Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1997-02-10
2001-05-08
Zitomer, Fred (Department: 1713)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S456000, C424S459000
Reexamination Certificate
active
06228396
ABSTRACT:
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™ (WO 90/09168) and the Time Clock Release System™ (Pozzi et al., APV course on Pulsatile Drug Delivery, Königswinter, 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™, 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™ and Salofalk™). 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 &mgr;m to 300 &mgr;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
Arnall Golden & Gregory LLP
West Pharmaceutical Services Drug Delivery & Clinical Research C
Zitomer Fred
LandOfFree
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