Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-04-13
2002-05-14
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S450000, C424S490000, C424S491000, C424S499000, C424S426000, C424S496000, C424S497000
Reexamination Certificate
active
06387408
ABSTRACT:
The present invention relates to a drug delivery composition and more particularly to a drug delivery composition for administration via the gastrointestinal tract.
The gastrointestinal (G.I.) tract is one of the major routes for the administration of pharmacological agents. Drugs are normally well absorbed from the intestines, and dosage forms such as capsules, tablets and suspensions are well accepted by the general population. In recent years there has been a tendency towards the development of controlled release dosage forms that will provide therapy over an extended period of time. Normally this would be once a day and it is believed that such a change in dosage regimen will reduce adverse reactions and side effects and also improve patient compliance.
The design and evaluation of controlled release dosage forms must, however, take into account the properties of the gastrointestinal tract, including the rapid transit of material through the small intestine, which is the important site for absorption for certain drugs. Recent work by Davis and others at Nottingham University has shown that this transit time can be of the order of 3 hours or less. Thus the disadvantage of very long release times, for example 24 hours, is that the drug could have passed through the small intestine before being released and therefore its curative property could be effectively nullified.
A considerable advantage can be gained if the dosage form is held in the small intestine so that it will be well absorbed into the systemic circulation over a long period of time.
Recently, work has been done into investigating the use of synthetic polymers that may have muco- or bio-adhesive properties, for example those disclosed in W0 85/02092, such as cross-linked acrylic acid and methacrylic acid polymers. The problem with the use of synthetic polymers lies in the mode of action of such materials and in particular whether it is intended to attach dosage forms to the mucus, which should easily slough off, or to attach dosage forms to the glycocalyx or directly to the cell surface of the enterocyte. Various in vitro tests conducted with excised portions of stomach and oesophagus are not considered to be realistic in terms of in vivo environmental conditions and transit phenomena.
It is an object of preferred aspects of the present invention to provide a drug delivery system for use in the gastrointestinal tract which obviates the above disadvantages and maintains the drug in the G.I. tract, for example in the small intestine, for a prolonged period thereby allowing the drug to be released at a desired rate over this prolonged period. By extending the period, the drug can if required be released more slowly, which may lead to less severe adverse reactions and side effects.
The present invention therefore provides a drug delivery system, preferably including a plurality of particles containing active drug material, preferably size 20 microns or less, and incorporating on the outer surface of at least some of the particles a bioadhesive material derived from a bacterium such that in use the bioadhesive material will adhere to the small intestine of the gut.
The term “drug” is used herein to include any pharmacologically active compound or antigen-comprising material.
The term “bioadhesive” is used to denote a material which adheres to the gut wall. The bioadhesive derived from a bacterium may be isolated therefrom or may be a synthetically prepared version thereof, or an analogue or fragment of such material.
Such bioadhesive materials have been previously proposed for use in medicine in W0 88/07078, but only as immobilising materials for binding biological material to a carrier, for example binding a blood clotting agent to a carrier substance. There was no suggestion that the bioadhesives could be used to direct medicaments to the gut wall.
The micro-organisms from which the adhesive material is derived or to which it corresponds will generally be those found in the G.I. tract, especially the (small) intestine, of the mammal being treated. Such micro-organisms include
E. coli,
Klebsiella spp. and Salmonella spp.
Preferably, the bioadhesive material is obtained from
Escherichia coli,
especially a human G.I. tract infesting strain thereof, or corresponds to such material.
In the small intestine certain bacterial flora are found to adhere extremely well.
Escherichia coli,
for example, adheres via surface proteins called fimbriae (pili).
E. coli
strains express the following fimbrial types:
(a) Type 1 or ‘common’ fimbriae whose adhesive properties are inhibited by mannose (mannose-sensitive fimbriae).
(b) P fimbriae (mannose-resistant).
(c) Colonisation factor antigens (CFAI and CFAII) which are mannose-resistant.
The present invention is concerned particularly with class (a). These materials, when purified, can be identified by the ability to haemagglutinate guinea-pig erythrocytes in the absence but not in the presence of &agr;-methylmannoside. In the case of Type 1 fimbriae from
E. coli,
the presence of a 17 kDa sub-unit protein may be detected on sodium dodecyl sulphate polyacrylamide gel electrophoresis after denaturation of fimbriae by saturated guanidine HCl. In other organisms, such as Klebsiella spp. the corresponding sub-unit may be slightly larger or smaller. Finally, Type 1 fimbriae material from a given organism would be expected to react in Dot and Western Immunoblots with a polyclonal antiserum raised against the Type 1 fimbriae from the same organism. The various test methods for all three of these tests are standard.
Type 1 fimbrial material from
E. coli
has previously been isolated and shown to comprise polypeptides of molecular weights of about 14 kDa, 17 kDa and 28 kDa. See, for example, Hanson & Brinton, Nature 332, 265 (1988) and Hanson et al,
J. Bact.
170(8), 3350 (1988). The 28 kDa polypeptide described therein is probably the same as the 29 kDa FimH polypeptide described by Abraham et al, (1988)
Infect.
&
Immun.
56(5), 1023-1029. This latter paper suggests using FimH in a vaccine to confer immunity against
E. coli
binding, but does not suggest using FimH to bind a drug or antigen to the gut wall. The 17 kDa polypeptide is the major polypeptide. Since micro-organisms can adhere firmly in the gastrointestinal tract through this adhesion process (which may be through an interaction between the adhesive molecule (“adhesin”) and sugar residues, eg mannosides, in the gastrointestinal tract) it is possible in accordance with the present invention to achieve similar adhesive effects by the isolation and purification of an individual adhesin polypeptide. When administered to rabbits the adhesin is seen to adhere to the gastrointestinal tract.
Alternatively, the larger bodies known as “fimbriosomes” may be used. These bodies are described in Abraham et al,
Infect.
&
Immun.
56(5), 1023,(1988).
In the present invention adhesins and similar bioadhesive materials produced from micro-organisms are used to design and develop controlled release dosage forms with extended gastrointestinal residence. The delivery system preferably consists of small particles (a few microns in size) so that the adhesive is able to attach the particle to the wall of the gastrointestinal tract through sugar residue, lectin-mediated processes. The adhesins may be coated onto particles or covalently bound (grafted) onto the surface of the particle. A preferred adhesin is the bacterial adhesin obtained from
E. coli
, but there are many other adhesin-producing bacteria available, for example
Pseudomonas aeruginosa.
It is also apparent that the adhesive characteristics of the fimbrial material do not necessarily reside in the complete fimbrial structure and that a suitably cleaved product or its synthetic equivalent comprising the correct sequence of amino acids demonstrates similar bioadhesive properties. The preparation of a peptide of this sort is described in Abraham & Beachey,
J. Bact.
169(6), 2460, (1987). More specifically, the peptide consisted of residues 23-35 of
E. coli
Type 1 fimbrial pr
Caston Antony James
Illum Lisbeth
Williams Paul
Akin Gump Strauss Hauer & Feld L.L.P.
Sheikh Humera N.
West Pharmaceutical Services Drug Delivery and Clinical Research
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