixture.
Be applicable to that water-soluble polymer of the present invention has at least about 1.0 weight %, preferably at least about the water solubility (as defined above) of 2.0 weight %.
Usually, the molecular weight of water-soluble polymer is about 50,000-7, and 000,000, preferred about 80,000-4,000,000, more preferably from about 100,000-750,000 gram/mole.The term of this paper " molecular weight " is meant weight average molecular weight.The method of measuring weight average molecular weight is that this area professional is known, comprises the method that is called as for example low-angle light scattering method.
The particle mean size of water-soluble polymer there is no strict regulations in the present invention, but is generally about 0.01 micron-1000 microns, and preferred about 50 microns-150 microns.
The preferred water soluble polymer has oxyalkylene functional group.More preferably described oxyalkylene is selected from ethylene oxide, propylene oxide and their mixture.Most preferred polymer comprises polyoxyalkylene (polyalkylene oxide) and oxyalkylated polysaccharide.
The present invention can use the polyoxyalkylene polymers that contains about 4 carbon atoms of the 2-that has an appointment in common every monomer molecule polymer.Preferred ethylene oxide and propylene oxide monomer.The present invention more preferably uses polyethylene oxide polymer.Polyethylene oxide polymer comprises: for example, and the copolymer of ethylene oxide homopolymer and ethylene oxide and one or more polymerizable oxyalkylene comonomers.Concrete comonomer is unessential among the present invention, and can contain for example hydro carbons substituent group of alkyl, cycloalkyl, aromatic radical, alkene and branched alkyl.Yet, comonomer for example 1, the amount of 2-propylene oxide necessarily can not be too much, in order to avoid make polyethylene glycol oxide water insoluble.Conventional oxyalkylene comprises 1,2-propylene oxide, 2,3-butylene oxide, 1,2-butylene oxide, styrene oxide, 2,3-epoxy hexane, l, 2-octylene oxide, butadiene list oxide (monomside), an oxidizing ethyle alkyl, 3-chloro-1,2 epoxy prapane etc.
For example polyethylene glycol oxide can be from Union CarbideCorporation to be applicable to the polyoxyalkylene of the inventive method, Danbury, and CT buys.About the detailed content that is applicable to polyoxyalkylene polymers of the present invention is that this area professional is known.
Oxyalkylated polysaccharide (also being called polysaccharide ether) also is applicable to method of the present invention.
That suitable polysaccharide raw material of the present invention comprises is natural, biosynthetic and deutero-carbohydrate polymer or their mixture.These raw materials comprise the heavy polymer that is connected by glycosidic inkage by monosaccharide unit.Above-mentioned raw materials can comprise, for example, and full starch and cellulose family; Pectin, chitosan, chitin; Seaweed products, for example agar and carrageenin; Alginate; Natural gum, for example guar gum, arabic gum and tragacanth gum; Biogum, for example xanthan gum etc.Preferred raw material comprises the cellulose that is usually used in preparing cellulose ether, for example chemistry cotton, velveteen, wood pulp, alkali cellulose etc.Above-mentioned raw materials can buy.
It is about 50 to be applicable to that polysaccharide molecular weight of the present invention is generally, 000-2, and 000,000 gram/mole, and preferred about 80,000-250,000 gram/mole.
The concrete derivative reagent (for example alkyl halide or oxyalkylene) that is used to prepare polysaccharide is unimportant in the present invention.Be applicable to that oxyalkylene of the present invention comprises about 2-24, preferred about 2-5 carbon atom/molecule.Concrete example comprises: ethylene oxide, propylene oxide and butylene oxide.Usually, the ether substituent group is to derive out by the reaction between polysaccharide and the preferred ethylene oxide of oxyalkylene on the cellulose.The substituent content of ether generally is about 1.5-6 and preferred about 2-4 mole ether substituent group/mole polysaccharide ether.Suitable alkyl halide comprises for example ethyl chloride or chloromethanes.
Polysaccharide ether can be replaced by one or more required substituent groups, for example cation, anion and/hydrophobic substituent.Hydrophobic substituent for know in this field and generally comprise alkyl, alkylidene, aryl alkylene or aralkyl with 8-24 carbon atom/molecule.The plain ether of hydrophobic modification fiber type discloses among 0 384 167 B1 open at for example United States Patent (USP) 4,228,277,5,120,328 and 5,504,123 and European patent.Cation hydrophobic is modified the plain ether of fiber type and is for example being put down in writing in the United States Patent (USP) 4,663,159.The substitution value of these substituent groups on each polysaccharide ether is generally about 0.001-0.1 and the preferred about 0.05 mole of substituent group of about 0.004-/mole polysaccharide ether.On polysaccharide ether, can have more than one specified substituent.
The viscosity of polysaccharide ether is generally between about 1-8000 centipoise, preferably about 100-3000 centipoise.Except as otherwise noted, term herein " viscosity " is meant that the aqueous solutions of polymers of 1.0 (weight) % is 25 ℃ of viscosity that record with the Brookfield viscometer down.This viscosimetric analysis technology is known and description to some extent in ASTM D2364-89 in this field.The particle mean size of polysaccharide ether there is no strict regulations, but preferably between about 0.01-1000 micron and more preferably between about 50-400 micron.
The prepared preferred polysaccharide ether of the present invention is cellulose ether, and this cellulose ether comprises; For example, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethylmethyl-cellulose, carboxymethyl cellulose, hydroxyethyl carboxymethyl cellulose and their derivant.
Can make water-soluble polymer consumption that the water solublity of water-fast substantially chemical compound effectively increases generally between about 1-500, preferably about 20-300, more preferably 50-250 restrains polymer/digest in the scope of compound.This concentration usually correspondingly be about 0.1 (weight) % limit of solubility of this polymer in liquid, aqueous, for example 25 (weight) % or lower extremely approximately of polymer concentration.Particularly, the polymer concentration scope is about 0.1-5 (weight) %, and preferred 0.1-2 (weight) % is in the aqueous solution gross weight.
Water-soluble polymer and chemical compound can be carried out physical mixed with drying regime, moisture state, perhaps when using thermoplastic polymer, with compound before or in the process with polymer melt and with polymer and chemical compound melting mixing.More specifically, the technology and equipment that mixes that is applicable to this purpose is that the professional knows in this field.
Can be by water-fast substantially chemical compound directly being joined in the Aquo-composition that contains water-solubility carrier or by under molten condition, carrier and water-fast substantially chemical compound blend being improved dissolubility.Be different from document United States Patent (USP) 4,687,662 (1987,8,18 mandates), 4,689,218 (1987,8,25 authorize), 4,834,966 (1989,5,30 authorize), 4,861,797 (1989,8,29 authorize) and WO96/19973 (open date 1996,7, that describes 4) mixes effervescent improving active substance (for example ibuprofen) dissolubility, or european patent application 0 228 164 A2 (the open date 1987,8,7) other technology of the use surfactant of Miao Shuing need not to add any mentioned reagent in the present invention.Also do not need to use United States Patent (USP) 5,225, disclosed organic solvent increases the dissolubility of water-fast substantially chemical compound in 204 (1993,7,6 authorize).
Except being used for improving the water-soluble polymer of water solubility, the present invention also can adopt known other polymer of this field professional.These polymer comprise: for example, be selected between acrylic copolymer between hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, cation cellulose ether, polyvinylpyrrolidone, carboxy vinyl polymer, hydroxypropylmethyl cellulose phthalate, acetic acid phthalic acid ester, Methyl metacrylate 99, Pioloform, polyvinyl acetal dialkyl amino yl acetate, an acrylic acid dimethylamino Arrcostab acrylic copolymer, acrylic acid 2-methyl-5-vinylpyrine methyl ester and ask acrylic copolymer, citric acid, urea, succinic acid and aminoacid.Except water-soluble polymer, the concentration of the polymer that suitable the present invention uses is unimportant, but usually between about 0.1-99 (weight) %, in the gross weight of water-soluble polymer, chemical compound and other polymer.About the selection of other above-mentioned polymer and the details of use are that these those skilled in the art are known.
Generally speaking of the present invention, with the consumption of the mutually blended water-soluble polymer of water-fast substantially chemical compound in solution dissolubility is increased effectively at least about 10%, preferably at least about 20%, more preferably at least about 30%, even preferably at least about 50%, extremely preferably at least about 100%, most preferably at least about 200%.Used water-soluble polymer can be a kind of incessantly.The increase of this dissolubility is usually with respect to the 100ppmw at least of the soluble compound of preparation during liquid, aqueous form, preferred 150ppmw at least, the more preferably concentration of 300ppm at least.
Can utilize the method for the invention that the stable composition that strengthens dissolubility that has of any desired form is provided.More particularly, compositions provided by the present invention can be liquid, solid or their mixture.Typical form can be thin film, adhesive tape, thin slice, gel, tablet, granule, aqueous solution, dispersion and other mobile liquid.The physical characteristic of the present composition will depend on the relative amount of polymer and chemical compound in the compositions.For example, the concentration of polyoxyalkylene or water-soluble polymer can change in the wide region of extremely low concentration to 99 (weight) % of for example 0.1 (weight) % or higher high concentration in the solid composite.Fluid composition, particularly oxyalkylated polysaccharide polymer will comprise the polymer of basic low amount usually, generally have 0.1-about 5 (weight) %.
Surprisingly, the present invention also can postpone to discharge chemical compound in aqueous solution except the enhanced compositions of dissolubility is provided.Have found that, when use has the water-soluble polymer of some molecular weight ranges, the release profiles feature can be transferred to required.Particularly, when need have the chemical compound release profiles that quite continues, for example above 12 hours, then the preferred water soluble polymer is a molecular weight ranges between about 900,000-7,000,000 polyethylene oxide polymer and molecular weight ranges are between 500,000-1,000,000 oxyalkylated polysaccharide polymer.On the contrary, when needs provide initial comparatively fast and subsequently more slowly during curve, the preferred molecular weight ranges that adopts is between about 100 in the water-soluble polymer, 000-600,000 polyethylene oxide polymer with molecular weight ranges between 100,000-400,000 oxyalkylated polysaccharide polymer.
Method and composition of the present invention has final use very widely, for example industrial use and personal health care applications there.Typical commercial Application comprises that the dissolubility that for example makes Antimicrobe compound, Biocide, dyes and dyestuffs, antiseptic, additive etc. improves.Typical individual health care purposes comprises for example multiple medicine and cosmetic composition.
The representative drugs tablet that adopts among the present invention can be by the known any method preparation of these those skilled in the art, for example direct compression, with suitable solvent granulating and the manufacturing of compacting, fusion manufacturing and dosage form subsequently.These can the solid form transmission medicine contain chemical compound, water-soluble polymer and other known component usually, comprise for example lactose, magnesium stearate or hard purport acid calcium, dicalcium phosphate, mannitol and microcrystalline Cellulose.Oxyalkylated polysaccharide polymer compositions also can be used as semisolid/liquid dosages and uses (for example be used to catch a cold and have a headache medicine) and discharge.The appointed condition and the technology of preparation above-mentioned composition are that the professional is known in this area.Referring to, United States Patent (USP) 5,273,758 (1993.12.28 mandates), 4,343,789 (1982.8.10 mandates) and United States Patent (USP) 5,116,145 (1992.11.24 mandate).
Be astoundingly, water-soluble polymer of the present invention has effectively improved the dissolubility of chemical compound in the acid environment, and it is about 5 that the preferred pH of described acid environment is lower than, more preferably less than about 3, and most preferably in gastric juice acidity, for example, about pH=1.1.
The following example be used for the explanation and and the described scope of unrestricted hereinafter claim.
Embodiment 1
In 100 milliliters of (" mL ") volumetric flasks and under 25 ℃ on the magnetic agitating plate preparation CELLOSIZE  HEC09L (80,000g/mol, Union Carbide Corp.Danbury, aqueous solution CT).The concentration of HEC solution is 0.5,1.0 and 2.0 (weight) %.In these solution, add the overdose of medicine thing and continue to stir 2 hours down to form saturated solution at 23 ℃.When this process of end, taking-up waits separatory on a small quantity and suitably dilutes through 0.45 micron (" m ") filter paper filtering and with filtrate, uses it for UV-VIS spectrophotometer (HewlettPackard) is measured absorption value under suitable wavelength blank.Measure drug solubility from the calibration curve of having set up.Data are listed in table 1.
Table 1
The increase of ibuprofen dissolubility in the CELLOSIZE HEC polymer solution
Sample Concentration (%w/v) Ibuprofen dissolubility (ppm)
CELLOSIZE?WP-09L ????0.0 ????50
CELLOSIZE?WP-09L ????1.0 ????140
CELLOSIZE?WP-09L ????2.0 ????230
CELLOSIZE WP-09L has the effect that improves dissolubility to ibuprofen, and the solution of 2.0% (w/v) has improved 4 times.
Embodiment 2
Whether can be used to improve the ibuprofen water solublity for measuring other pharmaceuticals industry with binding agent, also can detect: METHOCEL  K100 LV Prem CR[hydroxypropyl emthylcellulose (HPMC) following material, Dow chemical company, molecular weight: 23,000g/mol].According to producer (catalogue, Dow chemical company, Midland, MI.) method of Tui Jianing with the HPMC polymer dissolution in water.In this process, polymer is dispersed in the cold water under high shear, then temperature is slowly raise to promote polymer dissolution.Behind solubilising, temperature is cooled to room temperature.Polymer at room temperature is difficult for dissolving.In this solution, add excessive ibuprofen and analyze according to the description of embodiment 1.The result of these sample gained is as follows:
The table 2 ibuprofen contrast that dissolubility increases in hydroxypropyl emthylcellulose aqueous solution and hydroxyethyl cellulose aqueous solution knot
Really
Sample Concentration (%w/v) Ibuprofen dissolubility (ppm)
?CELLOSIZE?WP-09L ????0.0 ????50
?CELLOSIZE?WP-09L ????1.0 ????140
?CELLOSIZE?WP-09L ????2.0 ????230
?METHOCEL??K100 a ????1.0 ????50＜
?METHOCEL??K100 a ????2.0 ????50＜
According to data, compare with CELLOSIZE HEC WP-09L, HPMC is very little to the effect that the ibuprofen water solublity increases.
Embodiment 3
Whether other types of drug dissolubility is had the increase effect for measuring hydroxyethyl-cellulose, can be to (Sigma chemical company, St.Louis MO) wait amine type medicine to detect as tolbutamide.Mode according to embodiment 1 is handled sample, and the result is as shown in table 3:
Table 3
The dissolubility of tolbutamide in CELLOSIZE HEC WP 09 solution
Sample Concentration (%w/v) Tolbutamide dissolubility (ppm)
CELLOSIZE?HEC ????0.0 ????75
CELLOSIZE?HEC ????0.5 ????200
CELLOSIZE?HEC ????1.0 ????175
CELLOSIZE?HEC ????2.0 ????300
As can be seen, CELLOSIZE HEC aqueous solution helps the solubilising of amine type medicine.In the concentration range of 0.5%-2.0%, the dissolubility of tolbutamide has improved 75ppm-300ppm.Be not bound by any theory, obviously the solubilization of medicine can produce because of the interaction of chain between medicine and polymer.
The dissolubility increase effect of all said medicine is measured in water.Below, (symbol stomach pH) measures with the medium with low pH.
Embodiment 4
Mode according to embodiment 1 prepares sample.(SGF, concentration pH=1.1) is the physics dispersion of preparation tolbutamide among the CELLOSIZE HEC WP 09L of 0.5-2.0% being dissolved in simulated gastric fluid.Table 4 listed before and after the dosing pH and at the maxima solubility of this medium Chinese medicine.From this table, in 0.5% hydroxy ethyl fiber cellulose solution, the dissolubility of tolbutamide has been increased to 170ppm from 75ppm substantially.Hydroxyethyl-cellulose has not only improved the dissolubility of drugs of low aqueous solubility under condition of neutral pH, also improved the dissolubility under the low pH condition.
Table 4
Add before the medicine among the CELLOSIZE HEC WP 09L that in by SGF, prepares and pH value afterwards
Polymer Concentration (w/v) Medicine PH before the dosing PH after the dosing Dissolubility (ppm)
?HEC?WP?09 ????0.0 Tolbutamide ????1.21 ????1.21 ????70
?HEC?WP?09 ????0.5 Tolbutamide ????1.21 ????1.21 ????170
?HEC?WP?09 ????2.0 Tolbutamide ????1.21 ????1.21 ????120
From this table, obviously CELLOSIZE HEC can improve as the dissolubility of drugs of low aqueous solubility such as ibuprofen and tolbutamide in the water-bearing media with certain pH characteristic.
Embodiment 5
Hydrophilic adhesive-polyethylene glycol oxide that another kind of pharmaceuticals industry is commonly used is studied, whether can be improved the dissolubility of water-fast substantially chemical compound to measure it.Be not quite similar with hydroxyethyl-cellulose, this material is thermoplastic, that is, it can be by conventional melt-processed equipment remelt and reshaping under the condition of not losing molecular weight.
In the following example, the method and the technology of the molten mixture of preparation polyethylene glycol oxide and water-fast substantially chemical compound described.
100gPOLYOX  WSR N-80 is fed in the Cuisinart Pro Custom II TM WSR mixing drum.The consumption of distilled water with mist form and 5-15phr (part/hundred parts of resins) is sprayed in the above-mentioned tube.POLYOX  WSR and water are admixed nearly 2 minutes, stop agitator then and also all materials that are bonded on the barrel are scraped back in the mixing drum.And then with material mixing 2 minutes.At this moment, introduce active substance (25g) and continue to mix 2 minutes, collect and under 5 ℃, be stored in the Polythene Bag in order to later use with complete granulating.Free flowing granule after adding active substance still clearly.
The 50g granule is fed among the Brabender Plasticorder that two screw stirring-heads are housed.Tube temperature is according to used active substance and in 80-120 ℃ of scope.Mixing speed all is 30rpm in all cases.When joining granule in the mixing drum, 5 ℃-10 ℃ of temperature declines also slowly go back up to the design temperature point slowly after fusion.Make material mixing 2-3 minute.Stop to stir and melted material shoveled out in the mixing drum and on metal platen isothermal be cooled to room temperature.This final composition slightly is viscosity.
The melted material that makes from Brabender compresses in bulk at Greenard Press.The size of this piece is 63mm * 63mm * 3mm.Each system is carried out following and the irrelevant thermal cycle of used active substance: at 80 ℃ with do not add and depress heating 1 minute, heated 1 minute down at 2,000 pounds of/square inch pressure, isothermal is cooled to room temperature then.Under each situation, use Teflon  Release paper with material separation from the piece top.Stamp out the tablet that weight is 3.5g from above-mentioned.
Above-mentioned tablet is placed in the 100mL volumetric flask that contains distilled water and stirs on the flat board being placed on magnetic under 25 ℃.The concentration (%w/v) of POLYOX WSR solution is between 0.5-2.0.All contain the overdose of medicine thing in each solution to form saturated solution, this saturated solution was stirred 2 hours down at 23 ℃.
When this process finishes, migrate out a spot of separatory that waits also by the 0.45m filter paper filtering and with the filtrate suitable dilution, use it for the UV-VIS spectrophotometer is measured absorption value under suitable wavelength blank.Measure drug solubility from the calibration curve of having set up.Table 5 data declaration the application of low-molecular-weight peo resin and tolbutamide.
As seen from Table 5, the maxima solubility of tolbutamide in water (pH=7.0) and simulated gastric fluid (pH=1.1) is near 70ppm.When joining polyethylene glycol oxide in the aqueous solution simply, the dissolubility of tolbutamide has obviously increased by 3 times or 300%.Similar improvement is also arranged, outwardly a little more than 2 times in SGF.
Unexpectedly be, according to 5,10 and during 15phr the drug solubility of discovering to molten mixture obtain higher increase.For example, when 5phr, the dissolubility of tolbutamide in water improved more than 1.0 times when containing tolbutamide separately in the water.This improvement effect is than the effect height that only polymer and medicament mixed is produced in solution simply.Be not subjected to any particular theory and restriction conceptually, obviously the improvement by the caused drug solubility of melting mixing technology may be the result that reinforcement caused who is reacted to each other by the good mixing in the fusion mutually and polymer-medicine, the raising of dissolubility can further make the reinforcement that reacts to each other between polymer-medicine, has therefore increased water solublity.Irrelevant with the concentration of used plasticizer in this test, under all situations increase of the dissolubility of medicine in water all identical, all increased by 10 times.
In SGF, the solubility curve of molten mixture also has similar trend.All mixture make the tolbutamide dissolubility improve 8 times, and physical mixture only makes dissolubility increase twice.The superiority that the present invention determines makes the people can be by improving the dissolubility of water-fast substantially medicine in various pH value media with the melting mixing of hydrophilic thermoplastic polyethylene glycol oxide.The more important thing is that lower operative temperature can be used to reduce the degraded of producing Chinese medicine.
Table 5
In POLYOX WSR N-80 dispersion and the molten mixture
Tolbutamide is at H 2Dissolubility among O and the SGF
Sample POLYOX WSR concentration (%w/v) Plasticizer concentration (phr) c Medium Dissolubility (ppm)
??1 ????0.0 ????0.0 ????H 2O ????70
??2 ????0.0 ????0.0 ????SGF ????70
3 a ????1.0 ????0.0 ????H 2O ????225
4 a ????1.0 ????0.0 ????SGF ????125
5 a ????1.0 ????5.0 ????H 2O ????900
6 b ????1.0 ????5.0 ????SGF ????575
7 b ????1.0 ????10.0 ????H 2O ????925
8 b ????1.0 ????10.0 ????SGF ????610
9 b ????1.0 ????15.0 ????H 2O ????900
10 b ????1.0 ????15.0 ????SGF ????650
A: physics dispersion b: molten mixture c: part/100 parts of resins (water is plasticizer)
Embodiment 6
Whether other medicines are had similar effect for measuring polyethylene glycol oxide, prepare fusing sample, carry out the process of describing among the embodiment 5 then with sulfathiazole.These system gained data are listed in table 6.From table 6, when with this medicine and polyethylene glycol oxide melting mixing, the dissolubility of sulfathiazole has improved more than 2 times.But really not so for the physics dispersion, drug solubility wherein remains unchanged.That is to say, water-fast substantially chemical compound and polymer melt are mixed making dissolubility obtain increasing, and the increase of dissolubility and not obvious when being dispersed in two kinds of materials in the water.Dissolubility increases above 200%.
Table 6
Sulfathiazole in POLYOX WSR N-80 dispersion and the molten mixture is at H 2Dissolubility among the O
Sample POLYOX WSR concentration (%w/v) Plasticizer concentration (phr) c Dissolubility (ppm)
????1 ????0.0 ????0.0 ????550
????2 a ????1.0 ????0.0 ????605
????3 b ????1.0 ????5.0 ????1225
A: physics dispersion b: molten mixture c: part/100 parts of resins (water is plasticizer)
Embodiment 7
Whether other medicines are had similar effect for measuring polyethylene glycol oxide, prepare fusing sample, carry out the process of describing among the embodiment 5 then with hydroflumethiazide.These system gained data are listed in table 7.From table 7, when with this medicine and polyethylene glycol oxide melting mixing, the dissolubility of sulfathiazole has improved more than 2 times slightly.But really not so for the physics dispersion, drug solubility wherein remains unchanged.That is to say, water-fast substantially chemical compound and polymer melt are mixed making dissolubility obtain increasing, and the increase of dissolubility and not obvious when being dispersed in two kinds of materials in the water.
Table 7
Hydroflumethiazide in POLYOX WSR N-80 dispersion and the molten mixture
At H 2Dissolubility among O and the SGF
Sample POLYOX WSR concentration (%w/v) Plasticizer concentration (phr) c Medium Dissolving (ppm)
????1 ????0.0 ????0.0 ????H 2O ????400
????2 ????0.0 ????0.0 ????SGF ????275
????3 a ????0.5 ????0.0 ????H 2O ????500
????4 a ????0.5 ????0.0 ????SGF ????480
????5 b ????0.5 ????5.0 ????H 2O ????1075
????6 b ????0.5 ????5.0 ????SGF ????1025
A: physics dispersion b: molten mixture c: part/100 parts of resins (water is plasticizer)
Embodiment 8
Be solubility curve or the medicine rate of release in time of measuring physical mixture and molten mixture Chinese medicine, use is similar to the dissolver (people such as P.Mura, Il Farmco.-Ed.Pr.vol.426,149,1987) that Mura and colleague thereof adopt.Dissolve medium is made up of 300mL distilled water in the 600mL beaker that is stamped glass plate under 23 ℃ or 0.1N HCl (SGF).Medicament contg in each POLYOX WSR substrate tablet is higher than 1000ppm.Utilize two kinds of technology to prepare tablet.First method is in Carver Press[C type, Carver Lab Press, Menomokee Falls, WI] on, with time of staying of 2 tons pressure and 10 seconds directly the compacting size be the tablet of 28m * 5mm.
When using second method, be pressed on the POLYOX WSR compression molding piece with whole drift and prepare tablet.The geometry of these two kinds of tablets and weight differ and are no more than 0.01g.
Tablet is placed in the beaker and stirs with the 200rpm rotating speed with 5 leaf blade-paddle mixers.At reasonable time at interval, the separatory that waits with 5mL is shifted out and with 0.45m filter paper filtering and the additional fresh dissolve medium of 5mL from dissolution vessel (600mL beaker) transfer.Medicament contg in each interval solution is suitably diluted and is used for the blank of UV-VIS absorption measurement.Measure drug solubility according to the standard curve of having set up as time function.
Table 8 has been listed in water, is disperseed the polyethylene glycol oxide sample Chinese medicine rate of dissolution in time of preparation by melting mixing and physics.Find out that from this table molten mixture Chinese medicine burst size in time is high more a lot of than physical mixture.Simultaneously, total dissolubility of melting mixing system is more much higher than physics dispersion.The improvement of the dissolubility of discussing among above-mentioned rate of release data and the embodiment 5 is very relevant.
Table 8
The dissolubility of tolbutamide in water in external 23 ℃ of following physical mixtures and the molten mixture
Time (hr) Physical mixture dissolubility (ppm) Molten mixture dissolubility (ppm)
????0.0 ????0.3 ????1.0 ????2.0 ????3.0 ????4.0 ????5.0 ????6.0 ????7.0 ????0 ????160 ????255 ????380 ????410 ????360 ????400 ????330 ????350 ????0 ????220 ????480 ????660 ????870 ????840 ????830 ????720 ????700
Embodiment 9
Table 9 has been listed in SGF, by tolbutamide rate of dissolution in time in the polyethylene glycol oxide sample of melting mixing and physics dispersion preparation.From this table, molten mixture Chinese medicine burst size in time is high more a lot of than physical mixture.Simultaneously, total dissolubility of melting mixing system is more much higher than physics dispersion.The improvement of the dissolubility of discussing among above-mentioned rate of release data and the embodiment 5 is very relevant.
Table 9
The dissolubility of tolbutamide in SGF in external 23 ℃ of following physical mixtures and the molten mixture
Time (hr) Physical mixture dissolubility (ppm) Molten mixture dissolubility (ppm)
????0.0 ????0.3 ????1.0 ????2.0 ????3.0 ????4.0 ????5.0 ????6.0 ????7.0 ????0 ????51 ????90 ????109 ????100 ????105 ????110 ????103 ????105 ????0 ????65 ????230 ????420 ????525 ????562 ????510 ????565 ????520
Embodiment 10
Table 10 has been listed in water, by sulfathiazole rate of dissolution in time in the polyethylene glycol oxide sample of melting mixing and physics dispersion preparation.Find out that from this table molten mixture Chinese medicine burst size in time is than the outline height of physical mixture.Simultaneously, total dissolubility of melting mixing system is than physics dispersion height.The improvement of the dissolubility of discussing among above-mentioned rate of release data and the embodiment 6 is very relevant.
Table 10
The dissolubility of sulfathiazole in water in external 23 ℃ of following physical mixtures and the molten mixture
Time (hr) Physical mixture dissolubility (ppm) Molten mixture dissolubility (ppm)
????0.0 ????0.3 ????1.0 ????2.0 ????3.0 ????4.0 ????5.0 ????6.0 ????7.0 ????0 ????480 ????600 ????540 ????660 ????480 ????460 ????580 ????560 ????0 ????620 ????720 ????880 ????704 ????820 ????920 ????720 ????560
Embodiment 11
Table 11 has been listed in water, by hydroflumethiazide rate of dissolution in time in the polyethylene glycol oxide sample of melting mixing and physics dispersion preparation.Find out that from this table molten mixture Chinese medicine burst size in time is high more a lot of than physical mixture.Simultaneously, total dissolubility of melting mixing system is more much higher than physics dispersion.The improvement of the dissolubility of discussing among above-mentioned rate of release data and the embodiment 7 is very relevant.
Table 11
The dissolubility of hydroflumethiazide in water in external 23 ℃ of following physical mixtures and the molten mixture
Time (hr) Physical mixture dissolubility (ppm) Molten mixture dissolubility (ppm)
????0.0 ????0.3 ????1.0 ????2.0 ????3.0 ????4.0 ????5.0 ????6.0 ????7.0 ????0 ????110 ????300 ????375 ????220 ????230 ????260 ????230 ????265 ????0 ????500 ????1100 ????1280 ????704 ????540 ????500 ????410 ????440
Embodiment 12
Table 12 has been listed in SGF, by hydroflumethiazide rate of dissolution in time in the polyethylene glycol oxide sample of melting mixing and physics dispersion preparation.Find out that from this table molten mixture Chinese medicine burst size in time is high more a lot of than physical mixture.Simultaneously, total dissolubility of melting mixing system is more much higher than physics dispersion, reaches 4-5 doubly.The improvement of the dissolubility of discussing among above-mentioned rate of release data and the embodiment 7 is very relevant.
Table 12
The dissolubility of hydroflumethiazide in SGF in external 23 ℃ of following physical mixtures and the molten mixture
Time (hr) Physical mixture dissolubility (ppm) Molten mixture dissolubility (ppm)
????0.0 ????0.3 ????1.0 ????2.0 ????3.0 ????4.0 ????5.0 ????6.0 ????7.0 ????0 ????215 ????350 ????320 ????215 ????230 ????400 ????390 ????375 ????0 ????420 ????1040 ????1400 ????1600 ????1400 ????2100 ????1560 ????1560
Make in the method for water-fast substantially compound water-soluble degree of separating improvement the shelf time stability that important parameter is these chemical compounds for above-mentioned use carrier such as polyethylene glycol oxide.When preparing with water-fast substantially chemical compound, some carrier such as polyvinylpyrrolidone and Polyethylene Glycol make the structure of water-fast substantially chemical compound become amorphous from crystal.The problem that changes in this morphology is that therefore the crystallization again in time of this medicine has reduced water solublity.This trend can be observed (people such as Kedzierewicz, Int.J.Pharm, 117,247,1995) in PEG 6000-tolbutamide system.They find, when storage, and the solubility curve time to time change of the molten mixture of PEG 6000 and tolbutamide.The explanation that this solubility curve is changed may increase relevant 37 ℃ of degree of crystallinity of storing 6 middle of the month down with tolbutamide.Comprise that other example that uses PEG 6000 and indomethacin is the crystallization of the medicine rate of dissolution that reduced active substance people such as (, Drug.Dev.Comme.2,359,1976) Saboe.Other example is that the solubility curve of existing report changes, comprise use nifedipine-polyvinylpyrrolidone (PVP) type system (people such as Sugimoto, Drug.Dev.Ind.Pharm.6,137,1980), indomethacin PEG 6000 (people such as Ford., Pharma ActaHelv.54,353,1979), stable-PEG4000 (people such as Anastasiadou, Drug.Dev.Ind.Pharm.9,103,1983).Find that in these systems humidity is the main cause that causes water-fast substantially compound crystal degree to increase.
The demand of preparation that change in time, stability and durability is not increased.The following example relates to this concern.
Embodiment 13
Preparation among the embodiment 5 was at room temperature stored nearly about 1 year and tested in SGF and distilled water.Table 13 has been listed this system UV-max when t=0 days and t=355 days in water.The absorption value 1.51AU of discovery under 228nm.Be that absorption value is 1.52AU when sample being measured under 228nm again unexpectedly.The dissolubility of medicine in water do not change in time.
The dissolubility of sample in SGF too as can be seen from Table 14.Obtained the maximum absorption during t=0 is 1.64AU.Be that in the time of t=335 days, the obtained the maximum absorption under the 228nm still is 1.65AU astoundingly.The dissolubility of medicine in SGF do not change in time.
Table 13 is 23 ℃ of storage tolbutamide dissolvings in water in the POLYOX WER N-80 molten mixture after 335 days down
Degree
Sample Time (my god) Dissolubility (ppm) Wavelength result (AU)
????1 ????0 ????900 ????1.51
????2 ????335 ????900 ????1.52
Table 14 is the dissolubility of tolbutamide in SGF in the POLYOX WER N-80 molten mixture after 23 ℃ are stored 335 days down
Sample Time (my god) Dissolubility (ppm) Wavelength result (AU)
????1 ????0 ????590 ????1.64
????2 ????335 ????610 ????1.65
This embodiment clearly illustrates: water solubility and this improvement effect that polyoxyalkylene can improve water-fast substantially chemical compound do not change in time.
Embodiment 14
In the present embodiment, tolbutamide is prepared with POLYOX WSR and low molecular poly respectively.POLYOX WSR sample is according to embodiment 5 described method preparations.Polyethylene glycol samples is according to embodiment 1 described method preparation.The results are shown in table 15.Can find out that from this table under higher relatively 5.0% (W/v) polymer concentration, Polyethylene Glycol does not improve the dissolubility (being less than 10.0%) of tolbutamide substantially.Be astoundingly, really not so for high-molecular weight polyoxyalkylene.The dissolubility of this system has improved 800% when polymer concentration only is 1.0% (w/v).
The high molecular polyethylene glycol oxide has not only improved as the water-fast substantially chemical compound of the tolbutamide dissolubility under low pH, and the amount of required polymer is lacked 5 times than the consumption of Polyethylene Glycol.In addition, by using the high molecular polyethylene glycol oxide, people can carry out controlled release to water-fast substantially chemical compound in long-time.The quick dissolving of low molecular poly does not have this release profiles.
Table 15 is by the dissolubility of tolbutamide in SGF of POLYOX WSR N-80 and CARBOWAX PEG 8.000 preparations
Sample Polymer Concentration (%w/v) Dissolubility (ppm)
????1 Do not have ????0.0 ????70
????2 ?PEG?8.000 ????5.0 ????80
????3 ?WSR?N-80 ????1.0 ????575
Though the invention describes relevant concrete aspect, this field professional will recognize that others also belong in the scope of claim hereinafter.

Claims (10)

1. one kind is improved the method that water solubility is lower than the water-fast substantially compound water-soluble degree of separating of about 1000ppmw, comprising; This chemical compound is mixed with water-soluble polymer, this water-soluble polymer has 50,000-7,000,000 gram/molar weight average molecular weight and at least about the water solubility of 1.0 (weight) %, and the content of water-soluble polymer is for can make the water solubility of water-fast substantially chemical compound in sour environment improve 10% at least.
2. the process of claim 1 wherein that water-soluble polymer has oxyalkylene functional group.
3. the method for claim 2, wherein water-soluble polymer is a polyoxyalkylene.
4. the method for claim 2, wherein water-soluble polymer is the polysaccharide of alkoxide.
5. the method for claim 4, wherein water-soluble polymer is a cellulose ether.
6. the method for claim 1 comprises described water-fast substantially chemical compound and described water-soluble polymer is carried out the physical property mixing.
7. the method for claim 6, be included in before the described mixing or in the process with described water-soluble polymer fusion.
8. one kind contains water solubility and is lower than the water-fast substantially chemical compound of about 1000ppmw and the compositions of water-soluble polymer, described water-soluble polymer has 50,000-7,000,000 gram/molar weight average molecular weight and at least about the water solubility of 1.0 (weight) %, and the content of water-soluble polymer is for can make the water solubility of water-fast substantially chemical compound in sour environment improve 10% at least.
9. the compositions of claim 8, said composition is a solid form.
10. the compositions of claim 8.Said composition is a solid form.
CN 97192577 1996-11-04 1997-10-31 Method for enhancing solubility of substantially water-insoluble compounds Pending CN1211928A (en)

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