Title:  Colonic drug delivery composition

United States Patent:  6,228,396

Assignee:  West Pharmaceutical Services Drug Delivery & Clinical Research Centre (Nottingham, GB)

Appl. No.:  765347

PCT Filed:  June 21, 1995

371 Date:  February 10, 1997

PCT PUB.NO.:  WO95/35100

Foreign Application Priority Data:  Jun 21, 1994[GB] (9412394)

A colonic drug delivery composition is provided and comprises a starch capsule containing a drug, the starch capsule being provided with a coating such that the drug will only be released from the capsule in the colon. The coating may be a pH sensitive material, a redox sensitive material, or a material broken down by specific enzymes or bacteria present in the colon. The drug to be delivered may be one for local action in the colon or a systemically active drug to be absorbed from the colon.

Description of the Invention

The present invention relates to a drug delivery composition for delivering a drug to the colon.

There is currently considerable interest in the development of pharmaceutical formulations which are capable of selective delivery of drugs into the colon. Site specific delivery to the colon can have two major advantages for the development of pharmaceutical products:

1. Treatment of local conditions: colonic diseases which may benefit from selective delivery of drug include Crohns disease and ulcerative colitis, where established therapies include corticosteroids and mesalazine (5-aminosalicylic acid), irritable bowel syndrome (anti-motility drugs, antiinflammatories), spastic colon (anticholinergics), constipation (laxatives) and colon cancer (antineoplastics).

2. Improved absorption of difficult drugs: the products of biotechnology, such as peptides and proteins and carbohydrate drugs, are difficult to deliver except by injection. The ability to delivery such compounds orally can be of great importance. The colon is often identified as a preferred site because of slow transit, low volume and a lack of vigorous stirring, leading to an ability to create local conditions favourable to stabilisation and absorption enhancement, and a lack of digestive enzymes (proteases).

There are a number of technologies, both marketed and in development, that are claimed to provide colon specific delivery of drugs.

Two devices in which drug release is claimed to be entirely time-dependent dependent include the Pulsincap.TM. (WO 90/09168) and the Time Clock Release System.TM. (Pozzi et al., APV course on Pulsatile Drug Delivery, Konigswinter, May 20, 1992).

Site-specific delivery into the colon can also be achieved by the use of coating material that are specifically degraded in the colonic environment by the action of microorganisms and/or the reductive environment found there. Such materials include but are not limited to azopolymers and disulphide polymers (PCT BE91/00006), amylose (Milojevic et al, Proc. Int. Symp. Contr. Rel. Bioact. Mater., 20, 288, 1993), calcium pectinate (Rubenstein et al., Pharm. Res., 10, 258-263, 1993) chondroitin sulphate (Rubenstein et al., Pharm. Res., 9, 276-278, 1992), and modified guar gum (Rubenstein and Gliko-Kabir, S. T. P. Pharma Sciences 5, 41-46, 1995).

Site-specific delivery into the small intestine has been achieved for many years by the use of pH-sensitive (enteric) coatings. By applying more coating and/or raising the threshold pH at which dissolution of the coating begins, it is possible to achieve colon-specific delivery by the use of enteric polymers. Tablets containing mesalazine and coated with Eudragit S100, which dissolves above pH 7, are marketed in a number of countries (Asacol.TM., SmithKline Beecham in UK). Although this formulation is generally successful in achieving site-specific delivery of 5-ASA, failure of the coating to dissolve has been reported, with patients observing intact tablets in their stools (Schroeder et al., New Engl. J. Med., 317, 1625-1629, 1987). Mesalazine tablets coated with Eudragit L100, which dissolves above pH 6, are also commercially available (e.g. Claversal.TM. and Salofalk.TM.). A scintigraphic assessment indicated that in a group of thirteen patients more than 70% of administered Claversal tablets disintegrated in the lower small intestine, on average 3.2 h after gastric emptying (Hardy et al., Aliment. Pharmacol. Therap., 1, 273-380, 1987). Although enteric coatings are one of the simplest technologies available for colon-specific delivery, they also offer an advantage in terms of cost and ease of manufacture.

Coated dosage forms for colonic delivery are almost exclusively based on tablets. However, there are circumstances in which it would be beneficial to use a coated capsule formulation e.g. where the material to be delivered is a liquid, or is sensitive to compression. The known capsules are typically made from gelatin. Although it is possible to coat hard gelatin capsules, there are a considerable number of drawbacks with such a product. In particular, the capsule shell becomes brittle during coating or on long term storage. Furthermore, the smooth surface of the gelatin shell results in poor adhesion of the coating, there is a risk of the coat cracking on handling the capsule, and there is an interaction of the coating with the gelatin shell resulting in changed dissolution performance on long term storage. For these reasons an enteric capsule has not been an obvious choice if an enteric drug delivery device has to be selected.

Surprisingly we have now discovered that the drawbacks of the gelatin capsules and the general prejudice of capsules being unsuitable for enteric coating for colon delivery can be minimised by the use of injection moulded starch capsules.

The invention therefore provides a drug delivery composition for delivering a drug to the colonic region comprising a starch capsule containing the drug and wherein the starch capsule is provided with a coating such that the drug is predominantly released from the capsule in the colon and/or terminal ileum.

Preferably, substantially all of the drug is released in the terminal ileum and/or the colon.

The term "starch" is used to include modified starches and starch derivatives. The starches used should be of food or pharmaceutical quality.

By the term "derivatives" we particularly mean ester and ethers of the parent compound that can be unfunctionalised or functionalised to contain, for example, ionic groupings.

Suitable starch derivatives include hydroxyethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, succinate derivatives or starch and grafted starches. Such starch derivatives are well known and described in the art (for example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)).

The starch capsules are sold oral dosage forms in which a drug is enclosed in a starch container, which disintegrates in contact with water. The capsules may also contain dyes, opaquing agents such as titanium dioxide, dispersing agents and mould releasing agents. The capsules typically also contain between 12% and 16% of water.

The capsules are made using an injection moulding process. They comprise two components, a body and a cap. The body is filled with the drug to be delivered and the cap is then attached and sealed. Unlike gelatin capsules, there is no overlap between the body and the cap of the starch capsule and this allows for easy application of the coating. The method of making the starch capsules is well known in the art, and capsules and their method of manufacture described in EP-A-118240, WO-90/05161, EP-A-0304401, WO-92/04408 or GB-2187703 can be used.

The composition of the coating should be optimised to maximise disintegration of the coating within the colon whilst minimising the possibility of the coated capsules passing through the gastrointestinal tract intact.

Any coating can be used which ensures that the capsule does not break-up and release the drug until it is in the colon. The coating may be one which is pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria, such that the coating only dissolves or finishes dissolving in the colon. Thus the capsules will not release the drug until it is in the colon.

The thickness of the coating will typically be in the range of 80 .mu.m to 300 .mu.m. The thickness of the particular coating used will be chosen according to the mechanism by which the coating is dissolved.

Preferred coating materials are those which dissolve at a pH of 5 or above. The coatings therefore only begin to dissolve when they have left the stomach and entered the small intestine. A thick layer of coating is provided which will dissolve in about 3-4 hours thereby allowing the capsule underneath to breakup only when it has reached the terminal ileum or the colon. Such a coating can be made from a variety of polymers such as cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac as described by Healy in his article "Enteric Coatings and Delayed Release" Chapter 7 in Drug Delivery to the Gastrointestinal Tract, editors Hardy et al., Ellis Horwood, Chichester, 1989. For coatings of cellulose esters, a thickness of 200-250 .mu.m would be suitable.

Especially preferred materials are methylmethacrylates or copolymers of methacrylic acid and methylmethacrylate. Such materials are available as Eudragit polymers (trademark) (Rohm Pharma, Darmstadt, Germany). Eudragits are copolymers of methacrylic acid and methylmethacrylate. Preferred compositions are based on Eudragit L100 and Eudragit S100. Eudragit L100 dissolves at pH 6 and upwards and comprises 48.3% methacrylic acid units per g dry substance; Eudragit S100 dissolves at pH 7 and upwards and comprises 29.2% methacrylic acid units per g dry substance. Preferred coating compositions are based on Eudragit L100 and Eudragit S100 in the range of 100 parts L100:0 parts S100 to 20 parts L100:80 parts S100. The most preferable range is 70 parts L100:30 parts S100 to 80 parts L100:20 parts S100. As the pH at which the coating begins to dissolve increases, the thickness necessary to achieve colon specific delivery decreases. For formulations where the ratio of Eudragit L100:S100 is high, a coat thickness of the order 150-200 .mu.m is preferable. This is equivalent to 70-110 mg of coating for a size 0 capsule. For coatings where the ratio Eudragit L100:S100 is low, a coat thickness of the order 80-120 .mu.m is preferable, equivalent to 30 to 60 mg coating for a size 0 capsule.

The colonic region has a high presence of microbial anaerobic organisms providing reducing conditions. Thus the coating may suitably comprise a material which is redox-sensitive. Such coatings may comprise azopolymers which can for example consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesized by free radical polymerization, the azopolymer being broken down enzymatically and specifically in the colon, or disulphide polymers (see PCT/BE91/00006 and Van den Mooter, Int. J. Pharm. 87, 37, 1992).

Other materials which providing release in the colon are amylose, for example a coating composition can be prepared by mixing amylose-butan-1-ol complex (glassy amylose) with Ethocel aqueous dispersion (Milojevic et al., Proc. Int. Symp. Contr. Rel. Bioact. Mater. 20, 288, 1993), or a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Allwood et al GB 9025373.3), calcium pectinate (Rubenstein et al., Pharm. Res., 10, 258, 1993) pectin, a polysaccharide which is totally degraded by colonic bacterial enzymes (Ashford et al., Br Pharm. Conference, 1992, Abstract 13), chondroitin sulphate (Rubenstein et al. Pharm. Res. 9, 276, 1992) and resistant starches (Allwood et al., PCT WO 89/11269, 1989), dextran hydrogels (Hovgaard and Br.o slashed.ndsted, 3rd Eur. Symp. Control. Drug Del., Abstract Book, 1994, 87) modified guar gum such as borax modified guar gum (Rubenstein and Gliko-Kabir, S. T. P. Pharma Sciences 5, 41-46, 1995), .beta.-cyclodextrin (Sid ke et at., Eu. J. Pharm. Biopharm. 40 (suppl), 335, 1994), saccharide containing polymers, by which we include a polymeric construct comprising a synthetic oligosaccharide-containing biopolymer including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, raffinose and stachyose, or saccharide-containing, natural polymers including modified mucopolysaccharides such as cross-linked pectate (Sintov and Rubenstein PCT/US 91/03014); methacrylate-galactomannan (Lehmann and Dreher, Proc. Int. Symp. Control. Rel. Bioact. Mater. 18, 331, 1991) and pH-sensitive hydrogels (Kopecek et al., J. Control. Rel. 19, 121, 1992). Resistant starches, eg glassy amylose, are starches that are not broken down by the enzymes in the upper gastrointestinal tract but are degraded by enzymes in the colon.

The drug which is contained in the capsule may be any pharmaceutically or therapeutically active agent. The term "drug" is used herein to include any active agent that can have its effect locally or in the body after systemic absorption into the circulation or transport via the lymphatic system. The term also includes antigens and allergens for use as vaccine as well as DNA for use in gene therapy.

The starch capsules are especially advantageous over gelatin capsules because they can be filled with drug in any form including liquids, powders, pellets and mini-tablets.

The drug may be one which is locally acting in the colonic region to treat a colon disease such as irritable bowel syndrome, irritable bowel disease, crohns disease, constipation, post operative atony, gastrointestinal infections and for delivery of an antigenic material to the lymphoid tissue. Such drugs include those for the treatment of colon disease, for example, 5-ASA; steroids such as hydrocortisone, budesonide; laxatives; octreotide; cisapride; anticholinergics; opioids; calcium channel blockers, DNA for delivery to the cells of the colon, glucosamine, thromboxane A₂ synthetase inhibitor such as Ridogrel, 5HT3-antagonist such as ondansetron, antibodies against infectioneous bacteriae such as clostiduim defficle.

The composition can also be used for delivery of an antiviral agent for example the prophylaxis of HIV.

Alternatively, the drug may be one which is systemically active and for which absorption may be improved in the colon region. Such drugs include polar compounds such as: heparins; insulin; calcitonins; human growth hormone (hGH) growth hormone releasing hormone (GHRH); interferons; somatostatin and analogues such as octreotide and vapreotide; erythropoietin (EPO); granulocyte colony stimulating factor (G-CSF); parathyroid hormone (PTH); luteinising hormone releasing hormone (LHRH) and analogues; atrial natriuretic factor (ANF); vasopressin, desmopressin, calcitonin gene related peptide (CGRP) and analgesics such as morphine.

The composition can also be used for delivery of DNA either as a vaccine or for therapeutic purposes where a drug is expressed for local or systemic effect.

The drug delivery composition of the invention may also be used for once-daily administration of drugs such as: captopril; alfuzosine; bisphosphonates such as clodronate; carbamazepine; atenolol; benazepril. The colon may also be a useful place to delivery drugs to alter their metabolism, such as raloxifene and benazepril.

The starch capsules of the present invention are cheap and easy to manufacture fill and coat. They have been found to provide colon-specific delivery in a reliable manner. The starch capsules have been found to give good adhesion of the coating and their high density enables a good tumbling action. Aqueous coating is possible and the capsule walls have high mechanical strength and are non-flexible. Unlike gelatin capsules, the starch capsules are not brittle and this is particularly advantageous.

A further additional advantage of the use of a starch capsule is that the starch when released in the colonic environment will provide enhanced stabilisation of a peptide or protein drug.

It is known (Smith et al., Gastroenterology, 108 (suppl), 1995, A753) that the delivery of starch into the colon at a quantity of 10 mg/ml can lead to the reduced degradation of polypeptides. For the present invention the capsule comprises about 400 mg of starch. This will be delivered into a volume of about 50 ml leading to a starch concentration effective for polypeptide stabilisation.

Claim 1 of 13 Claims

What is claimed is:

1. A drug delivery composition for delivering a drug to the colonic region comprising a starch capsule containing the drug,

wherein the starch capsule is provided with a coating comprising a poly(methylmethacrylate) or a copolymer of methacrylic acid and methyl methacrylic which dissolves at a pH of 5 or higher, and

wherein the coating has a thickness between 80 .mu.m and 200 .mu.m and dissolves to expose the capsule about 3 to 4 hours after oral administration of the composition such that the capsule will not release the drug until the capsule is in the colon and/or terminal ileum.

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