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

Abstract

A method of increasing the water solubility of a substantially water-insoluble compound having a solubility in water of less than about 1000ppmw is disclosed which comprises mixing the compound with a water-soluble polymer, such as a polyalkylene oxide or a cellulose ether, having a weight average molecular weight of from 50,000 to 7,000,000 g/g and being present in an amount which increases the solubility of the substantially water-insoluble compound in an acidic environment, for example a pH of less than about 5. Compositions comprising compounds having improved aqueous solubility are also disclosed.

Description

Method for increasing the solubility of substantially water-insoluble compounds

field of invention

The present invention relates to a method of increasing the water solubility of substantially water-insoluble compounds comprising admixing said compounds with certain water-soluble polymers.

Background of the invention

Many hydrophobic drugs have limited solubility and dissolution rate due to their low water solubility. It is this rate of dissolution, which is governed by the surface area of dissolution, that limits the bioavailability of many drugs of poor water solubility. Therefore, reducing the particle size has been used to improve the bioavailability of drugs such as griseofulvin (Atkinson et al., Antibiotic Chemotherapy 12, 232, 1962), sulfisoxazole (Fincher et al., J. Pharm. Sci., 4, 704, 1965). However, unless the formulation of the micronized drug (Yamamato et al., Journal of Pharmaceutical Sciences, 65, 1484, 1976) is carefully controlled, there will be a problem due to aggregation (Lin et al., Journal of Pharmaceutical Sciences, 57, 2143, 1968), Agglomeration (Finholt et al., Med. Norsk. Farm. Selskap., 28, 17, 1966) or air absorption lead to low powder wettability which reduces the effective surface area and bioavailability cannot be improved accordingly.

For the above reasons, techniques involving solvent deposition, freeze-drying, solvate formation, micellation with surfactants, and solid dispersion have all been used to improve drug bioavailability (Jun et al., J. Kor. Pharm. Sci. 20, 1120, 1990). The concept of the solid dispersion method was proposed by Sekiguchi and Obi (Chemical Drug Bulletin, 9, 866, 1961). In their study, they found that the eutectic mixture of low water-soluble drug-sulfathiazole and physiologically inert water-soluble carrier-urea has higher absorption and excretion after oral administration than sulfathiazole alone. Other water-soluble solvents used in solid dispersion methods include polyethylene glycol ("PEG") (Simonelli et al., Journal of Pharmaceutical Sciences, 65, 3, 355, 1976 and Chin. Arch. Pharm. Res. 2(1), 49 , 1979), polyvinylpyrrolidone (Kollidon® polyvinylpyrrolidone in the pharmaceutical industry, Volker Buhler, BASF, Ludwigshafen, 88, 1993) and cyclodextrins (ElBarma et al., Pharmazie 30, 788, 1993). Such materials generally have relatively low molecular weights, eg, less than about 80,000 g/mol, and are not sufficiently effective in acidic environments, eg, pH below about 5.

Therefore, there is an urgent need for methods capable of increasing the water solubility of substantially water-insoluble compounds, especially in acidic environments. There is a need for improved compositions with increased solubility that can be administered in both solid and liquid forms.

Summary of the invention

The present invention provides improved methods of increasing the water solubility of substantially water insoluble compounds. The method comprises: combining a substantially water-insoluble compound with an effective amount of a water-soluble polymer having a weight average molecular weight of about 50,000 to about 7,000,000 g/mole to enhance the water solubility of the compound in an acidic environment (e.g., pH below about 5). Mixed in an effective amount.

In view of the advantages of the present invention, the water solubility of substantially water insoluble compounds can be increased by at least about 10% to about 500% or more herein. Therefore, when the method of the present invention is used to increase the water solubility of substantially water-insoluble drugs such as ibuprofen and tolbutamide, although the amount of ibuprofen or tolbutamide required to treat a patient is reduced, the An effective amount to treat the condition provided is not reduced. In addition, by selecting the appropriate molecular weight range of the water-soluble polymer or polymer conjunct, the release profile of the compound from solution can be tuned to a desired rate.

The present invention also provides compositions comprising a substantially water-insoluble compound in admixture with a water-soluble polymer. Detailed description of the invention

There is no critical limitation on the particular substantially water-insoluble compounds suitable for use in the present invention. Generally, such compounds will have a water solubility of less than 1,000 parts per million by weight ("ppmw"), preferably less than about 600 ppmw. Here, the term "water solubility" means the amount of a compound or polymer dissolved in distilled water (pH=7.0) at 25°C and 1 atmosphere, unless otherwise specified. Typical water-insoluble compounds include, for example, drugs, ie, compounds that have medicinal, therapeutic or diagnostic effects on mammals; and other compounds, such as antimicrobials, biocides, inks, colorants, preservatives, additives, and the like.

Specific classes of drugs that can be used in the methods and compositions of the invention include; for example, abortifacients, hypnotics, sedatives, tranquillizers, anti-inflammatory agents, antihistamines, antitussives, anticonvulsants, muscle relaxants, antineoplastic agents drugs (such as those that treat malignant neoplasia), local anesthetics, agents for Parkinson's disease, topical or dermal agents, diuretics (such as those containing potassium such as potassium iodide), drugs for the treatment of mental disorders (such as those that treat Lithium-containing medicines for manic depression), anticonvulsants, antiulcers, preparations containing various substances for the treatment of pathogen-type infections (including antifungals such as metronidazole), antiparasitics and other antimicrobials, Antibiotics, antibacterials, antiseptics, antimalarials, hormonal cardiovascular agents (eg, androgenic estrogens and progestogens), rare steroids (eg, estradiol), sympathomimetics, hypoglycemic agents , nutritional supplements, preparations containing multiple active types of enzymes (such as chymotrypsin), analgesics (such as aspirin) and agents with other types of action (including nematocides) and other veterinary drugs, contraceptives (such as spermicides), virucides, vitamins, vasodilators, antacids, kerolytic agents, antidiarrheal agents, anti-hair loss agents, glaucoma agents, dry eye compositions, wound healing agents, etc.

Examples of drugs that are substantially insoluble in water and suitable for use in the present invention include: ibuprofen, ketoprofen, chlorthalidone, sulfamethazine, papaverine, sulfamethoxine, hydrochlorothiazide, bendrofluthiazide, acesulfame Urine, diazepam, glipizide, nifedipine, griseofulvin, acetaminophen, indomethacin, chlorpropamide, phenoxybenzamine, sulfathiazole, nitrazepam, furosemide, Phenytoin, hydroflumethazide, tolbutamide, thiakylperazine maleate, dizoxin, reserpine, acetazolamide, methazolamide, bendroflumethazide, chlorpropamide, chlormadinone acetate Esters, acetaminophen, salicylic acid, methotrexate, acesulfamethoxazole, erythromycin, progestogens, estrogens, progestational hormones, corticosteroids, etc.

Preferred drugs suitable for use in the method of the invention are selected from the group consisting of ibuprofen, tolbutamide, sulfathiazole and hydrofluorothiazide and mixtures thereof.

Water-soluble polymers suitable for use in the present invention have a water solubility (as defined above) of at least about 1.0% by weight, preferably at least about 2.0% by weight.

Typically, the molecular weight of the water-soluble polymer is about 50,000-7,000,000, preferably about 80,000-4,000,000, more preferably about 100,000-750,000 g/mol. The term "molecular weight" herein refers to weight average molecular weight. Methods for determining weight average molecular weight are well known to those skilled in the art and include methods known as, for example, small angle light scattering.

The average particle size of the water-soluble polymer is not critical in the present invention, but generally ranges from about 0.01 micron to 1000 microns, and preferably from about 50 microns to 150 microns.

Preferably the water soluble polymer has oxyalkylene functionality. More preferably the alkylene oxide is selected from ethylene oxide, propylene oxide and mixtures thereof. Most preferred polymers include polyalkylene oxides and alkoxylated polysaccharides.

Polyoxyalkylene polymers generally containing from about 2 to about 4 carbon atoms per monomer molecule in the polymer can be used in the present invention. Ethylene oxide and propylene oxide monomers are preferred. Polyethylene oxide polymers are more preferably used in the present invention. Polyethylene oxide polymers include, for example, ethylene oxide homopolymers and copolymers of ethylene oxide with one or more polymerizable alkylene oxide comonomers. The particular comonomer is not critical in the present invention and may contain hydrocarbon substituents such as alkyl, cycloalkyl, aryl, olefin, and branched chain alkyl. However, the amount of comonomers such as 1,2-propylene oxide must not be too high so as not to render the polyethylene oxide insoluble in water. Conventional alkylene oxides include 1,2-propylene oxide, 2,3-butylene oxide, 1,2-butylene oxide, styrene oxide, 2,3-epoxyhexane, 1,2-epoxyoctane, Butadiene monooxide (monomside), cyclohexane monoxide, 3-chloro-1,2-propylene oxide, and the like.

Polyoxyalkylenes suitable for use in the process of the invention, such as polyethylene oxide, are commercially available from Union Carbide Corporation, Danbury, CT. Details regarding polyoxyalkylene polymers suitable for use in the present invention are known to those skilled in the art.

Alkoxylated polysaccharides (also known as polysaccharide ethers) are also suitable for use in the process according to the invention.

Polysaccharide materials suitable for the present invention include natural, biosynthetic and derivatized carbohydrate polymers or mixtures thereof. These materials consist of high molecular weight polymers consisting of monosaccharide units linked by glycosidic bonds. Such raw materials may include, for example, whole starches and celluloses; pectin, chitosan, chitin; seaweed products such as agar and carrageenan; alginates; natural gums such as guar, acacia and Tragacanth gum; biological gum, such as xanthan gum, etc. Preferred raw materials include celluloses commonly used in the preparation of cellulose ethers, such as chemical cotton, cotton linters, wood pulp, alkali cellulose, and the like. The aforementioned raw materials are commercially available.

Polysaccharides suitable for use in the present invention generally have a molecular weight of about 50,000-2,000,000 g/mol, and preferably about 80,000-250,000 g/mol.

The particular derivatizing reagent (eg, alkyl halide or alkylene oxide) used to prepare the polysaccharide is not critical in the present invention. Alkylene oxides suitable for use in the present invention comprise from about 2 to 24, preferably from about 2 to 5 carbon atoms per molecule. Specific examples include: ethylene oxide, propylene oxide and butylene oxide. Typically, ether substituents are derivatized on cellulose by reaction between polysaccharides and alkylene oxides, preferably ethylene oxide. The level of ether substituents is generally about 1.5-6 and preferably about 2-4 moles of ether substituents per mole of polysaccharide ether. Suitable haloalkanes include, for example, ethyl chloride or methyl chloride.

The polysaccharide ethers may be substituted with one or more desired substituents, such as cationic, anionic and/hydrophobic substituents. Hydrophobic substituents are well known in the art and generally comprise alkyl, alkylene, arylalkylene or aralkyl groups having 8-24 carbon atoms per molecule. Hydrophobically modified cellulose ethers are disclosed, for example, in US Patents 4,228,277, 5,120,328 and 5,504,123 and European Patent Publication 0 384 167 B1. Cationic hydrophobically modified cellulose ethers are described, for example, in US Pat. No. 4,663,159. The degree of substitution of these substituents on each polysaccharide ether is generally from about 0.001 to 0.1 and preferably from about 0.004 to about 0.05 moles of substituent per mole of polysaccharide ether. There may be more than one specific substituent on the polysaccharide ether.

The polysaccharide ether generally has a viscosity of about 1-8000 centipoise, preferably about 100-3000 centipoise. Unless otherwise stated, the term "viscosity" herein refers to the viscosity of a 1.0% by weight aqueous polymer solution measured with a Brookfield viscometer at 25°C. Such viscometry techniques are known in the art and described in ASTM D2364-89. The average particle size of the polysaccharide ether is not critical, but is preferably between about 0.01-1000 microns and more preferably between about 50-400 microns.

The preferred polysaccharide ethers produced by the present invention are cellulose ethers, which include; for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose Hydroxyethylmethylcellulose, carboxymethylcellulose, hydroxyethylcarboxymethylcellulose and their derivatives.

The amount of water-soluble polymer effective to increase the water solubility of the substantially water-insoluble compound is generally in the range of about 1-500, preferably about 20-300, more preferably 50-250 grams of polymer per gram of compound. Such concentrations typically range accordingly from about 0.1% by weight of the polymer to about the limiting solubility of the polymer in the aqueous liquid, eg 25% by weight or less. Specifically, the polymer concentration ranges from about 0.1 to 5% by weight, preferably 0.1 to 2% by weight, based on the total weight of the aqueous solution.

The water soluble polymer can be physically mixed with the compound in the dry state, wet, or when a thermoplastic polymer is used, the polymer can be melted and melt mixed with the compound before or during mixing with the compound. More specifically, incorporation techniques and equipment suitable for this purpose are well known to those skilled in the art.

Solubility can be enhanced by adding the substantially water-insoluble compound directly to the aqueous composition containing the water-soluble carrier or by blending the carrier and the substantially water-insoluble compound in the molten state. Unlike literature US Patent 4,687,662 (1987,8,18 authorized), 4,689,218 (1987,8,25 authorized), 4,834,966 (1989,5,30 authorized), 4,861,797 (1989,8,29 authorized) and WO96/19973 (published Incorporation of effervescent agents to improve the solubility of active substances (e.g. ibuprofen) as described in date 1996, July 4) or the use of surfactants as described in European patent application 0 228 164 A2 (published date 1987, August 7) In the present invention, there is no need to add any of the above reagents. There is also no need to use organic solvents as disclosed in US Pat. No. 5,225,204 (issued Jul. 6, 1993) to increase the solubility of substantially water-insoluble compounds.

In addition to water-soluble polymers used to enhance water solubility, other polymers known to those skilled in the art may also be employed in the present invention. These polymers include, for example, those selected from the group consisting of hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, cationic cellulose ethers, polyvinylpyrrolidone, carboxyvinyl polymers, hydroxypropylmethylcellulose phthalates Formate, Acetate Phthalate, Methyl Acrylate Meta Acrylic Copolymer, Polyvinyl Acetal Dialkylaminoacetate, Dimethylaminoalkyl Meta Acrylate Meta Acrylic Copolymer, Acrylic 2 -Methyl-5-vinylpicolyl ester Interacrylic acid copolymer, citric acid, urea, succinic acid and amino acids. Concentrations of polymers suitable for use in the present invention, other than water-soluble polymers, are not critical, but generally range from about 0.1 to 99% by weight, based on the total weight of water-soluble polymers, compounds, and other polymers. Details regarding the selection and use of the other polymers described above are known to those skilled in the art.

In general terms of the invention, the amount of water-soluble polymer in solution in combination with the substantially water-insoluble compound is effective to increase solubility by 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%. More than one type of water-soluble polymer may be used. This increase in solubility is generally relative to a concentration of at least 100 ppmw, preferably at least 150 ppmw, more preferably at least 300 ppm of the soluble compound when the aqueous liquid form is prepared.

The methods described herein can be utilized to provide stable compositions with enhanced solubility in any desired form. More specifically, the compositions provided by the present invention may be liquid, solid or mixtures thereof. Typical forms may be films, tapes, sheets, gels, tablets, granules, aqueous solutions, dispersions and other free-flowing liquids. The physical properties of the compositions of the present invention will depend on the relative amounts of polymers and compounds in the composition. For example, the concentration of polyoxyalkylene or water-soluble polymer in the solid composition can vary over a wide range from very low concentrations such as 0.1% by weight to very high concentrations of 99% by weight or more. Liquid compositions, especially alkoxylated polysaccharide polymers, will generally contain substantially lower amounts of polymer, generally from 0.1 to about 5% by weight.

Surprisingly, the present invention, in addition to providing compositions with enhanced solubility, also provides delayed release of compounds in aqueous solutions. It has been found that when using water soluble polymers having a certain molecular weight range, the release profile profile can be tailored to a desired level. In particular, when a relatively sustained release profile of the compound is desired, e.g., over 12 hours, the preferred water-soluble polymers are polyethylene oxide polymers in the molecular weight range of about 900,000-7,000,000 and polyoxyethylene polymers in the molecular weight range of 500,000-1,000,000. Alkoxylated polysaccharide polymer. Conversely, polyethylene oxide polymers with molecular weights in the range of about 100,000-600,000 and alkanes with molecular weights in the range of 100,000-400,000 are preferred among water-soluble polymers when it is desired to provide a profile that starts faster and then is slower. Oxylated polysaccharide polymers.

The methods and compositions described herein have a wide variety of end uses, such as industrial uses and personal healthcare applications. Typical industrial applications include, for example, enhanced solubility of antimicrobial compounds, biocides, dyes and colorants, preservatives, additives, and the like. Typical personal care applications include, for example, various pharmaceutical and cosmetic compositions.

Representative pharmaceutical tablets employed in the present invention can be prepared by any method known to those skilled in the art, such as direct compression, granulation with a suitable solvent followed by compression, melt manufacturing, and manufacture of dosage forms. These solid form deliverables typically contain compounds, water soluble polymers and other known ingredients including, for example, lactose, magnesium or calcium stearate, dicalcium phosphate, mannitol and microcrystalline cellulose. The alkoxylated polysaccharide polymer composition can also be delivered as a semi-solid/liquid dosage application such as a medicament for colds and headaches. Equipment conditions and techniques for preparing the above compositions are known to those skilled in the art. See, US Patent 5,273,758 (issued on December 28, 1993), 4,343,789 (issued on August 10, 1982), and US Patent 5,116,145 (issued on November 24, 1992).

Surprisingly, the water soluble polymers of the present invention are effective in increasing the solubility of compounds in acidic environments, preferably at a pH below about 5, more preferably below about 3, and most preferably at a gastric acidity, e.g., about pH=1.1.

The following examples are intended to illustrate and not to limit the scope of the following claims.

Example 1

An aqueous solution of CELLOSIZE(R) HEC09L (80,000 g/mol, Union Carbide Corp. Danbury, CT) was prepared in a 100 milliliter ("mL") volumetric flask at 25°C on a magnetic stir plate. The concentrations of the HEC solutions were 0.5, 1.0 and 2.0% by weight. Excess drug was added to these solutions and stirring was continued at 23°C for 2 hours to form saturated solutions. At the conclusion of the process, a small aliquot was removed and filtered through a 0.45 micron ("m") filter paper and the filtrate diluted appropriately, was used in a UV-VIS spectrophotometer (Hewlett Packard) to measure absorbance at the appropriate wavelength. Blank control. Drug solubility was determined from established calibration curves. The data are listed in Table 1.

Table 1

Increased Solubility of Ibuprofen in CELLOSIZE HEC Polymer Solutions sample Concentration (%w/v) Solubility of ibuprofen (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 of improving the solubility of ibuprofen, and the 2.0% (w/v) solution has increased by 4 times.

Example 2

To determine whether other pharmaceutical industry binders can be used to increase the water solubility of ibuprofen, the following material was also tested: METHOCEL® K100 LV Prem CR [Hydroxypropylmethylcellulose (HPMC), Dow Chemical Company, Molecular Weight : 23,000 g/mol]. The HPMC polymer was dissolved in water according to the manufacturer's (Catalogue, Dow Chemical Company, Midland, MI.) recommendation. In this process, the polymer is dispersed in cold water under high shear, and then the temperature is slowly raised to facilitate polymer dissolution. After solubilization, the temperature was cooled to room temperature. The polymer is not easily soluble at room temperature. To this solution was added excess ibuprofen and analyzed as described in Example 1. The results obtained for these samples were as follows:

                                                                    

fruit sample Concentration (%w/v) Solubility of ibuprofen (ppm) CELLOSIZE WP-09L 0.0 50 CELLOSIZE WP-09L 1.0 140 CELLOSIZE WP-09L 2.0 230 METHOCEL ^K100a 1.0 50＜ METHOCEL ^K100a 2.0 50＜

According to the data, HPMC had little effect on the increase in the water solubility of ibuprofen compared to CELLOSIZE HEC WP-09L.

Example 3

To determine whether hydroxyethyl cellulose has an increasing effect on the solubility of other types of drugs, amine-type drugs such as tolbutamide (Sigma Chemical Company, St. Louis, MO) can be tested. Process sample according to the mode of embodiment 1, the result is as shown in table 3:

table 3

Solubility of tolbutamide in solution of CELLOSIZE HEC WP 09 sample Concentration (%w/v) Tolbutamide solubility (ppm) CELLOSIZE HEC 0.0 75 CELLOSIZE HEC 0.5 200 CELLOSIZE HEC 1.0 175 CELLOSIZE HEC 2.0 300

It can be seen that CELLOSIZE HEC aqueous solution is helpful for the solubilization of amine drugs. In the concentration range of 0.5%-2.0%, the solubility of tolbutamide increases by 75ppm-300ppm. Without being bound by any theory, it appears that solubilization of the drug may result from interactions between the drug and the polymer chains.

The solubility increasing effect of all the above mentioned drugs was determined in water. In the following, the determination is carried out with a medium having a lower pH (symbolized gastric pH).

Example 4

Samples were prepared in the manner of Example 1. A physical dispersion of tolbutamide was prepared in CELLOSIZE HEC WP 09L at a concentration of 0.5-2.0% dissolved in simulated gastric fluid (SGF, pH=1.1). Table 4 lists the pH before and after dosing and the maximum solubility of the drug in this medium. From the table, in 0.5% hydroxyethyl cellulose solution, the solubility of tolbutamide has basically increased from 75ppm to 170ppm. Hydroxyethyl cellulose not only improves the solubility of poorly water-soluble drugs under neutral pH conditions, but also improves solubility under low pH conditions.

Table 4

pH before and after drug addition in CELLOSIZE HEC WP 09L prepared in SGF polymer Concentration (w/v) drug pH before dosing pH after dosing Solubility (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 the table, it is clear that CELLOSIZE HEC can improve the solubility of low water-soluble drugs such as ibuprofen and tolbutamide in aqueous media with certain pH characteristics.

Example 5

Polyethylene oxide, another hydrophilic binder commonly used in the pharmaceutical industry, was investigated to determine whether it could increase the solubility of substantially water-insoluble compounds. Unlike hydroxyethyl cellulose, this material is thermoplastic, ie, it can be remelted and reshaped by conventional melt processing equipment without loss of molecular weight.

In the following examples, methods and techniques for preparing molten mixtures of polyethylene oxide and substantially water-insoluble compounds are described.

100 g of POLYOX® WSR N-80 was charged into a Cuisinart Pro Custom II™ WSR mixing bowl. Spray distilled water into the above-mentioned barrel in the form of a fine mist and in an amount of 5-15 phr (parts per hundred parts of resin). The POLYOX(R) WSR and water were blended for approximately 2 minutes, then the mixer was stopped and all material stuck to the walls of the bowl was scraped back into the bowl. The materials were then mixed for an additional 2 minutes. At this point, the active material (25 g) was introduced and mixing was continued for 2 minutes for complete granulation, collected and stored in polyethylene bags at 5°C for later use. The free-flowing granules are still evident after adding the active.

50 g of granules were fed into a Brabender Plasticorder fitted with a twin screw mixing head. The cylinder temperature is in the range of 80-120°C depending on the active substance used. The stirring speed was in all cases 30 rpm. When the granules are added to the mixing drum, the temperature drops by 5°C-10°C and slowly rises back to the set temperature point after melting. Allow the materials to mix for 2-3 minutes. Stirring was stopped and the molten material was scooped out of the mixing bowl and allowed to cool isothermally to room temperature on a metal platen. The final composition was slightly viscous.

The molten material from the Brabender was compressed into blocks on a Greenard Press. The size of the block is 63mm x 63mm x 3mm. Each system was thermally cycled independently of the active material used: heating at 80°C for 1 minute without pressure, heating at 2,000 psig for 1 minute, and then cooling isothermally to room temperature. The material was in each case separated from the top of the block with Teflon(R) Release paper. Tablets weighing 3.5 g are punched out from the above block.

The above tablets were placed in a 100 mL volumetric flask containing distilled water and placed on a magnetic stir plate at 25°C. The concentration (% w/v) of POLYOX WSR solution is between 0.5-2.0. Each solution contained an excess of drug to form a saturated solution, which was stirred at 23°C for 2 hours.

At the end of the process, a small aliquot was transferred and filtered through a 0.45 m filter paper and the filtrate was diluted appropriately and used as a blank for UV-VIS spectrophotometer absorbance at the appropriate wavelength. Drug solubility was determined from established calibration curves. The data in Table 5 illustrate the use of low molecular weight polyethylene oxide resins and tolbutamide.

It can be seen from Table 5 that the maximum solubility of tolbutamide in water (pH=7.0) and simulated gastric juice (pH=1.1) is close to 70ppm. When polyethylene oxide was simply added to the aqueous solution, the solubility of tolbutamide was significantly increased by a factor of 3 or 300%. There is a similar improvement in SGF, apparently a little over 2x.

Surprisingly, a higher increase in drug solubility was found from studies of the melt mixture at 5, 10 and 15 phr. For example, at 5phr, the solubility of tolbutamide in water is more than 1.0 times higher than that of water containing tolbutamide alone. This improvement is higher than that produced by simply mixing the polymer and drug in solution. Without being bound by any particular theory or concept, it is apparent that the improvement in drug solubility induced by the melt mixing technique may be the result of good mixing in the melt phase and enhanced polymer-drug interaction, which can be further enhanced. Enhances the polymer-drug interaction, thus increasing water solubility. Regardless of the concentration of plasticizer used in this test, the increase in solubility of the drug in water was the same, 10-fold, in all cases.

In SGF, the solubility curves of molten mixtures also showed a similar trend. All mixtures increased tolbutamide solubility by a factor of 8, the physical mixture only increased solubility by a factor of two. The advantages identified by the present invention allow one to improve the solubility of substantially water-insoluble drugs in media of various pH values by melt mixing with hydrophilic thermoplastic polyethylene oxide. More importantly, lower operating temperatures can be used to reduce drug degradation during production.

table 5

      POLYOX WSR N-80 in dispersions and melt mixtures

Solubility of Tolbutamide in H ₂ O and SGF sample POLYOX WSR Concentration (% w/v) Plasticizer concentration (phr) ^c medium Solubility (ppm) 1 0.0 0.0 H ₂ O 70 2 0.0 0.0 SGF 70 ^3a 1.0 0.0 H ₂ O 225 ^4a 1.0 0.0 SGF 125 ^5a 1.0 5.0 H ₂ O 900 ^6b 1.0 5.0 SGF 575 ^7b 1.0 10.0 H ₂ O 925 ^8b 1.0 10.0 SGF 610 ^9b 1.0 15.0 H ₂ O 900 ^10b 1.0 15.0 SGF 650 a: Physical dispersion b: Melt mixture c: Parts/100 parts of resin (water is plasticizer)

Example 6

To test whether polyethylene oxide has similar effects on other drugs, sulfathiazole was used to prepare molten samples and the procedure described in Example 5 was followed. The data obtained for this system are listed in Table 6. From Table 6, when the drug is melt-mixed with polyethylene oxide, the solubility of sulfathiazole is increased by more than 2 times. But this is not the case for physical dispersions, where drug solubility remains constant. That is, melt mixing of a substantially water-insoluble compound and a polymer results in an increase in solubility, whereas dispersion of the two substances in water does not increase solubility significantly. Solubility increases over 200%.

Table 6

Solubility of Sulfathiazole in _H2O in POLYOX WSR N-80 Dispersions and Melt Mixtures sample POLYOX WSR Concentration (% w/v) Plasticizer concentration (phr) ^c Solubility (ppm) 1 0.0 0.0 550 ^2a 1.0 0.0 605 ^3b 1.0 5.0 1225 a: Physical dispersion b: Melt mixture c: Parts/100 parts of resin (water is plasticizer)

Example 7

To test whether polyethylene oxide has similar effects on other drugs, hydrofluorothiazide was used to prepare molten samples and the procedure described in Example 5 was followed. The data obtained for this system are listed in Table 7. From Table 7, when the drug is melt-mixed with polyethylene oxide, the solubility of sulfathiazole is slightly increased by more than 2 times. But this is not the case for physical dispersions, where drug solubility remains constant. That is, melt mixing of a substantially water-insoluble compound and a polymer results in an increase in solubility, whereas dispersion of the two substances in water does not increase solubility significantly.

Table 7

  Hydrofluoromethiazide in POLYOX WSR N-80 Dispersions and Melt Mixtures

Solubility in H ₂ O and SGF sample POLYOX WSR Concentration (% w/v) Plasticizer concentration (phr) ^c medium dissolved (ppm) 1 0.0 0.0 H ₂ O 400 2 0.0 0.0 SGF 275 ^3a 0.5 0.0 H ₂ O 500 ^4a 0.5 0.0 SGF 480 ^5b 0.5 5.0 H ₂ O 1075 ^6b 0.5 5.0 SGF 1025 a: Physical dispersion b: Melt mixture c: Parts/100 parts of resin (water is plasticizer)

Example 8

To determine the dissolution profile or release rate of the drug over time in both physical and molten mixtures, a dissolution apparatus similar to that employed by Mura and co-workers (P. Mura et al., Il Farmco.-Ed. Pr. vol. .426, 149, 1987). The dissolution medium consisted of 300 mL of distilled water or 0.1 N HCl (SGF) in a 600 mL beaker covered with a glass plate at 23°C. The drug content in each POLYOX WSR matrix tablet is higher than 1000ppm. Tablets are prepared using two techniques. The first method was direct compression of tablets measuring 28 m x 5 mm on a Carver Press [type C, Carver Lab Press, Menomokee Falls, WI] at a pressure of 2 tons and a dwell time of 10 seconds.

When using the second method, tablets are prepared by compressing the full punch onto the POLYOX WSR compression-molded block. The geometry and weight of the two tablets differed by no more than 0.01 g.

The tablets were placed in a beaker and stirred with a 5-blade paddle mixer at 200 rpm. At appropriate time intervals, 5 mL aliquots were transferred from the dissolution vessel (600 mL beaker) and filtered through 0.45 m filter paper and replenished with 5 mL of fresh dissolution medium. The drug content in the solution at each time interval was appropriately diluted and used as a blank control for UV-VIS absorption determination. Drug solubility was determined according to established standard curves as a function of time.

Table 8 lists the drug dissolution rates over time in water for polyethylene oxide samples prepared by melt mixing and physical dispersion. From this table it can be seen that the amount of drug released over time is much higher from the molten mixture than from the physical mixture. At the same time, the total solubility of the melt mixing system is much higher than that of the physical dispersion system. The above release rate data correlates very well with the improvement in solubility discussed in Example 5.

Table 8

Solubility of tolbutamide in water in physical mixtures and molten mixtures at 23°C in vitro time (hour) Physical mixture solubility (ppm) Melt mixture solubility (ppm) 0.00.31.02.03.04.05.06.07.0 0160255380410360400330350 0220480660870840830720700

Example 9

Table 9 lists the dissolution rate of tolbutamide in SGF over time in polyethylene oxide samples prepared by melt mixing and physical dispersion. From this table, it can be seen that the amount of drug released over time is much higher from the molten mixture than from the physical mixture. At the same time, the total solubility of the melt mixing system is much higher than that of the physical dispersion system. The above release rate data correlates very well with the improvement in solubility discussed in Example 5.

Table 9

Solubility of tolbutamide in SGF in physical mixtures and molten mixtures at 23°C in vitro time (hour) Physical mixture solubility (ppm) Melt mixture solubility (ppm) 0.00.31.02.03.04.05.06.07.0 05190109100105110103105 065230420525562510565520

Example 10

Table 10 lists the dissolution rate of sulfathiazole in water over time in polyethylene oxide samples prepared by melt mixing and physical dispersion. From this table it can be seen that the amount of drug released over time is slightly higher from the molten blend than from the physical blend. At the same time, the total solubility of the melt mixing system is higher than that of the physical dispersion system. The above release rate data correlates very well with the improvement in solubility discussed in Example 6.

Table 10

Solubility of sulfathiazole in water in physical and molten mixtures at 23 °C in vitro time (hour) Physical mixture solubility (ppm) Melt mixture solubility (ppm) 0.00.31.02.03.04.05.06.07.0 0480600540660480460580560 0620720880704820920720560

Example 11

Table 11 lists the dissolution rate of hydrofluoromethiazine over time in polyethylene oxide samples prepared by melt mixing and physical dispersion in water. From this table it can be seen that the amount of drug released over time is much higher from the molten mixture than from the physical mixture. At the same time, the total solubility of the melt mixing system is much higher than that of the physical dispersion system. The above release rate data correlates very well with the improvement in solubility discussed in Example 7.

Table 11

Solubility of hydroflumethiazine in physical mixtures and molten mixtures in water at 23°C in vitro time (hour) Physical mixture solubility (ppm) Melt mixture solubility (ppm) 0.00.31.02.03.04.05.06.07.0 0110300375220230260230265 050011001280704540500410440

Example 12

Table 12 lists the dissolution rate of hydrofluoromethiazine over time in polyethylene oxide samples prepared by melt mixing and physical dispersion in SGF. From this table it can be seen that the amount of drug released over time is much higher from the molten mixture than from the physical mixture. At the same time, the total solubility of the melt mixing system is much higher than that of the physical dispersion system, up to 4-5 times. The above release rate data correlates very well with the improvement in solubility discussed in Example 7.

Table 12

Solubility of hydrofluoromethiazine in SGF in physical mixtures and molten mixtures at 23 °C in vitro time (hour) Physical mixture solubility (ppm) Melt mixture solubility (ppm) 0.00.31.02.03.04.05.06.07.0 0215350320215230400390375 04201040140016001400210015601560

An important parameter for the aforementioned methods of improving the water solubility of substantially water-insoluble compounds using carriers such as polyethylene oxide is the shelf-life stability of these compounds. Certain carriers, such as polyvinylpyrrolidone and polyethylene glycol, change the structure of the substantially water-insoluble compound from crystalline to amorphous when formulated with the substantially water-insoluble compound. The problem with this morphological change is that the drug may recrystallize over time, thus reducing water solubility. This trend was observed in the PEG 6000-tolbutamide system (Kedzierewicz et al., Int. J. Pharm, 117, 247, 1995). They found that the dissolution profile of the molten mixture of PEG 6000 and tolbutamide changed with time upon storage. The explanation for this change in the dissolution profile may be related to the increased crystallinity of tolbutamide during storage at 37°C for 6 months. Other examples involving the use of PEG 6000 and indomethacin are that crystallization of the drug reduces the dissolution rate of the active substance (Saboe et al., Drug. Dev. Comme. 2, 359, 1976). Other examples are reported changes in dissolution profiles, including the use of nifedipine-polyvinylpyrrolidone (PVP) type systems (Sugimoto et al., Drug. Dev. Ind. Pharm. 6, 137, 1980), indomethacin PEG 6000 (Ford. et al., Pharma Acta Helv. 54, 353, 1979), Diazepam-PEG4000 (Anastasiadou et al., Drug. Dev. Ind. Pharm. 9, 103, 1983). In these systems, humidity was found to be the main cause of increased crystallinity of substantially water-insoluble compounds.

The demand for stable and durable formulations that do not change over time is increasing. The following examples address this concern.

Example 13

The formulation in Example 5 was stored at room temperature for approximately 1 year and tested again in SGF and distilled water. Table 13 lists the UV-max of the system in water at t=0 day and t=355 day. Absorption at 228 nm was found to be 1.51 AU. Surprisingly, the sample was then measured at 228 nm with an absorbance of 1.52 AU. The solubility of the drug in water does not change with time.

It can be seen from Table 14 that the solubility of the samples in SGF is also the same. The maximum absorption value at t=0 is 1.64AU. Surprisingly, at t=335 days, the maximum absorption value at 228nm is still 1.65AU. The solubility of the drug in SGF does not change with time.

Table 13 Dissolution of tolbutamide in POLYOX WER N-80 molten mixture in water after storage at 23°C for 335 days

Spend sample time (days) Solubility (ppm) Wavelength Results (AU) 1 0 900 1.51 2 335 900 1.52

Table 14 Solubility of tolbutamide in SGF in POLYOX WER N-80 melt mixture after storage at 23°C for 335 days sample time (days) Solubility (ppm) Wavelength Results (AU) 1 0 590 1.64 2 335 610 1.65 This example clearly demonstrates that polyoxyalkylenes can increase the water solubility of substantially water-insoluble compounds and that this improvement does not change over time.

Example 14

In this example, tolbutamide was formulated with POLYOX WSR and low molecular weight polyethylene glycol respectively. POLYOX WSR samples were prepared according to the method described in Example 5. Polyethylene glycol samples were prepared according to the method described in Example 1. The results are listed in Table 15. As can be seen from the table, at the relatively high polymer concentration of 5.0% (W/v), polyethylene glycol did not substantially improve the solubility of tolbutamide (less than 10.0%). Surprisingly, this is not the case for high molecular weight polyoxyalkylenes. The solubility of this system increased by 800% at a polymer concentration of only 1.0% (w/v).

High molecular weight polyethylene oxide not only improves the solubility of substantially water-insoluble compounds such as tolbutamide at low pH, but also requires five times less polymer than polyethylene glycol. Furthermore, by using high molecular weight polyethylene oxide, one can achieve controlled release of substantially water-insoluble compounds over extended periods of time. Low molecular weight polyethylene glycols that dissolve quickly do not have this release profile.

Table 15 Solubility of tolbutamide in SGF prepared by POLYOX WSR N-80 and CARBOWAX PEG 8.000 sample polymer Concentration (%w/v) Solubility (ppm) 1 none 0.0 70 2 PEG 8.000 5.0 80 3 WSR N-80 1.0 575

While the disclosure has been described with respect to particular aspects, those skilled in the art will recognize other aspects that are also within the scope of the following claims.

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.