The invention provides a number of methods for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water. In one preferred embodiment, solubilization of the active ingredient is enhanced by combining it with .beta.-cyclodextrin in an aqueous complexation medium comprising .beta.-cyclodextrin and a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with .beta.-cyclodextrin and its inclusion complexes.

SUMMARY AND OBJECTS OF THE INVENTION

The present invention involves formation of guest/host inclusion complex microaggregates and their industrial applications. These aggregates are invisible to the human eye and cannot be detected by a conventional light microscope and, thus, their diameter is less than the wavelength of visible light (less than about 600 nm). Because they in most cases do not produce light scattering, their diameter is most probably less than one quarter of the wavelength of visible light, or less than about 140 nm. Such microaggregates will appear transparent or translucent due to diminished light scattering. The diameter of .beta.-cyclodextrin is approximately 1.5 nm.

More specifically, the present invention involves non-inclusion solubilization of water-insoluble compounds within such aggregates. Such systems consist of cyclodextrin (host), lipophilic or hydrophilic compound which is able to form an inclusion complex with cyclodextrin (guest) and compound which does not readily form a complex with cyclodextrin (accompanying guest). The guest can be a water-soluble compound but it must be able to form an inclusion complex with cyclodextrin. The accompanying guest is predominately included within the microaggregate without forming an inclusion complex with the cyclodextrin, a structure that resembles solubilization of the accompanying guest in a microemulsion in which the guest/host inclusion complexes form the surfactant.

Furthermore, this invention involves stabilization of such microaggregate systems by including polymers. Polymers are well-known to stabilize micelles (as well as other microparticular systems), i.e., regular emulsions which sometimes are called macroemulsions, and to enhance their ability to solubilize water-insoluble compounds (D. AttWOOD AND A. T. FLORENCE: Surfactant Systems, their Chemistry, Pharmacy and Biology,Chapman and Hall, London, 1983, pp. 361 365).

Another aspect of this invention is inclusion of a component which solubilizes and stabilizes the microaggregate. These components can have comparable effects to those of cosurfactants in microemulsions, i.e., to enhance the stability of the microaggregates and prevent further aggregation and precipitation, and/or enhance their solubilizing effect.

In one aspect of the invention (A), there is thus provided a method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising combining said active ingredient with .beta.-cyclodextrin in an aqueous complexation medium, said medium comprising from about 0.1% to about 80% (weight/volume) of .beta.-cyclodextrin and from about 0. 1% to about 5% (weight/volume) of a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with .beta.-cyclodextrin and its inclusion complexes, said charged compound being acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

In another aspect of the invention (B), there is provided a method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising combining said active ingredient with .beta.-cyclodextrin in an aqueous complexation medium, said medium comprising from about 0.1% to about 80% (weight/volume) of .beta.-cyclodextrin; from about 0.1% to about 10% (weight/volume) of a pharmaceutically inactive water-soluble polymer acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition; and from about 0.1% to about 5% (weight/volume) of a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with .beta.-cyclodextrin and its inclusion complexes, said charged compound being acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

In still another aspect of the invention (C), there is provided a method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water and which does not readily form an inclusion complex with cyclodextrin, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising adding said active ingredient to an aqueous complexation medium which comprises from about 0.1% to about 70% (weight/volume) of said cyclodextrin, said complexation medium being saturated, prior to addition of said active ingredient, with a compound which forms an inclusion complex with said cyclodextrin and which is acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

In yet another aspect of the invention (D), there is provided a method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water and which does not readily form an inclusion complex with cyclodextrin, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising adding said active ingredient to an aqueous complexation medium which comprises from about 0.1% to about 70% (weight/volume) of said cyclodextrin and from about 0.01% to about 10% (weight/volume) of a pharmacologically inactive water-soluble polymer acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition, said complexation medium being saturated, prior to addition of said active ingredient, with a compound which forms an inclusion complex with said cyclodextrin and which is acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Cyclodextrins for use in the present invention in aspects (C) and (D) summarized above include the natural cyclodextrins and their derivatives, including the alkylated and hydroxyalkylated derivatives and the branched cyclodextrins. Cyclodextrins and their derivatives which have been previously described as useful for complexation with drugs are of particular interest herein. In addition to .alpha.-, .beta.-, and .gamma.-cyclodextrins, the ether and mixed ether derivatives and those derivatives bearing sugar residues are of special interest. Especially useful herein are the hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of .alpha.-, .beta.-, and .gamma.-cyclodextrin; the maltosyl, glucosyl and maltotriosyl derivatives of .alpha.-, .beta.-, and .gamma.-cyclodextrin, which may contain one or more sugar residues, e.g., glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g., a mixture of maltosyl and dimaltosyl derivatives; and the variously substituted sulfoalkyl ethers of .alpha.-, .beta.-, and .gamma.-cyclodextrins, particularly when the alkyl group is of moderate length such as C.sub.4 C.sub.8. Specific cyclodextrin derivatives for use herein include hydroxypropyl-.beta.-cyclodextrin, hydroxyethyl-.beta.-cyclodextrin, hydroxypropyl-.gamma.-cyclodextrin, hydroxyethyl-.gamma.-cyclodextrin, dihydroxypropyl-.beta.-cyclodextrin, glucosyl-.alpha.-cyclodextrin, glucosyl-.beta.-cyclodextrin, diglucosyl-.gamma.-cyclodextrin, maltosyl-.alpha.-cyclodextrin, maltosyl-.beta.-cyclodextrin, maltosyl-.gamma.-cyclodextrin, maltotriosyl-.beta.-cyclodextrin, maltotriosyl-.gamma.-cyclodextrin and dimaltosyl-.beta.-cyclodextrin, and mixtures thereof such as maltosyl-.beta.-cyclodextrin/dimaltosyl-.beta.-cyclodextrin, as well as methyl-.beta.-cyclodextrin, and the sulfobutyl ether and sulfoheptyl ether derivatives of .beta.-cyclodextrin (developed by CyDex, Kansas City, Kans.). Procedures for preparing the various cyclodextrin derivatives named above are well-known, for example, from Bodor U.S. Pat. No. 5,024,998 dated Jun. 18, 1991, and references cited therein. Particularly preferred cyclodextrins for use in the present invention are .gamma.-cyclodextrin, .alpha.-cyclodextrin, .beta.-cyclodextrin, and the hydroxypropyl, hydroxyethyl, dihydroxypropyl, glucosyl, maltosyl, methylated and sulfobutyl ether derivatives of .alpha.-, .beta.-, and .gamma.-cyclodextrin, and their mixtures, especially those having a molar degree of substitution of from about 0.05 to about 10. The expression "molar degree of substitution" is used in the same sense as employed in Brauns and Muller European Patent No. 0149197 B1.

In the case of aspects (A) and (B) of the invention as summarized hereinabove, the cyclodextrin is .beta.-cyclodextrin, i.e., the natural, non-derivatized cyclodextrin. The reasons for particular interest in improving complexation with this natural cyclodextrin, which can be achieved in accord with the present invention, are discussed below.

FDA has introduced a Biopharmaceutics Classification System (BCS) for oral drug products. In this system, drugs are classified into four groups based on the ability of a given drug substance to permeate biological membranes and its aqueous solubility. The groups/classes are as follows: Class I: highly soluble; highly permeable Class II: poorly soluble; highly permeable Class III: highly soluble; poorly permeable Class IV: poorly soluble; poorly permeable

In the BCS, a given drug substance is considered "highly soluble" when the highest dose strength is soluble in less than 250 mL of water over a pH range of 1 to 7.5 and "highly permeable" when the extent of absorption in humans is determined to be .gtoreq.90% of an administered dose (in solution), based on mass-balance or related to an intravenous reference dose. Thus, for rapidly dissolving solid oral dosage forms (like conventional tablets), the dose-to-solubility ratio (D:S) of the drug must be less than 250 mL over a pH range of 1 to 7.5. For other types of solid dosage forms (such as sublingual or buccal tablets, and rectal and vaginal tablets), the D:S ratio must be less than 5 to 10 mL.

Class I consists of water-soluble drugs that are well-absorbed from the gastrointestinal tract and, in general, have the preferred physicochemical properties. For immediate release dosage forms, the absorption rate will be controlled by the gastric emptying rate. However, to secure constant high bioavailability, the dissolution rate must be relatively fast, or over 85% dissolution in 15 minutes.

Class II consists of water-insoluble drugs which, when dissolved, are well-absorbed from the gastrointestinal tract. The dissolution rate in vivo is usually the rate-limiting step in drug absorption.

Class III consists of water-soluble drugs that do not readily permeate biomembranes. For these drugs, the rate-limiting factor in drug absorption is their permeability.

Class IV consists of water-insoluble drugs which when solubilized do not readily penetrate biomembranes. These drugs are usually very difficult to formulate for effective oral delivery.

Through complexation with water-soluble cyclodextrins it is possible to move Class II drugs, and sometimes even Class IV drugs, into Class I by increasing their apparent solubility in water. The natural cyclodextrins and their complexes have, however, limited aqueous solubility. For example, the solubility of .beta.-cyclodextrin in water is only about 18.5 mg/mL at room temperature and the maximum amount of hydrocortisone which can be dissolved in saturated .beta.-cyclodextrin solution (water saturated with .beta.-cyclodextrin) is 2.2 mg/mL (See Tables 3 and 4 in Experiments C and D to follow). Various water-soluble cyclodextrin derivatives have been synthesized. These derivatives and their complexes are much more water-soluble than the parent .beta.-cyclodextrin. Cyclodextrin derivatives of current pharmaceutical interest include 2-hydroxypropyl-.beta.-cyclodextrin, 2-hydroxypropyl-.gamma.-cyclodextrin, sulfobutyl ether .beta.-cyclodextrin, randomly methylated .beta.-cyclodextrin, and some branched cyclodextrins such as maltosyl-.beta.-cyclodextrin.

Including cyclodextrins in pharmaceutical formulations will increase the formulation bulk of solid dosage forms. Even under the best conditions, cyclodextrin complexation will on the average result in about a 10-fold increase in the formulation bulk. This limits the use of cyclodextrins in solid oral dosage forms to relatively potent drugs that possess good complexing properties. Cyclodextrin derivatives have greater molecular weight (MW) than their parent cyclodextrins and thus result in greater increase in the formulation bulk, i.e., in the case of natural cyclodextrins, the drug occupies a greater fraction of the complex powder. Based on the molecular weights given in the above Table, it can be seen that if the cyclodextrin derivatives can be replaced by the natural cyclodextrin, the formulation bulk will be decreased by as much as 50%. However, this can only be done if the D:S ratio is below 250 mL for conventional oral formulations (e.g., tablets and capsules) and, for example, below 5 mL for sublingual tablets. By the present invention, the aqueous solubility of .beta.-cyclodextrin and its complexes can be enhanced, lowering the D:S ratio to an acceptable level, in other words, to a level which is sufficient to move a given water-insoluble drug from Class II to Class I.

Suitable polymers for use herein in aspects (B) and (D) summarized above are those which are soluble in water, are acceptable for use in pharmaceuticals and are pharmacologically inactive. Such polymers are well-known excipients commonly used in the field of pharmaceutical formulations. [See, for example, Remington's Pharmaceutical Sciences, 18th edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291 294; ALFRED MARTIN, JAMES SWARBRICK AND ARTHUR COMMARAM, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition, Lea & Febinger, Philadelphia, Pa., 1983, pp. 592 638; A. T. FLORENCE AND D. ATTWOOD, Physicochemical Principles of Pharmacy, 2nd edition, Chapman and Hall, New York, N.Y. 1988,PP. 281 334.] Suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (such as the water-soluble derivatives of cellulose) and water-soluble synthetic polymers. The natural polymers include polysaccharides such as inulin, pectins, algin derivatives (e.g., sodium alginate) and agar, and polypeptides such as casein and gelatin. The semisynthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose. The synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g., carbomer). Other natural, semi-synthetic and synthetic polymers not named here which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered to be within the ambit of the present invention. Particularly preferred polymers for use herein are sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

Water-soluble polymers for use with drugs herein, as pointed out above, need to be pharmaceutically acceptable and pharmacologically inactive. Generally speaking, such water-soluble polymers will also be acceptable for use with food additives, cosmetic additives and agrochemicals (agricultural chemicals), since the most stringent requirements are usually placed on pharmaceuticals, particularly for parenteral use. Conversely, however, a polymer which is not pharmaceutically acceptable could, for example, nevertheless be agriculturally acceptable, particularly for non-crop applications; such a polymer is intended for use herein in compositions with those non-drug materials, e.g., agrochemicals, which do not require pharmaceutical acceptability. Similarly, the water-soluble polymers for use with food and cosmetic additives need only be acceptable for use in foods and cosmetics.

As insoluble or sparingly soluble food additives which are contemplated herein for use, there can be mentioned, by way of example, flavoring agents, preservatives, antioxidants, sweetening agents, vitamins and coloring agents. Illustrative of such additives are flavors such as vanillin, aromatic flavoring oils such as lemon oil, cinnamon oil, oil of anise, oil of bitter almond or benzaldehyde, oil of clove, oil of orange, oil of peppermint, garlic oil, onion oil and menthol; sweeteners such as aspartame and saccharin; colors such as methyl yellow as well as natural colors; preservatives such as methylparaben, propylparaben, chlorbutol, benzoic acid and salicylic acid; and antioxidants such as butylated hydroxyanisol. Some food additives may also be classified as drugs, e.g., the vitamins, discussed in more detail hereinbelow.

In the case of cosmetic additives contemplated for use in this invention, many of the same classes of ingredients (including some of the same specific ingredients) noted above as food additives are intended; in some cases, cosmetic additives may also be classified as drugs as discussed more fully below, for example, the vitamins, including the retinoids. Illustrative classes of cosmetic additives include preservatives, antioxidants, aromatic oils (fragrances), coloring agents and vitamins (also noted as drugs herein). Specific additives of interest for cosmetics include fragrant aromatic oils such as lavender oil, pine oil, oil of geranium, oil of rose, oil of sweet bay, oil of lemon, oil of lemon grass, preservatives such as camphor and vitamins such as vitamin D.sub.2 (cholecalciferol), vitamin D.sub.3, and vitamin E, as well as vitamin A and the other retinoids such as retinoic acid.

With regard to agrochemicals, those contemplated for use in this invention include pesticides (including, for example, insecticides and nematocides), fungicides, herbicides and plant growth regulators. Illustrative of such agrochemicals are pesticides such as pentachlorophenol, mevinphos, piperonyl butoxide, hydroprene, methoprene and kinoprene; fungicides such as 4-chloro-3-methylbenzothiazolone and pyrrolnitrin; and herbicides such as pentachlorophenol and 2,6-dichlorobenzonitrile. Yet other agrochemicals contemplated for use in the instant methods and compositions include herbicides such as atrazine, barban, bromoxynil, butachlor, carbetamide, chlorpropham, chlortoluron, 2,4-D, 2,4-DB, diallate, dicamba, dichlorprop, diuron, EPTC, ethofumesate, fluometuron, ioxynil, isoproturon, linuron, MCPA, mecoprop, metamitron, methabenzthiazuron, metribuzin, oxadiazon, pebulate, phenmedipham, prometryn, propachlor, propanil, propham, simazine, thiobencarb, isoxaflutole, triallate and trifluralin; fungicides such as 2,6-dimethyl-4-tridecylmorpholine, methyl N-(1-butylcarbarmoylbenzimidazol-2-yl)carbamate, 1,2-bis(3-methoxycarbonyl-2-thioureido)benzene, isopropyl 1-carbamoyl-3-(3,5-dichlorophenyl)hydantoin and 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one; acaricides such as dicofol and antiparasitic antibiotics, such as ivermectin, avermectins and milbemycins, which are also insecticidal; and insecticides such as chlorpyrifos, dementon-S-methyl, disulfoton, ethoprofos (or ethoprop), fenitrothion, malathion, parathion, phosalone, cyfuthrin, cypermethrin, deltamethrin, fenpropathrin, fenvalerate, permethrin, bendiocarb, endosulfan, lindane, fipronil, and synthetic pyrethroids, for example, permetrin and cypermethrin.

It is well-known that a number of food and cosmetic additives, particularly flavors, fragrances and colors, as well as agrochemicals (pesticides, herbicides, insecticides and fungicides) can be complexed with cyclodextrin, while others cannot be.

Among the insoluble or sparingly soluble drugs which are contemplated for use in the methods of the present invention, there can be mentioned antineoplastics (anticancer/antitumor agents), sedatives, antiinflammatory steroids (glucocorticoids), tranquilizers, anticonvulsants, antivirals, antihistaminics, vitamins/nutritional factors, emetics, anticoagulants, cardiotonics (including cardiac glycosides), diuretics, non-steroidal analgesic and/or anti-inflammatory agents (NSAID's), androgens, estrogens, anabolic agents, vasodilators, antidepressants, antipsychotics, hypnotics, antifungals, progestins, antiprotozoals, anthelmintics, anesthetics, vasoconstrictors, hypoglycemics, antibacterials/antibiotics, and anti-infectives, platelet inhibitors, muscle relaxants, antiemetics, radiodiagnostics, antispasmodics, antiarrythmics, carbonic anhydrase inhibitors, gastrointestinal agents (including H.sub.2-antagonists and other anti-ulcer agents), antihypertensives especially including those useful as anti-glaucoma agents, serotonin antagonists, narcotic antagonists, narcotic agonists, mixed narcotic agonists-antagonists, pharmacologically active proteins such as peptide hormones, enzymes, antibodies and other biologically produced substances, anti-Parkinsonism/dopamineric agents and drugs for treating Alzheimer's disease.

It is now well-known that insoluble or sparingly soluble drugs which complex with cyclodextrin have the required shape and size to fit at least partially into the cavity of the hydrated cyclodextrin molecule; see, for example, Brauns and Muller European Patent No. 0149197 B1. Drugs whose water solubility can be improved by complexation with cyclodextrins exhibit significantly increased complexation and water solubility when treated in accord with the present invention.

Specific drugs contemplated for use in the present invention include antineoplastics such as chlorambucil, lomustine, melphalan, methotrexate, hexamethylmelamine, teniposide, etoposide, semustine (methyl CCNU), fazarabine (Ara-AC), mercaptopurine, tubulazole, carmofur, carmustine, amsacrine, doxorubicin, bruceantin, diaziquone, dideminin B, echinomycin and PCNU; anti-inflammatory steroids such as betamethasone, fludrocortisone, dexamethasone, cortisone, hydrocortisone, triamcinolone, triamcinolone acetonide, prednisone and prednisolone; estrogens such as 17.beta.-estradiol, 17.alpha.-ethynylestradiol (ethinylestradiol), ethynylestradiol 3-methyl ether, estrone, mestranol and estriol; progestins such as dimethisterone, norethindrone, norethindrone acetate, norgestrel, norethynodrel, ethisterone, medroxyprogesterone acetate and progesterone; synthetic estrogens such as diethylstilbestrol, benzestrol, dienestrol, hexestrol and the like; immunosuppressive agents such as cyclosporine (also known as cyclosporin A); anticonvulsants such as phenytoin (diphenylhydantoin) and carbamazepine; barbiturates such as pentobarbital, phenobarbital and secobarbital, variously useful as hypnotics, anticonvulsants and sedatives; antivirals such as acyclovir, trifluridine, zidovudine, vidarabine and virazole (also known as ribavirin); vitamins/nutritional factors such as retinol (vitamin A), vitamin A-acetate, cholecalciferol, retinal, retinoic acid (also known as tretinoin or Retin-A.TM.), isotretinoin, etretinate, acitretin and .beta.-carotene, collectively referred to herein as retinoids, as well as other fat-soluble vitamins such as the E, D and K vitamins; .beta.-blockers such as timolol, atenolol, propranolol, nadolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, metoprolol, penbutolol, pindolol and sotalol, variously of interest not only as antihypertensives but also as anti-glaucoma agents; emetics such as apomorphine; diuretics such as chlorthalidone, furosemide and other sulfonamide-type diuretics and spironolactone, an aldosterone antagonist-type diuretic; anticoagulants such as dicumarol; cardiotonics such as digoxin and digitoxin; non-steroidal analgesics and/or anti-inflammatory agents such as aspirin, ibuprofen, indomethacin, piroxicam, sulindac and flurbiprofen; androgens such as 17-methyltestosterone and testosterone; mineral corticoids such as desoxycorticosterone; steroidal hypnotics/anesthetics such as alfaxalone; anabolic agents such as fluoxymesterone and methanstenolone; antidepressants such as sulpiride; antibiotics such as ampicillin and penicillin G; anti-infectives, such as benzalkonium chloride, cetylpyridinium chloride and chlorhexidine; coronary vasodilators such as nitroglycerin, flunarizine, lidoflazine and mioflazine; hypnotics such as etomidate; carbonic anhydrase inhibitors such as acetazolamide, chlorzolamide, ethoxzolamine, methazolamide, L-671,152 and MK-927; antifungals such as imidazole-type antifungals, e.g., econazole, clotrimazole, oxiconazole, bifonazole, metronidazole (metronidazole benzoate), fenticonazole, miconazole, sulconazole, tioconazole, isoconazole, butoconazole, ketoconazole, doconazole, parconazole, orconazole, valconazole and lombazole, and triazole-type antifungals, e.g., terconazole and itraconazole; antiprotozoals such as imidazole-type antiprotozoals, e.g., metronidazole, ornidazole, carnidazole, ipronidazole, tinidazole and nimorazole, and benzimidazole-type antifungals, e.g., flubendazole; H.sub.2-antagonists, including those of the imidazole-type, e.g., burimamide, metiamide, cimetidine and oxmetidine; imidazole-type antineoplastics, such as tubulazole, a microtubule inhibitor; anthelmintic agents, including those of the benzimidazole-type, for example, thiabendazole, oxibendazole, cambendazole, fenbendazole, flubendazole, albendazole and oxfendazole; antihistaminics, including benzimidazoles such as astemizole, piperidines such as levocabastine and piperazines such as flunarizine, oxatomide and cinnarizine; antipsychotics, including those of the piperidine-type such as fluspirilene, pimozide and penfluridole; gastrointestinal agents, including piperidine derivatives such as loperamide and cisapride; serotonin antagonists, for example those of the piperidine-type such as ketanserin, ritanserin and altanserin, and those of the piperazine-type such as mianserin (also an antihistaminic); anesthetics such as lidocaine; hypoglycemics such as acetohexamide; anti-emetics such as dimenhydrinate; antibacterials such as cotrimoxazole; dopaminergic agents such as L-DOPA; anti-Alzheimer's agents such as THA; famotidine, an anti-ulcer agent/H.sub.2-antagonist; benzodiazepines, for example chlordiazepoxide, diazepam, medazepam, oxazepam, lorazepam, flunitrazepam, estazolam, flurazepam, loprazolam, lormetazepam, nitrazepam, quazepam, temazepam and triazolam, variously useful as sedatives, hypnotics, anticonvulsants, tranquilizers and muscle relaxants; prostaglandins, for example PGE's such as PGE.sub.1 (alprostadil), a vasodilator, and PGI.sub.2 (prostacyclin or epoprostenol), a platelet inhibitor; angiotensive converting enzyme inhibitors (ACE inhibitors), such as enalaprilic acid (the diacid, sometimes called `enalaprilate`), the ethyl ester of enalaprilic acid (sometimes called enalapril), captopril, lisinopril and SCH-33861, useful as antihypertensives; tetracycline antibiotics, such as tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline and minocycline; and macrolide antibiotics, such as erythromycin, josamycin, rosamycin, tylosin, troleandomycin and spiramycin.

In particularly preferred aspects of the present invention, the drug contemplated for use herein is a steroid, particularly an anti-inflammatory steroid (glucocorticoid) such as hydrocortisone, a steroidal estrogen such as estradiol, a synthetic estrogen such as diethylstilbestrol, a benzodiazepine such as alprazolam, or an immunosuppressive such as cyclosporin A.

In the case of aspects (C) and (D) of the invention as summarized hereinabove, the active ingredient is one of the above-described active ingredients which is insoluble or sparingly soluble in water but which also does not readily form an inclusion complex with cyclodextrin. An insoluble/sparingly soluble active ingredient meeting this second criteria, that is, which does not readily form an inclusion complex with cyclodextrin, can be defined in terms of its solubility. Thus, an active ingredient which has a solubility of less than 10 mg/mL in 60% (weight/volume) aqueous hydroxypropyl-.beta.-cyclodextrin at 25.degree. C., preferably, less than 5 mg/mL, is considered an active ingredient which does not readily form an inclusion complex with cyclodextrin. Appropriate active ingredients can be readily selected from those discussed above by simply determining what their solubility is in 60% (weight/volume) hydroxypropyl-.beta.-cyclodextrin at 25.degree. C. Poorly soluble drugs that do not readily form cyclodextrin complexes, or do it very poorly, include: antifungal drugs such as amphotericin, clotrimazole, econazole, fluconazole, griseofulvin, intraconazole, ketoconazole, miconazole and nystatin; benzodiazepines such as alprazolam, diazepam, oxazepam and triazolam; antihypertensive agents such as allopurinol and rofecoxib; tetracyclines such as tetracycline, doxycycline and minocycline; steroids such as 17-methyltestosterone and norgestrel; retinoids such as all-trans-retinoic acid, all-trans-retinal and retinal; macrobides such as erythromycin, amphotericin B and nistatin; vitamins such as cholecalciferol; and antiviral drugs such as acyclovir.

In the case of aspects (A) and (B) of the invention as summarized hereinabove, a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with .beta.-cyclodextrin and its inclusion complexes is required. These solubility enhancing agents, which must be acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition, include negatively-charged compounds such as sodium salicylate, sodium benzoate, sodium gentisate, sodium acetate and sodium propionate; the potassium salts of such compounds; non-steroidal antiinflammatory and/or analgesic agents which are in the salt form of a carboxylic acid which has at least one benzene ring, the salt being that of an alkali-metal (e.g., sodium or potassium), alkaline-earth metal (e.g., calcium or magnesium) or aluminum. Specific salts of such aromatic ring-containing antiinflammatory or analgesic agents include amfenac sodium, bromfenac sodium, diclofenac sodium, diflumidone sodium, enolicam sodium, fenoprofen calcium, ibuprofen aluminum, indomethacin sodium, magnesium salicylate, meclofenamate sodium, naproxen sodium, sodium salicylate, tifurac sodium, tolmetin sodium and zomepirac sodium.

Thus, it can be said that suitable negatively-charged compounds fall into two groups.

The first group consists of salts of monofunctional carboxylic acids which do not form inclusion complexes with beta-cyclodextrin or do so very poorly. The term "monofunctional" refers to acids which do not have any functional groups (e.g., hydroxy groups) in addition to the carboxylic acid moiety. Such salts are typified by sodium acetate, sodium propionate and other alkali metal, alkaline-earth metal or aluminum salts of acids such as acetic and propionic.

The second group consists of salts of carboxylic acids having a lipophilic moiety or moieties that fit into the .beta.-cyclodextrin cavity and thus form inclusion complexes with .beta.-cyclodextrin. Often the members of this group have an aromatic moiety. Such salts are typified by sodium benzoate, sodium salicylate and the aforenoted salts of nonsteroidal antiinflammatory or analgesic carboxylic acids, all of which likewise can be alkali metal, alkaline-earth metal or aluminum salts.

Positively-charged compounds useful for this purpose include, for example, benzalkonium chloride.

In the experimental data to follow, it is shown that cyclodextrin complexes form aggregates. The consequences of the aggregate formations include the following possibilities in accord with this invention: (a) solubilization of drugs which do not form complexes with .beta.-cyclodextrin and its derivatives (such as 2-hydroxypropyl-.beta.-cyclodextrin) or do it very poorly (by formation of non-inclusion complexes within the aggregates) using a compound that forms cyclodextrin complexes; (b) solubilization of .beta.-cyclodextrin complexes by addition of a compound that associates with the rather water-insoluble .beta.-cyclodextrin complex aggregates (e.g., salicylate and acetate ions); and (c) stabilization and further solubilization of .beta.-cyclodextrin complexes by addition of a small amount of a water-soluble polymer (e.g., 0.1% w/v hydroxypropyl methylcellulose) to the aggregates mentioned in (b).

Compounds which form cyclodextrin complexes which can further solubilize drugs which do not readily form cyclodextrin complexes include, for example, sodium diflunisal and cholesterol, as discussed in more detail above. Poorly soluble drugs that do not readily form cyclodextrin complexes, or do it very poorly, are likewise fully discussed above, as are the negatively-charged and positively-charged compounds that can enhance the aqueous solubility of .beta.-cyclodextrin complexes. Also see aspects (A) through (D) of the invention summarized above.

.beta.-Cyclodextrin and its complexes have very limited solubility in water. Thus, phase-solubility diagrams (as that shown in FIG. 8 below) frequently level off at a .beta.CD concentration between 1 and 2% (w/v). Addition of a water-soluble polymer increases somewhat the solubility of the complex. This effect of polymers is well-documented in the literature. However, it has now been discovered that by adding sodium acetate or sodium salicylate or other charged compounds as discussed hereinabove, one can solubilize the drug/.beta.CD complexes and observe much greater drug solubility (Examples B to E below). Addition of a polymer to such systems increases the amount of dissolved complex even further, as determined by the amount of dissolved drug. See, in particular, aspects (A) and (B) of the invention summarized above.

When a water-soluble polymer is used in a process according to the present invention, notably in aspects (B) and (D) summarized above, the aqueous medium is typically maintained from about 30.degree. C. to about 150.degree. C. for from about 0.1 to about 100 hours after the active ingredient is added. Other conditions useful in these processes are known, for example, from Loftsson U.S. Pat. No. 5,472,954.

In the case of aspects (C) and (D) of the invention as summarized hereinabove, in addition to the active ingredient which does not readily form an inclusion complex with cyclodextrin, a further compound is required which does form an inclusion complex with said cyclodextrin and which can be thus used to further solubilize the difficultly.gamma.-complexed active ingredient. This further compound, with which the complexation medium is saturated prior to adding the active ingredient, must of course be acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition. In addition, it should have a log P value (where P stands for the octanol/water partition coefficient) greater than about 3.5, and preferably greater than about 4.0, in its unionized form. When ionized, the ionizable compound should preferably possess surface activity. Compounds with appropriate log P values include cholesterol (8.5), carotene (>10), dehydrocholesterol (7.8), retinoic acid (6.3), triclosan (4.8), and non-steroidal antiinflammatory drugs (NSAIDs) which have log P values of 3.5 (e.g., ibuprofen) or preferably higher, such as diclofenac (4.4), diflunisal (4.4), fenclofenac (4.8) and indomethacin (4.3). Compounds which are highly lipophilic, such as cholesterol, or which are surface active drugs, such as diflunisal, are preferred. The log P values of many compounds are known or can be readily determined by known methods.
 

Claim 1 of 24 Claims

1. A method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising combining said active ingredient with .beta.-cyclodextrin in an aqueous complexation medium, said medium comprising from about 0.1% to about 80% (weight/volume) of .beta.-cyclodextrin; from about 0.1% to about 10% (weight/volume) pharmacologically inactive and pharmaceutically, cosmetically or agriculturally acceptable water-soluble polymer which is a polysaccharide, a polypeptide, a cellulose derivative, a polyoxyethylene derivative, a polyvinyl derivative or a copolymer of acrylic acid; and from about 0.1% to about 5% (weight/volume) of a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with .beta.-cyclodextrin and its inclusion complexes, said charged compound being pharmaceutically, cosmetically or agriculturally acceptable, said negatively-charged compound being a salt of a monofunctional carboxylic acid which forms a non-inclusion complex with .beta.-cyclodextrin or a salt of a carboxylic acid having a lipophilic moiety which forms an inclusion complex with .beta.-cyclodextrin.

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