Title:  Colon selective drug delivery composition

United States Patent:  6,319,518

Assignee:  Samyang Corporation (KR)

Filed:  August 29, 1997

Foreign Application Priority Data:  Jul 03, 1997[KR] (97-30767)

A composition comprising gelatin and a polysaccharide which is degradable by a colonic enzyme and, optionally, with an aldehyde and/or a polyvalent metal ion and/or an additional polysaccharide, which is not degraded or disintegrated in the upper gastrointestinal tract, thereby rendering the active substance loaded therein to be selectively delivered to the colon and to be effectively released in the colon.

DETAILED DESCRIPTION OF THE INVENTION

As described previously, calcium pectinate which has been employed in the prior art readily converts to a water soluble sodium or potassium pectinate in the digestive fluid of the upper gastrointestinal tract, thereby rendering a pharmaceutical composition containing calcium pectinate susceptible to premature release of the drug loaded therein before the composition reaches the colon.

To solve this problem, the present invention provides a composition comprising gelatin and a polysaccharide to enhance the strength of the composition. Gelatin employed in the drug delivery composition in accordance with the present invention forms a complex with a polysaccharide by complicated intermolecular forces including ionic bonding, hydrogen bonding, steric forces and so on, thus providing a composition with a mechanical strength higher than that of calcium pectinate.

Although gelatin itself may be degraded by a protease present in the upper gastrointestinal tract, the complex of gelatin with the polysaccharide according to the present invention is hardly degraded in the upper gastrointestinal tract, as demonstrated in Example 6. This is considered to be due to the fact that the chains of the polysaccharide molecules penetrate into the chains of gelatin molecules and inhibit access of protease to the gelatin chains.

Therefore, when the delivery composition of the present invention is loaded with a drug as an active substance, the drug release in the upper gastrointestinal tract can be prevented, rendering the drug colon selective.

Further, in case of a composition comprising a chemically modified polysaccharide or the hydrophobic polymer in the prior art, the composition frequently would not effectively release the drug even in the colon. The composition of the present invention comprising an unmodified hydrophilic pectinate/gelatin, however, can release the active substance effectively in the colon because the hydrophilic polysaccharide which is not chemically modified can be easily degraded by colonic enzymes in the colon. Furthermore, the gelatin complex can be degraded by a small but significant amount of protease present in the colon, thus providing a synergistic effect on the degradation of the polysaccharide by a colonic enzyme. Accordingly, the inventive drug delivery composition enables a rapid release of the active substance in the colon.

In the inventive drug delivery composition, gelatin may be employed in an amount ranging from 0.01 to 99.99% by weight, preferably 1 to 99% by weight of the composition.

The polysaccharide of the present invention may be an acidic or an anionic polysaccharide and representative examples thereof may include pectinate, pectate, alginate, chondroitin sulfate, polygalacturonic acid, tragacanth gum, arabic gum, and a mixture thereof. The polysaccharide may be employed in an amount ranging from 0.01 to 99.99% by weight, preferably 1 to 99% by weight of the composition.

A colonic disease such as ulcerative colitis and Crohn's disease may occur at various sites on the colon. The composition of the present invention comprising gelatin and the polysaccharide may release all of the active substance at the ascending colon and, therefore, may not deliver the active substance to the downstream region of the colon. In order to retard the active substance release, the composition may further comprise an additional component to provide the composition with a semi-interpenetrating polymer network or an interpenetrating polymer network, thus controlling the targeting site in the colon.

As the additional component, the composition of the present invention may comprise an aldehyde which can crosslink gelatin. Representative examples of the aldehyde may include formaldehyde, gluteraldehyde, terpene, cinnamaldehyde, aldose, and a mixture thereof. The aldehyde must be employed in the present invention in an amount less than 1% by weight.

The aldehyde used in the present invention reacts with an amino group of gelatin, not with a hydroxyl group of the polysaccharide, to form a semi-interpenetrating polymer network (SIPN) structure into which the polysaccharide molecules penetrate. The SIPN structure retards disintegration of the crosslinked gelatin but easily breaks down once the polysaccharide begins to be degraded. Thus, a colon selective drug delivery composition comprising an aldehyde crosslinked gelatin penetrated by non-crosslinked polysaccharide is suitable for delivering the active substance to a deep site in the colon.

The composition of the present invention may further comprise a polyvalent metal ion. Representative examples of the polyvalent metal ion include calcium, magnesium, strontium, barium, ferrous or ferric, zinc, aluminum, bismuth and zirconium ions, and a mixture thereof. Preferred polyvalent metal ion is a calcium ion. The polyvalent metal ion may be employed in an amount ranging from 0.0001 to 50% by weight, preferably 0.0001 to 20% by weight of the composition.

The polyvalent metal ion may be reacted with the carboxylic group of the polysaccharide as a role of crosslinking agent to form a polymer network. In case the polyvalent metal ion is incorporated with the molecules of the polysaccharide penetrating into the network of gelatin, the polysaccharide molecules are crosslinked with the polyvalent metal ion to form another network, the two polymer networks being interpenetrated, not crosslinked. The interpenetrating polymer network (IPN) structure thus produced has a higher mechanical strength than that of the SIPN formed by the addition of the aldehyde compound alone, and therefore, is not easily disintegrated at the start site of the colon and has a longer lag time than that of the SIPN structure. Accordingly, the colon selective drug delivery composition comprising a gelatin, a polysaccharide, an aldehyde and a polyvalent metal ion is suitable for delivering the active substance loaded therein to a deeper site in the colon.

The composition of the present invention may further comprise an additional colon-degradable polysaccharide which does not form a complex with gelatin and is degradable by colonic enzymes. When the additional polysaccharide is incorporated with the SIPN or IPN structure of the present invention, it forms another polymer chain which is not crosslinked with, but penetrates into the network, thus increasing the mechanical strength of the composition by strengthened hydrogen bonding and other intermolecular forces. In addition, the additional polysaccharide contained in the composition can function as another barrier to drug diffusion and render the composition unable to release the drug in the upper gastrointestinal tract. However, the composition is easily degraded in the colon because the additional polysaccharide is easily degraded by the colonic enzymes present in the colon and functions to shorten the lag time of the active substance in the colon, contrary to the function of an aldehyde and a polyvalent metal ion.

The additional polysaccharide may be neutral and representative examples thereof may includes dextran, amylose, arabinogalactan, arabinoxylan, cellulose, guar gum, laminarin, locust bean gum, pectin, starch, xylan, or a mixture thereof. The preferred additional polysaccharide is dextran. The additional polysaccharide may be employed in an amount ranging from 0.0001 to 45% by weight of the composition.

The delivery composition of the present invention may further comprise a pharmaceutically acceptable additive. Examples of such an additive may include a plasticizer, a pigment, a sweetening agent and the like. Representative examples of the plasticizer which may be employed to facilitate the formulation of the composition may include glycerin, triacetin, sorbitol, polyethylene glycol, propylene glycol, citrate, phthalate, castor oil and the like. The preferred plasticizers are glycerin, triacetin and sorbitol. The plasticizer may be employed in an amount ranging from 0.1 to 100 parts by weight, preferably 35 to 100 parts by weight, per a part by weight of the total polymeric components (dry weight basis) in the composition.

With the composition containing gelatin and a polysaccharide, and, optionally, an aldehyde and/or a polyvalent metal ion and/or an additional polysaccharide, as described above, in accordance with the present invention, various pharmaceutical formulations including coated tablets, capsules, pills and so on may be easily manufactured, and an active substance is easily loaded in the formulation. Therefore, the colon selective drug delivery composition of the present invention satisfies all the conditions required for a composition for selectively delivering a drug to the colon: (1) the composition is not degraded or disintegrated at the upper gastrointestinal tract; (2) the composition does not release the drug loaded therein at the upper gastrointestinal tract; (3) the composition releases the drug effectively at the targeting site of the colon; and (4) the composition is easy to formulate in a form suitable for loading the drug. Further, the delivery composition of the present invention also has a good processing property.

The present invention also provides a colon selective pharmaceutical composition comprising a biologically active substance and the inventive colon selective drug delivery composition as mentioned above.

Representative examples of the active substance which may be employed in the pharmaceutical composition of the present invention may include topical active drugs for the treatment of colon diseases, e.g., ulcerative colitis, Crohn's disease, hypersensitive colon symptom, colon cancer and constipation. Specifically, the active substance may include mesalazine, sulfasalazine, ibuprofen, prednisolone, dexamethasone, budesonide, beclomethasone, flucticasone, thioxocortal, hydrocortisone, cyclosporins, methotrexate, domperidone, 5-fluorouracil, bisacodyl, a dietary fiber, bifidobacteria and a mixture thereof. Further, the active substance may include a systemic active drug such as peptide or protein, or an agent for the treatment of asthma, rheumatism, arthritis, calcium antagonist and the like; specifically, insulin, vasopressin, a growth hormone, a growth factor, a colony stimulating factor, calcitonin, immunoglobulins, diltiazem, verapamil, nifedipin, captopril, theophylline, naproxen and a mixture thereof. Also, the pharmaceutical composition of the present invention may include diagnostic reagents and nutrients as active substances. The active substance which may be used in the pharmaceutical composition of the present invention is not limited to those mentioned above.

The pharmaceutical composition of the present invention may be prepared by inserting a biologically active substance into a capsule made of the inventive delivery composition, or by coating any known pharmaceutical formulation with the inventive drug delivery composition. The pharmaceutical composition may be in the form of a capsule, a coated tablet, a coated pill, a coated seed, or a coated capsule.

When the delivery composition of the present invention is coated on a known pharmaceutical formulation, the coating process may be conveniently conducted by spraying the colon selective drug delivery composition of the present invention. The coating amount of the delivery composition of the present invention may range from 1 to 100 mg/cm², preferably from 20 to 50 mg/cm², of the surface area of the formulation.

In a preferred embodiment, the inventive delivery composition to be coated on a known pharmaceutical formulation may contain 0.1 to 99.9%, preferably 5 to 50% by weight, of gelatin and 0.1 to 99.9%, preferably 50 to 95% by weight, of a pectinate and, optionally, 0 to 99.9%, preferably 0 to 45% by weight of dextran on the basis of the weight of the composition. The delivery composition may further comprise a plasticizer in an amount ranging from 10 to 100% by weight based on the weight of the polymeric components.

The aldehyde and/or polyvalent metal ion which may be employed in the present invention as an additional component, may be applied on a pharmaceutical formulation coated with a coating composition containing no such additional components. The additional components may be applied by dipping the previously coated formulation into a solution containing the aldehyde and/or the polyvalent metal ion. Formaldehyde and gluteraldehyde are preferred for such an application and they may be employed in the form of 0.01 to 50 wt %, preferably 0.01 to 20 wt %, of an alcohol solution. The dipping process of the aldehyde compound may be carried out with stirring for a period ranging from 1 second to 60 minutes, preferably from 1 to 30 min. The polyvalent metal ion, which is employed to cross-link the polysaccharide, may be used in the form of an aqueous solution having a concentration of 0.01 to 99.9 wt %, preferably 0.1 to 30 wt %, and the dipping process thereof may be conducted for a period ranging from 1 min. to 72 hrs, preferably from 10 min. to 2 hrs.

Although the coated formulation is preferably dried by drying slowly at a relative humidity of less than 20% for 48 hours or longer, other drying procedures may also be used.

Alternatively, the aldehyde and/or polyvalent metal ion may be employed directly in the composition to be coated on the formulation. The aldehyde which may be employed directly in the coating composition is preferably terpene, cinnamaldehyde, or aldose.

Besides a coated capsule formulation, a capsule formulation may be prepared by shaping the drug delivery composition of the present invention into a capsule and filling a biologically active substance into the capsule. The capsule may be a hard or soft capsule and may be prepared by using a pin molder or a rotary die. The capsule formulation has the advantage that more drugs having widely varying properties can be formulated than possible with other forms of formulation.

In another embodiment, a soft capsule may be prepared using the delivery composition of the present invention by exploiting the phenomenon that the sol-gel transition of gelatin occurs at a temperature ranging from 40 to 50^oC. An example of a composition for the production of a soft capsule is one containing 0.1 to 99.9%, preferably 50 to 99.9%, by weight of gelatin and 0.1 to 99.9%, preferably 0.1 to 50%, by weight of pectinate and, optionally, 0 to 45% by weight of dextran. Preferably, the soft capsule composition contains an excess amount of gelatin sufficient to induce the gel-sol phase change which facilitates the processing step for the preparation, e.g., a rotary die. Further, the inventive soft capsule composition may contain a plasticizer in an amount of 5 to 100% by weight based on the total weight of the polymeric components in the composition.

A biologically active substance may be filled into a capsule in the form of an oily dispersion, powder, granules or pellets.

The pharmaceutical composition of the present invention is not limited to the above mentioned embodiments and modification and change may be made thereto by a person skilled in the art.

Claim 1 of 13 Claims

What is claimed is:

1. A colon selective drug delivery composition comprising a pharmaceutical matrix of a complex of gelatin and an anionic polysaccharide which is degradable by a colonic enzyme.

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