Title:  Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides

United States Patent:  6,413,494

Inventors:  Lee; Seung Seo (Taejon-si, KR); Lim; Chang Baeg (Taejon-si, KR); Pai; Chaul Min (Taejon-si, KR); Lee; Sujung (Taejon-si, KR); Park; In (Taejon-si, KR); Seo; Moon Gun (Taejon-si, KR); Park; Heenam (Taejon-si, KR)

Assignee:  Samyang Corporation (KR)

Appl. No.:  318579

Filed:  May 25, 1999

A colonic drug delivery composition contains a first polysaccharide and a second polysaccharide wherein both polysaccharide are degradable by colonic enzymes and are mixed at a environmental pH of about 7 or above, without use of a cross-linking agent. A colon selective pharmaceutical composition and dosage form for oral delivery of a drug, diagnostic reagent, or mixture thereof includes the drug, diagnostic reagent, or mixture thereof in contact with the polysaccharide composition. A method of preparing such a colonic drug delivery composition and the colon selective pharmaceutical composition and dosage from are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

Before the present composition and method for colonic drug delivery are disclosed and described, it is to be understood that this invention is not limited to the particular configurations, process steps, and materials disclosed herein as such configurations, process steps, and materials may vary somewhat. It is also to be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

In must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a galactomannan" includes a mixture of one or more galactomannans, reference to "a pectin salt" includes reference to one or more of such pectin salts, and reference to "a coating" includes reference one or more of such coatings.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out herein.

As used herein, "colon-specific drug delivery system" and similar terms mean devices and methods for oral administration that release biologically active ingredients in the colon without substantial release into the upper gastrointestinal tract, e.g. stomach and intestine.

As used herein, the term "drug" or "pharmacologically active agent" or any other similar term means any chemical or biological material or compound suitable for administration by the methods previously known in the art and/or by the methods taught in the present invention, that induces a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism and preventing an undesired biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, and/or (3) either alleviating, reducing, or completely eliminating the disease from the organism. The effect may be local, such as providing for a local anaesthetic effect, or it may be systemic. This invention is not drawn to novel drugs or to new classes of active agents. Rather it is limited to the mode of delivery of agents of drugs that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention. Such substances include broad classes of compounds normally delivered into the body. In general, this includes but is not limited to: antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; helminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants ;antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators; including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; probiotics. By the method of the present invention, both ionized and nonionized drugs may be delivered, as can drugs of either high or low molecular weight.

As used herein, "nutrient" means a substance that affects the nutritive or metabolic processes of the body. Nutrients include essential nutrients, i.e. those nutrients such as proteins, minerals, carbohydrates, fats, and vitamins necessary for growth, normal functioning, and maintaining life, and secondary nutrients, i.e. substances that stimulate the intestinal microflora to synthesize other nutrients.

As used herein, "diagnostic reagent" means a substance used to produce a chemical reaction so as to detect or measure another substance.

As used herein, "simulated intestinal fluid" or "SIF" means a composition prepared by dissolving 6.8 g of monobasic potassium phosphate in 250 ml of water, then adding 190 ml of 0.2 N NaOH, 400 ml of water and 10 g of pancreatin, and finally adding 0.2 N NaOH to adjust the pH to 7.5, and then diluting with water to 1000 ml.

As used herein, `simulated gastric fluid` or `SGF` means a composition prepared by dissolving 2 g of NaCl and 3.2 g pepsin in 7 ml of HCl, and then adding water to 1000 ml. The resulting fluid has a pH of about 1.2.

As used herein, `derivatives of pectin` and similar terms includes cation salts of pectin such as sodium pectinate, potassium pectinate, and ammonium pectinate, and the like.

As used herein, `effective amount` means an amount of a drug or pharmacologically active agent that is nontoxic but sufficient to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment. An effective amount of a nutrient is an amount sufficient to provide a selected nutritive benefit. An effective amount of a diagnostic reagent is an amount sufficient to be efficacious in a selected diagnostic test or assay.

The present invention relates to a colonic drug delivery composition comprising a mixture of (a) a polysaccharide selected from the group consisting of pectin, derivatives of pectin, and mixtures thereof, and (b) galactomannan. The mixture is made by combining the ingredients in an aqueous medium at a pH of about 7 or above.

In a preferred embodiment of the invention, the composition comprises (a) pectin or a derivative of pectin or a mixture thereof and (b) galactomannan. The composition is prepared at a pH of about 7 or above. The ratio of ingredients is limited only by functionality. Preferably, however, the composition has a polysaccharide: galactomannan weight ratio of about 50:50 to about 99.9:0.01, more specifically, about 2:1 to about 5:1. A coating prepared with the instantly claimed composition will generally have a mass to area ratio in the range of about 1-100 mg/cm², and preferably about 1-40 mg/cm². A hard capsule shell will generally have a thickness of about 1-100 .mu.m, preferably 1-40 .mu.m.

A key feature of this invention is based on a change in the properties of a mixture of these two polysaccharides, which is degradable in the colon by colonic bacterial enzymes, as compared to either polysaccharide alone. When pectin or galactomannan (such as guar gum or locust bean gum) is used alone as a drug carrier, e.g., coating material, the coating is easily dissolved and/or disintegrated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). However, a mixture of these two polysaccharides prepared at a pH of about 7 or above produces a strong, elastic, and insoluble gel that is not dissolved or disintegrated in the simulated gastric and intestinal fluids, thus protecting drugs coated with the mixture from being released in the upper GI tract. On the other hand, under conditions encountered in the colon, the coating is degraded by pectinolytic enzymes and galactomannanase, thus disintegrating the dosage form and rapidly releasing the drugs. When the coating is prepared at below pH 7, such coating is easily disintegrated and dissolved in the upper GI tract.

Pectin and galactomannan are both degradable by colonic bacterial enzymes. When the mixture of pectin and galactomannan arrives in the colon, it is rapidly degraded by the synergic action of colonic bacterial enzymes. Accordingly, the composition of the present invention can prevent the drug deactivation in upper GI and also produces the burst-like drug release pattern in ascending colon, which is preferred to treat local colon disease such as ulcerative colitis, Crohn's disease. Thus, the composition of the present invention can be used advantageously for specific drug delivery in the colon as compared to known drug delivery systems.

The pH at which the mixture is prepared is a determining factor of the properties of the composition. As shown by experimental data presented herein, films of such mixtures prepared at a pH of about 7 or above were stronger, more elastic and less soluble than films cast from mixtures prepared at a pH below 7. In addition, all films cast with the mixtures prepared at a pH below 7 were easily dissolved in SIF, while films cast from mixtures prepared at a pH of about 7 or above were not extensively dissolved or not dissolved at all in SIF. Either pectin or galactomannan is soluble in aqueous media. Below pH 7, there is no binding force between pectin and galactomannan, whereas, at about pH 7 or above, it is likely that pectin and galactomannan interact each other to form a specific complex gel. Galactomannan is a non-gelling polysaccharide but it can be gelled synergically when mixed with some polysaccharides. Proposed binding forces are synergic action of hydrogen bonding, hydrophobic force and the formation of interjunction zone. The conformational change of polysaccharide chains at pH 7 or above results in the strong interaction. Synergic gellation and interaction of galactomannan and polysaccharides are referred to in C. M. D. Iain, et al., 31 Adv. Carbohydrate. Chem. Biochem. 241-312(1975).

The ratio of the two polysaccharides determines the rate of enzymatic degradation of the composition and dosage disintegration through GI tract, which in turn enables the composition to release the drug site specifically in the colon. More particularly, the ratio of the two polysaccharides enables the composition to release the drug more specifically in the colon such as the ascending, transverse, descending colon. Between the two polysaccharides, the more galactomannan(e.g. guar gum) there is, the less soluble in SIF and the less degradable by colonic enzymes. By increasing the proportion of galactomannans, the composition releases the drug at a site further on than the ascending colon, e.g. the transverse or descending colon. In addition, by changing the dimensions of the dosage form, the site where drugs are released can be controlled. The thickness of a coating or the diameter of a matrix formulation which drug is incorporated can be selected to achieve site specificity within the colon. Thus, the ratio of polysaccharides and the dimensions of the composition are important factors for determining the site of drug release in the colon. By manipulation of these factors in the manufacture of dosage forms according to the present invention, drug delivery can be selectively targeted to the ascending colon or more distally to the transverse or descending colon.

Another improvement of the present invention is that the composition can be used in many different types of dosage forms. The composition can be used as a coating material for tablets, soft capsules, granules, seeds, and the like. Further, it can be used advantageously in hard capsules and matrix pellets.

The composition can be used to deliver a wide range of biologically active ingredients. For example, topically acting drugs such as those for IBD, Crohn's disease, laxatives and colon cancer; systemically acting drugs such as peptide or protein drugs, calcium antagonists, antiasthmatics, hypoglycemic agents, antirheumatic, and the like can be loaded and delivered to the colon with the composition of the present invention. Likewise, nutrients can be loaded and delivered into the colon for a better absorption. Further, pharmaceutically acceptable excipients may be included in the composition.

Because both the pectin and galactomannan components of the composition of the present invention are specifically degraded in the colon, there is a burst of drug release in the colon due to the synergic effect of the colonic enzymatic activities. Compared to the instant invention, previously known dosage forms are much slower and gradual with respect to disintegration, dissolution, or drug release in the colon. The synergic effect of the enzymatic activities is referred to in T Ooya et al., 25 Proc. Int'l Symp. Control. Rel. Bioact. Mater. 731-732(1998).

As stated above, the composition of the present invention can be used as a coating material, hard capsule shell material, or matrix.

Illustrative examples of drugs that can be used in the composition and the dosage form of the invention include: mesalamine, balsalazide, olsalazine, ibuprofen, prednisolone, dexamethasone, budesonide, beclomethasone, flucticasone, tioxocortal, hydrocortisone, metronidazole, cyclosporin, methotrexate, domperidone, 5-fluorouracil, bisacodyl, senna, insulin, vasopressin, growth hormones, colony stimulating factors, calcitonin, immunoglobulin, glibenclimide, diltiazem, verapamil, nifedipine, captopril, benazepril, enalapril, theophylline, naproxen, diclofenac, acyclovir, omeprazole, lovastatin, alendronate, desmopressin, metformin, metoprolol, cisapride, tacrine, mixtures thereof and probiotics. Also, the pharmaceutical composition of the present invention may include diagnostic reagents and nutrients as active substances. The active substances that may be used in the pharmaceutical composition of the present invention are not limited to those mentioned above.

Claim 1 of 32 Claims

What is claimed is:

1. A pharmaceutical composition comprising an effective amount of a drug, diagnostic reagent, or mixture thereof, and a polysaccharide mixture formed in an aqueous medium at a pH of about 7 or above of (a) a polysaccharide selected from the group consisting of pectin, derivatives of pectin, and mixture thereof, and (b) galactomannan, without use of a cross-linking agent, wherein the drug is an antiinfective, analgesic, anotexic, helminthic, antiarthritic, antiasthmatic, anticonvulsant, antidepressant, antidiabetic, antidiarrheal, antihistamine, antiinflammatory, antimigraine, antinauseant, antineoplastic, antiparkinsonism, antipruritic, antipsychotic, antipyretic, antispasmodic, anticholinergic, sympathomimetic, xanthine derivative, potassium channel blocker, calcium channel blocker, beta-blocker, alpha-blocker, antiarrhythmic, antihypertensive, diuretic, antidiuretic, vasodilator, central nervous system stimulant, vasoconstrictor, decongestant, hormone, hypnotic, immunosuppressive, muscle relaxant, parasympatholytic, psychostimulant, sedative, tranquilizer, or a combination thereof.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.