GB2490671A

GB2490671A - Pharmaceutical preparation and use

Info

Publication number: GB2490671A
Application number: GB1107652.8A
Authority: GB
Inventors: Stephen Brown
Original assignee: MW Encap Ltd
Current assignee: MW Encap Ltd
Priority date: 2011-05-09
Filing date: 2011-05-09
Publication date: 2012-11-14
Anticipated expiration: 2031-05-09
Also published as: GB201107652D0; GB2490671B

Abstract

There is provided a pharmaceutical dosage unit comprising an outer housing defined by an outer wall, one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall is adapted to disintegrate or partially disintegrate within the small intestine of a mammal, releasing the first antibiotic compositions and wherein said inner wall(s) are adapted to disintegrate or partially disintegrate within the large intestine of a mammal, in particular the colon of the mammal, releasing the second antibiotic composition. There is also provided a dosage unit for use in therapy, in particular, infections of the GI tract.

Description

PHARMACEUTICAL PREPARATION AND USE

Field of the Invention

The present invention relates to pharmaceutical dosage units for the topical administration of antibiotics in the large intestine. There is also provided a method of medical treatment.

Background to the Invention

Antibiotics are widely used, both in human/veterinary medicine and also agriculture, and this has lead to an increasing problem of drug resistance to currently available antibiotics. This is particularly relevant to infectious conditions or diseases that are treated with single antibiotics (otherwise known as monotherapy). As such, there is a significant need not just for effective and safe new treatments but those that have a mode of action that minimises or negates the risk of eventual development of drug resistance in target pathogen populations and for therapies that can be used in combination with other treatments in order to minimise the opportunity for resistance and extending the utility of currently available antimicrobials.

Bacterial infections of the gastrointestinal (G.I.) tract, and in particular the large intestine are common. Antibiotic treatment of C. d4fflcile infections can be difficult, due both to antibiotic resistance as well as physiological factors of the bacteria itself (spore formation, protective effects of the pseudo membrane). A side effect of such infections is that the contents of the G.I. tract are cleared from the body very quickly. Antibiotics used to treat such infections are also cleared from the G.I. tract meaning that contact of the antibiotics with the site of the infection is limited and the effectiveness of conventional antibiotic preparations is limited accordingly.

Systemic administration of antibiotics has been associated with serious side effects including major allergic reaction, overgrowth of yeast species, severe blood diseases, ear and kidney damage and tendon damage. In addition, systemic administration of antibiotics increases the amount of antibiotic to be used exacerbating the potential for antibiotic resistance in target pathogen populations. There is therefore an advantage in the local treatment of gastro-intestinal infections using antibiotics which are not systemically absorbed, or by the targeted delivery of systemically bioavailable drugs directly to the site of infection, which is normally the small intestine or colon.

Known antibiotic preparations include those which release the antibiotic in the stomach.

Drugs which are not absorbed systemically travel through the gut to the large intestine. The antibiotic active may be degraded in the low pH of the stomach. Symptoms of G.I. tract infection such as c. difficile include diarrhoea and vomiting. The contents of the stomach and the colon are thus cleared very quickly and it is difficult to maintain levels of antibiotic in the colon. This leads to a complex treatment regime, often involving the frequent administration of low dosages of antibiotic. Patient compliance is limited accordingly.

GB 2365336 discloses a delivery device comprising an inner capsule within an outer capsule, the inner and outer capsule containing the same active principle. The inner and outer capsules may release their contents at different locations within the gastrointestinal tract, in particular the stomach and the colon. The only specific active principle disclosed in this document is simethicone and dimethicone used in the treatment of dissolved intestinal gases.

There remains a need for better therapies for treating and preventing bacterial infections, in particular those associated with the G.I tract such as the colon. In addition there remains a need to limit the amount of antibiotics used with the introduction of novel, replacement therapies or adjunct treatments that can improve the effectiveness of antibiotics currently available for the treatment or prevention of bacterial infections.

Statement of Invention

According to a first embodiment there is provided a pharmaceutical dosage unit comprising an outer housing defined by an outer wall, one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall is adapted to disintegrate or partially disintegrate within the small intestine of a mammal and wherein said inner wall(s) are adapted to disintegrate or partially disintegrate within the large intestine of a mammal, in particular the colon of the mammal.

Disintegration or partial disintegration of the inner and/or outer walls allows release of the second and/or first antibiotic compositions respectively.

According to one embodiment, the pharmaceutical dosage unit comprises an outer capsule housing a first antibiotic composition, one or more inner capsules within the outer capsule, said inner capsules housing a second antibiotic composition, wherein said outer capsule includes an enteric coating allowing disintegration of the outer capsule in the small intestine of a mammal and said inner capsule(s) include a colonic coating allowing disintegration of the inner capsule(s) in the colon of the mammal.

According to a second aspect of the present invention there is provided a method of treating or preventing an infection of the gastrointestinal tract (0.1. tract) comprising the steps of administering one or more pharmaceutical dosage units as described above to a patient in need thereof.

According to a third aspect of the present invention there is provided a pharmaceutical dosage unit as described above for use in therapy.

According to a fourth aspect of the present invention there is provided a pharmaceutical dosage unit as described above for use in the treatment or prevention of an infection of the gastrointestinal tract of a human or animal.

According to a fifth aspect of the present invention there is provided the use of a pharmaceutical dosage unit as described above in the manufacture of a medicament for the treatment or prevention of an infection of the gastrointestinal tract of a human or animal.

Detailed Description

Definitions As used herein, the term "pharmaco-kinetie profile" relates to the balance between the release/absorbance rate of an active component compared to its removal rate from the site of release, for example through excretion or metabolism.

The term "small intestine" relates to the length of intestine following the stomach to the large intestine. The small intestine comprises the duodenum, the jejunum and the ileum.

The term "large intestine" relates to the length of intestine following the small intestine to the anus. The large intestine comprises the cecum and the colon.

The term "vaneomycin" refers to the tricyclic glycopeptide antibiotic derived from Amycolalopsis orientalis (formerly Nocardia orientalis). In some embodiments, the hydrochloride form of vancomycin is used. This form of vancomycin has a molecular formula of C66H75C12N9024.HCl and a molecular weight of about 1485.73. One of skill in the art will appreciate that other forms of vancomycin can be used in the embodiments described herein.

The term "gel" is used to refer to a colloid in which the solid disperse phase forms a network in combination with the fluid continuous phase, resulting in a viscous semi rigid material.

The term "enteric" is used to refer to something which is of, within or pertaining to the small intestine.

The term "colonic" is used to refer to something which is of, within or pertaining to the colon.

The term "capsule" is used to refer to a dosage unit comprising a wall encasing a pharmaceutical composition.

A soft capsule is generally formed and filled in one procedure. Typically two ribbons of material are joined together to form an open housing, the capsule is filled and then the open housing is closed to form a capsule. Soft capsules are not designed to be opened and sealed.

A hard capsule is generally formed in one procedure and filled in separate procedure. Hard capsules may be opened and closed after formation.

A time delayed, erodible coating is eroded upon contact with the conditions of the body following administration. By tailoring its properties, its site of disintegration can be tailored.

The site of disintegration of a time delayed, erodible coating may be tailored, in particular by tailoring the thickness of the coating, and/or the rate of erosion of the materials forming the coating under acidic conditions such as those found in the stomach of a mammal. Generally a time delayed, erodible coating is formed or comprises shellac and/or a polymer matrix.

The term "immediate release composition" refers to an embodiment where the first and/or second antibiotic composition is immediately available to the body of the patient following disintegration or partial disintegration of the outer or inner wall respectively. In particular, an immediate release composition releases substantially its entire active ingredient (e.g., an antibiotic) within 5 minutes to about 60 minutes. The term "substantially all," when used in reference to the amount of antibiotic released, means over 70%, 85%, 90%, 95%, or 99% of the amount of antibiotic in the formulation component has been released.

The term "sustained release composition!! refers to an embodiment where the first and/or second antibiotic composition releases substantially all of its active ingredient (the antibiotic) within about 180 minutes to about 600 minutes. The antibiotic release times for the immediate and/or sustained release components can be measured using standard dissolution assays known to one of skill in the art.

By an "effective" amount or "therapeutically effective amount" is meant an amount of one or more active substances which, within the scope of sound medical judgment, is sufficient to provide a desired effect without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "fluid" or derivatives thereof is used to describe a material which is a liquid or a semisolid but not a gas, a liquid being defined as a material which flows under ambient conditions without external influences, whilst a semisolid is defined as a material or mixture of material which has a consistency that varies according to its conditions within an ambient range and which may have characteristics of both a liquid and a solid. Examples of semisolids include creams, pastes, ointments, suspensions, emulsions, thixotrope and waxes.

Changes in ambient conditions, such as a temperature change, could alter a semisolid to a more liquid state, whilst agitation, such as shaking, could change a thixotrope from a more solid state to a more liquid state.

The term "antibiotic" is used to refer to antibacterial agents that may be derived from bacterial sources. Antibiotic agents may be bactericidal and/or bacteriostatic.

Pharmaceutical Dosage unit According to a first embodiment there is provided a pharmaceutical dosage unit comprising an outer housing defined by an outer wall, one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall is adapted to disintegrate or partially disintegrate within the small intestine of a mammal and wherein said inner wall(s) arc adapted to disintegrate or partially disintegrate within the large intestine of a mammal, typically the colon of the mammal.

According to one embodiment the pharmaceutical dosage unit of the present invention comprises an outer housing defined by an outer wall one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall comprises an enteric coating and said inner wall(s) comprise a colonic coating.

According to one embodiment, the present invention provides a pharmaceutical dosage unit comprising an outer capsule housing a first antibiotic composition, one or more inner capsules within the outer capsule, said inner capsules housing a second antibiotic composition, wherein said outer capsule includes an enteric coating allowing disintegration or partial disintegration of the outer capsule in the small intestine of a mammal and said inner capsule(s) include a colonic coating allowing disintegration or partial disintegration of the inner capsule(s) in the colon of the mammal.

The pharmaceutical dosage unit of the present invention allows delayed release of the antibiotic compositions contained therein. A desired amount of antibiotic is predictably and consistently delivered over a desired time period to a desired location in the body. For example the dosage unit of the present invention can deliver a minimum inhibitory concentration of antibiotic to the colon for up to about 4, about 6, about 12, about 18, or about 24 hours. The antibiotic compositions are not released from the inner and outer housings immediately after administration of the dosage unit to the patient. The antibiotic compositions do not act systemically, avoiding the significant side effects referred to above.

The antibiotic compositions are not released in the stomach, and degradation in the low pH of the stomach is therefore avoided, maximising the dose of antibiotic which contacts the small or large intestine where the infection of the G.I. tract is likely to be.

The dosage unit of the present invention provides two administrations of antibiotic, one from the outer housing and one from the inner housing. The number of individual dosages required to be administered to the patient is minimised accordingly and so the patient compliance is increased. The first pharmaceutical composition is administered directly to the small intestine, and the second pharmaceutical composition is administered directly to the large intestine, in particular the colon. Contact of the antibiotic compositions with the direct site of the infection to be treated (generally the colon) is thus maximised. The dosages of antibiotic required are minimised accordingly. Reduced dosages of antibiotics minimise side effects again increasing patient compliance. In addition, the risk of possible drug resistance is minimised. The dosage unit of the present invention allows administration of two dosages of antibiotic with a single preparation. The amount of antibiotic composition present in the inner and outer housings depends on the specific antibiotic used. However the ratio of first antibiotic composition: second antibiotic composition is generally 10:90 to 90:10.

Where the antibiotic compositions comprise Vancomycin, the dosage unit of the present invention may allow administration of two dosages of 100 to 250 mg antibiotics daily. Where the antibiotic compositions are Vancomycin compositions, the dosage unit of the present invention suitably includes a dose of 100 to 150 mg, preferably 125 mg Vancomycin in the outer housing and 60 to 100 mg Vancomycin in the inner housing. Such a dosage unit is generally administered two times a day. Current treatment regimes involve the administration of 125 to 250 mg antibiotics four times daily. As well as reducing the number of pharmaceutical dosage units which a patient must take, the dosage administered is also reduced.

The outer wall defining the outer housing disintegrates or partially disintegrates upon contact with the conditions of the small intestine of the patient, releasing the first antibiotic composition in the small intestine. The inner wall(s) defining the inner housing(s) disintegrate or partially disintegrate upon contact with the conditions of the large intestine, in particular the colon of the patient, releasing the second antibiotic composition in the large intestine.

Materials adapted to disintegrate or partially disintegrate under the conditions of a particular environment require some contact with that environment before disintegration. Accordingly, all dosage units comprising materials adapted to disintegrate or partially disintegrate in the large intestine will have to travel some way down the large intestine before disintegration occurs. As such, the release of a pharmaceutical composition from a housing defined by such materials occurs some way down the large intestine, and the start of the large intestine is not contacted with the pharmaceutical composition. The first antibiotic composition is released in the small intestine and then permeates to the colon. This ensures that the antibiotic composition contacts all of the large intestine, including the start of the large intestine, enabling all of the sites of infection to be directly contacted with the antibiotic composition, allowing a reduced dosage and maximising the effectiveness of the antibiotic composition.

In severe cases of infections of the colon, such as c. difficile, the infection may ithabit some of the small intestine as well as the large intestine. Release of the first antibiotic composition in the small intestine ensures contact with the site of the infection even in cases where the infection has spread to the small intestine.

The dosage unit of the present invention provides a reliable, predictable means of controlling the site of administration of the antibiotic compositions, and of controlling the pharmaco-kinetic profile of the antibiotic composition in the colon.

The outer wall of the dosage unit of the present invention generally comprises an enteric coating. Typically, the enteric coating disintegrates or partially disintegrates at the pH ranges encountered in the small intestine and this allows disintegration or partial disintegration of the outer wall. Time delayed, erodible coatings may also be used to ensure that the disintegration of the outer wall occurs in the small intestine rather than the stomach.

Preferably the disintegration of the outer wall is triggered by contact with the pH range of the small intestine only.

According to one embodiment, the outer wall is adapted to disintegrate at a pH of 5 to 8, preferably 5 to 7.5. According to one embodiment, the outer wall is adapted to disintegrate at the start of the small intestine, which is at or shortly after the duodenum. In such embodiments, the outer wall is adapted to disintegrate at a pH of 5 to 6.5, preferably 5 to 6.

The exact site of disintegration can be tailored. In one embodiment the outer wall may be adapted to disintegrate at the start of the small intestine, typically at the duodenum or shortly thereafter. In such embodiments, the antibiotic composition then permeates from the small intestine to the large intestine, in particular the colon. The first antibiotic composition would be dissolved in bodily fluids during transit though the small intestine, and would arrive in the large intestine over a sustained period at relatively low concentrations. The pharmaco-kinetic profile would be relatively constant. As such, release of the first antibiotic composition would provide a relatively low concentration of the first antibiotic composition in the large intestine over a relatively sustained period, ensuring contact of the large intestine with the antibiotic composition for sustained periods regardless of how quickly the colon was cleared.

In a further embodiment, the outer wall may be adapted to disintegrate towards the end of the small intestine, typically at the ileum or shortly prior to the ileum. In such embodiments, the first antibiotic composition reaches the large intestine relatively quickly after release from the dosage form, at a high concentration. The associated pharmaco-kinetic profile would include a relatively steep sided peak. In such embodiments, the first antibiotic composition travels from the small intestine to the large intestine (in particular the colon) relatively rapidly providing a pulse of first antibiotic composition to the colon, at a relatively high concentration for a relatively short period.

Healthy intestinal flora includes bacteria which are useful in promoting the health of the G.I.

tract and compete against colonisation of the G.I. by bacteria, such as E.coli and C. difficile which are associated with G.I. infections. Such bacteria help to maintain the health of the small intestine and are useful in preventing G.I. infections. However, contact with antibiotics, in particular broad spectrum antibiotics, results in the number of bacteria which form part of healthy intestinal flora being greatly diminished. This affects the health of the G.I. tract after the infection has been treated and increases the likelihood of recurrence of the infection.

Recent studies have found that G. I. infections caused by or associated with C. difficile have a recurrence rate of 20%, rising to 40 to 60% for subsequent recurrences. Releasing the first antibiotic composition at or near the ileum minimises contact with the healthy flora of the small intestine, thus minimising the recurrence of infection. In addition, minimising contact of the small intestine with the antibiotic composition means that broad spectrum antibiotics can be used more readily.

The inner wall of the dosage unit of the present invention generally comprises a colonic coating. Typically, the colonic coating disintegrates or partially disintegrates at the pH ranges and/or upon contact with the specific micro-organisms of the large intestine (in particular the colon), and this allows disintegration or partial disintegration of the inner wall, releasing the second antibiotic compositions. Advantageously, the disintegration of the inner wall may be dual triggered by contact with the pH range of the large intestine and contact with the specific micro-organisms of the large intestine (in particular the colon).

Alternatively, the colonic coating may be adapted to disintegrate upon contact with the specific micro-organisms of the large intestine independent of pH. According to a further embodiment, the colonic coating may be adapted to disintegrate upon contact with the specific pH range of the large intestine independent of contact with the micro-organisms of the large intestine. Time delayed, erodible coatings may be used alone or in combination with the coatings triggered by pH and/or contact with micro-organisms. Such erodible coatings would ensure that the disintegration of the inner wall occurs in the colon rather than the stomach or small intestine.

The inner wall(s) defining the inner housing(s) disintegrate upon contact with the conditions of the large intestine of the patient (in particular the colon), releasing the second antibiotic composition in the large intestine. According to one embodiment, the inner coating is adapted to disintegrate at a pH of 6 to 8, preferably 6.5 to 7.5. According to one embodiment, the inner coating(s) may disintegrate upon contact with specific microorganisms which inhabit the colon. Optionally, the inner coating(s) may disintegrate at the specific pH ranges noted above, in combination with contact with specific micro-organisms.

There is some overlap between the pH ranges in the small and large intestine. Where the disintegration of the inner wall is dual triggered, release of the second antibiotic composition in the large intestine is ensured.

The specific micro-organisms inhabiting the large intestine are listed in Table I, and include one or more of Achromobacter spp., Acidaminococcus fermentans, Acinetobacter cacoaceticus, Aeromonas spp., Alcaligenes faecalis, Bacillus spp., Bifidobacterium spp., Butyriviberio fibrosolvens, Campylobacter spp., Clostridium spp., Clostridium difficile, Clostridium sordellii, Flavobacterium spp., Mycobacteria spp., Mycoplasma spp., Peptococcus spp., Propionibacterium spp., Pseudomonas aeruginosa, Ruminococeus bromii, Ruminococcus spp., Sarcina spp., Veillonella spp., Staphylococcus aureus, Streptococcus viridans, Vibrio spp. and Yersinia enterocolitica.

Advantageously, the inner wall disintegrate upon contact with one or more of Acidaimnococcus fermentans, Acinetobacter cacoaceticus, Bacillus spp., Bifidobacterium spp., Butyriviberio fibrosolvens, Campylobacter spp., Clostridium difficile, Propionibacterium spp., Ruminococcus bromii, Ruminococcus spp., Sarcina spp. and Yersinja enterocolitica.

In particular, the inner wall may disintegrate or partially disintegrate upon contact with one or more of the micro-organisms listed above; in particular when in combination with the specific pH of the large intestine. The pH in the small intestine may be unusually high, in particular in those who are suffering from 0.1. tract infections. As such there may be some overlap between the pH ranges in the small and large intestine. Where the disintegration of the inner wall is dual triggered, release of the second antibiotic composition in the large intestine is ensured.

According to one embodiment, the pharmaceutical dosage unit is a capsule, and both the inner and outer walls are formed from a gel.

Generally, the outer wall defines a hard gel capsule, and the inner wall defines a soft or hard gel capsule. Preferably both the inner and outer walls define hard gel capsules.

The inner and/or the outer wall is generally formed from one or more of gelatine, plasticised gelatine, hydroxyl propyl methyl cellulose (HPMC), starch, Pululan, PVA or agar. The inner and/or the outer wall may be coated or uncoated.

Where one or more of the inner and/or outer walls define a hard gel capsule, it may be formed from hard gelatine, HPMC, Pululan or starch.

Where one or more of the inner and/or outer walls define a soft gel capsule, it may be formed from soft gelatine or agar.

Preferably, the outer wall is coated with an enteric coating. As noted above, the outer wall may be adapted to disintegrate upon contact with the pH range of the small intestine and/or upon contact with the specific micro-organisms present in the small intestine. Where the outer wall is adapted to disintegrate upon contact with the pH range of the small intestine it may be coated with an enteric coating including a material susceptible to disintegration upon contact with a pH of about 5 or above, in particular about 5 to 6 or alternatively 7 to 7.5, depending on the specific location of disintegration in the small intestine required. According to one embodiment the material is an anionic copolymer of (meth)acrylie acid and (meth)aerylic acid C1-4 alkyl ester, an anionic co-polymer of methacrylie acid and methacrylic acid methyl ester, typically of the ratio 1:2, preferably Eudragit(R) S. The material may be a cellulose polymer or a polyvinyl-based polymer, including a copolymer of methacrylie acid and ethyl acrylate.

Where the outer wall comprises a time delayed erodible coating, the outer wall may comprise shellac or similar materials.

Where the inner wall(s) are adapted to disintegrate upon contact with the specific pH range of the large intestine, it may be coated with a colonie coating susceptible to disintegration upon contact with a pH of about 6 or above, typically 6.4 to 7.5. According to one embodiment the material is an anionic eopolymer of (meth)aerylic acid and (meth)acrylic acid Cl-4 alkyl ester, an anionic co-polymer of methacrylie acid and methacrylie acid methyl ester, typically of the ratio 1:2, preferably Eudragit(R) S. The material may be a cellulose polymer or a polyvinyl-based polymer, including a eopolymer of methacrylic acid and ethyl acrylate.

Where the inner wall is adapted to disintegrate upon contact with the specific micro-organisms of the large intestine, the inner wall is generally coated with a colonic coating comprising a material which is susceptible to attack by these micro-organisms. This material may comprise at least one polysaceharide in particular at least one polysaccharide selected from the group consisting of starch; amylose; amylopectin; chitosan; ehondroitin sulfate; cyclodextrin; dextran; pullulan; eanageenan; seleroglucan; ehitin; eurdulan and levan.

Preferably, the enterie coating comprises at least one amylose.

Where the inner wall comprises a time delayed erodible coating, the inner wall may comprise shellac or similar materials.

Preferably the outer wall is formed from hard gelatine, HPMC, Pululan or starch, and is coated with an enterie coating susceptible to disintegration or partial disintegration upon contact with a pH of 5 or above. Alternatively or additionally, the inner wall may be formed from hard gelatine, Pululan, HPMC or starch, and is coated with a colonic coating susceptible to disintegration or partial disintegration upon contact with a pH of 6 or above in combination with contact with the specific micro-organisms of the large intestine.

Where the outer coating disintegrates upon contact with the dual triggers of pH range and presence of specific micro-organisms, the colonic coating may comprise the two materials detailed above, preferably substantially homogeneously mixed. The proportion of the bacteria susceptible material to the pH susceptible material may in some circumstances be up to 50:50, preferably up to 65:35 and most preferably from 15:85 to 30:70.

The enteric and/or colonic coatings may also include conventional excipients such as plasticisers for film formation (for example triethyl citrate) and anti-tack agents (such as glyceiyl monostearate) may be included in amounts up to 30% by weight of the enteric/colonic coating.

The inner and outer walls may be caused to disintegrate by dissolution upon contact with the conditions of the small intestine and large intestine respectively. Alternative methods of disintegration include the wall(s) becoming greatly weakened upon contact with the necessary conditions of disintegration and thus allowing release of the first or second antibiotic composition. Generally the inner and outer walls are disintegrated through dissolution.

Typically, disintegration or partial disintegration of the inner and/or outer walls allows immediate release of the first and/or second antibiotic compositions, suitably within 5 to 10 minutes of contact with the conditions of the small intestine or large intestine respectively, generally 5 minutes or less. As noted above, as the first antibiotic composition is released in the small intestine, the portion of the colon adjacent the small intestine is contacted with one of the antibiotic compositions regardless of the fact that the inner wall requires contact with the conditions of the large intestine for a period of time before disintegration of the inner wall(s) takes place.

Alternatively, disintegration or partial disintegration of the inner and/or outer walls may allow sustained release of the first and/or second antibiotic compositions, wherein release of the antibiotic composition(s) suitably begins within 5 to 10 minutes of contact with the conditions of the small intestine or large intestine respectively, and substantially all of the first and/or second antibiotic composition is released within about 4 hours.

According to one embodiment, both of the first and second antibiotic compositions are in immediate release form.

According to a further embodiment, the first antibiotic composition is in sustained release form and the second antibiotic composition is in immediate release form.

The ratio of volume of first antibiotic composition: volume of second antibiotic composition in the products of the invention may be from 1:10 to 10:1.

Preferably the first and second antibiotic compositions comprise vancomycin as the only antibiotic agent and the product contains the first and second antibiotic compositions at a ratio from 1:4 to 4:1, suitably 2:1 up to 4:1. According to a further embodiment the ratio may be approximately 1:1.

The dosage unit of the present invention generally comprises a single inner housing.

Typically the outer housing is a capsule of capsule size 0 (body volume 0.68 ml), or of capsule size I (body volume 0.5 ml).

Typically the inner housing is a capsule of capsule size 2 (body volume 0.37 ml), or of capsule size 3 (body volume 0.3 ml).

According to a further embodiment the dosage unit of the present invention comprises more than one inner housing. Generally in such embodiments, all of the inner housings contain the same antibiotic composition.

Antibiotic Compositions Typically the first and second antibiotic compositions comprise the same antibiotic or mixture of antibiotics. However, the first and second antibiotic compositions may comprise the same or different pharmaceutically acceptable excipients.

Alternatively, the first and second antibiotic compositions may comprise different antibiotics.

According to one embodiment, the first and second antibiotic compositions are in the form of a fluid. Preferably, the fluid is a liquid at body temperature (around 35 to 40 degrees Celsius).

The fluid is generally a solution or suspension. The liquid may comprise suspended solids which may be a powder, pellet, or granules and which may be coated or uncoated. The liquid may also be thermosoftening.

Alternatively, the first and/or second compositions may be in the form of a semi-solid at body temperature, particularly where the first and/or second compositions are in the form of sustained release compositions.

Advantageously, the first and second compositions are in the form of a liquid at body temperature.

According to one embodiment, the first antibiotic composition is available for immediate release upon disintegration or partial disintegration of the outer wall.

Additionally or alternatively, the second antibiotic composition is preferably available for immediate release upon disintegration or partial disintegration of the inner wall(s).

Advantageously, the first and second antibiotic compositions are available for immediate release upon disintegration of the outer and inner walls respectively. According to one such embodiment, the pharmaco-kinetic profile comprises two relatively steep sided peaks, the first peak being associated with the release of the first antibiotic composition, the second peak being associated with the release of the second antibiotic composition. The pharmaco-kinetic profile may return to initial levels in between the two peaks where the first antibiotic composition is associated with a relatively high removal rate. Alternatively, the pharmaco-kinetic profile may remain at an elevated level between the two relatively steep sided peaks where the first antibiotic composition is associated with a relatively low removal rate. Such pharmaco-kinetic profiles are generally associated with embodiments where the outer wall disintegrates at or near the ileum, allowing the first antibiotic composition to arrive in the colon relatively soon after release.

According to one embodiment, the first and second antibiotic compositions are available for immediate release upon disintegration of the outer and inner walls respectively. Where the outer wall disintegrates at the start of the small intestine, for instance at or proximal to the duodenum, the pharmaco-kinetic profile may comprise a peak followed by a relatively gentle upward slope. The peak is associated with the release of the second antibiotic composition in the large intestine, and the gentle upward slope is associated with the arrival of the first antibiotic composition in the colon. Such pharmaco-kinetic profiles are generally associated with embodiments where the outer wall degrades at or near the duodenum, allowing the first antibiotic composition to arrive in the colon a relatively long time after release. In such embodiments, the first antibiotic composition is generally diluted in bodily fluids upon transit from the site of release to the colon.

According to a thrther embodiment, the first and/or second antibiotic compositions may be in the form of a sustained release formulation. The formulations can be so constituted that they release the active antibiotic agent(s) over a period of time following disintegration of the inner and/or outer walls. Sustained release coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, waxes or other material compositions with melting points above body temperature.

In one embodiment, the first antibiotic composition is in the form of an immediate release composition and the second antibiotic composition is in the form of a sustained release composition. In such embodiments, the pharmaco-kinetic profile comprises a relatively steep sided peak, being associated with the release of the first antibiotic composition, following by a gentle upward slope.

Generally the first and second antibiotic compositions comprise the same antibiotic or combination of antibiotics. Typically, the first and second antibiotic composition comprises one or more of the antibiotic agents as described below.

Generally the antibiotic agent is of the group consisting of aminoglycosides, ansamycins, earbacephem, earbapenems, eephalosporins (including first, second, third, fourth and fifth generation cephalosporins), lincosaniides, macrolides, monobactams, nitrofurans, quinolones, penicillin, sulfonamides, polypeptides and tetracyclins. Alternatively or additionally the antibiotic agent may be effective against mycobacteria.

According to one embodiment, the antibiotic agent may be an amino glycoside such as Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin or Paromomycin.

According to one embodiment, the antibiotic agent may be a benzoquinone ansamycin antibiotic that http://en.wikipedia.org/wjkj/Ansamycin such as Geldanamycin and Herbimycin Alternatively the antibiotic agent may be a carbacephem such as Loracarbef.

According to a ftirther embodiment, the antibiotic agent is a carbapenem such as Ertapenem, Doripenem, Imipenem/Cilastatin or Meropenem.

Alternatively the antibiotic agent may be a cephalosporins (first generation) such as Cefadroxil, Cefazolin, Cefalexin, Cefalotin or Cefalothin, or alternatively a Cephalosporins (second generation) such as Cefaclor, Cefamandole, Cefoxitin, Cefjxozil or Cefuroxime.

Alternatively the antibiotic agent may be a Cephalosporins (third generation) such as Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefjodoxime, Ceflibuten, Ceftizoxime and Ceftriaxone or a Cephalosporins (fourth generation) such as Cefepime and Ceftobiprole.

The antibiotic agent may be a lincosamides such as Clindamycin and Azithromycin, or a macrolide such as Azithromycin, Clarithromycin, Dirithromycin, Erytbromyein, Roxithromycin, Troleandomyein, Telithromyein and Spectinomycin.

Alternatively the antibiotic agent may be a monobactams such as Aztreonam, or a nitrofuiran such as Furazolidone or Nitrofurantoin.

The antibiotic agent may be a penicillin such as Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Meziocillin, Nafeillin, Oxacillin, Penicillin G or V, Piperacillin, Temoeillin and Ticarcillin.

The antibiotic agent may be a sulfonamide such as Mafenidc, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim, and Trimethoprim-Sulfamethoxazole (Co-trimoxazole) (TMP-SMX).

The antibiotic agent may be a quinolone such as Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxaein, Moxifloxacin, Nalidixie acid, Norfioxacin, Ofloxacin, Trovafloxaein, Grepafloxaein, Sparfioxacin and Temafloxacin.

The antibiotic may be a Lantibiotic, being a class of peptide antibiotic, that contain the characteristic polycyelic thioether amino acids lanthionine or methytlanthionine, as well as the unsaturated amino acids dehydroaanine and 2-aminoisobutyric acid.

According to one embodiment, the antibiotic agent may be a polypeptide such as Bacitracin, Colistin and Polymyxin B. Alternatively, the antibiotic agent may be a tetracycline such as Demeelocycline, Doxycycline, Minocycline and Oxytetracycline Alternatively or additionally the antibiotic agent may be effective against myeobaeteria.

According to one embodiment, the antibiotic agent may be Clofazimine, Lamprene, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine or Streptomycin.

The antibiotic in the first and/or second antibiotic composition may be selected from the group consisting of beta-lactam antibiotics, azithromycin, clarithromyein, erythromyein (or other macrolide antibiotics), ciprofloxacin, flucloxacillin, ofloxacin, norfioxacin, enoxacin (or other fluoroquinolones), rifaximin, and metronidazole.

Generally the first and/or second antibiotic composition comprises one or more of vancomycin, teicoplanin, ramoplanin, difimicin, kanarnycin, neomycin (or other aminoglycosides) and colistin.

Advantageously, at least one of the first and second antibiotic compositions comprise one or more of Clindamycin, Streptomycin, Gentamicin, Metronidazole, Linezolid, Ramoplanin, * Fidaxomicin and Vancomycin: S Preferably the first and second antibiotic compositions comprise vancomycin, advantageously as the sole antibiotic component.

* Generally, the first and second antibiotic compositions comprise antibiotic(s) effective against G.l. tract infections, in particular infections of the large intestine, especially the colon.

Typical G.I. tract infections to be treated include gastroenteritis, antibiotic associated diarrhoea, pseudomembranous colitis (PMC), haemolytic-uremic syndrome, inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhoea, ulcerative colitis andlor colonic inflammation.

Advantageously, the first and second antibiotic compositions comprise antibiotic(s) effective against gram-negative or gram-positive bacteria such as Bscherichia coli and Clostridium, in particular Clostridium difficile.

According to one embodiment, the dosage units can comprise an antibiotic in an amount from about 50 mg to about 800 mg, about 150 mg to 500 mg, or about 175 mg to about 400 mg.

The active antibiotic agents mentioned in this specification can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the agents.

The first and second antibiotic compositions generally comprise one or more pharmaceutically acceptable excipients, diluents or carriers such as, for example, solvents, surfactants, binders, preservatives. Conventional additives such as water, saline, lactose; mannitol, corn starch or potato starch may be used. Binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatines may be useful as well as disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose and lubricants such as talc or magnesium stearate. The compositions may comprise one or more carriers such as saline, dextrose or water.

The pharmaceutically acceptable excipients, diluents or carriers of the first and second antibiotic compositions may vary.

As the environment of the colon is drier than the environment of the small intestine, the second antibiotic composition may be in a form more readily dispersible than the first antibiotic composition following disintegration of the inner and outer walls respectively. In particular, the second antibiotic composition may comprise a greater proportion of solvent.

Method of Medical Treatment According to a second aspect of the present invention there is provided a method of treating or preventing an infection of the gastrointestinal tract (01 tract) comprising the steps of administering one or more pharmaceutical dosage units as described above to a patient in need thereof Thus the product of the invention may be useful in the prevention of, delay of progression of, or treatment of a gastrointestinal tract infection, including an infection associated with or caused by indwelling of medical devices such as colostomy bags.

The 0.1. tract infection may comprise any bacterial infection, including an infection caused by more than one microorganism, for example bacteria and any one of fungi, yeast, viruses and protozoa.

The 0.1. tract infection may be associated with gram-negative or gram-positive bacteria such as Escherichia coli and Clostridium, in particular Clostridium difficile.

In general, the 0.1. tract infection is an infection of the large intestine, in particular the colon.

In some embodiments the infection is an infection of the large intestine and the small intestine, in particular an infection of the colon and the small intestine. Typically the infection does not affect the stomach of the patient.

Typical 0.1. tract infections to be treated include gastroenteritis, diarrhoea (including antibiotic associated diarrhoea), pseudo membranous colitis (PMC), haemolytic-uremie syndrome inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhoea, ulcerative colitis and/or colonic inflammation.

The amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, as well as the pharmaco-kinetic properties of the individual treated, and thus may vary widely. The dosage will generally be lower if the compounds are administered for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.

One of skill in the art will appreciate that the dosage regime or therapeutically effective amount of the inhibitor to be administrated may need to be optimized for each individual. The pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably from about 1 to 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day, typically one or two dosages per day.

Generally the first antibiotic composition provides a dose of 100 to 300 mg, twice daily, preferably 125 to 250 twice daily. Typically the outer housing comprises 100 to 150 mg antibiotic, preferably 125 mg antibiotic and the inner housing comprises 50 to 100 mg antibiotic, preferably 80 mg antibiotic. In such embodiments, the dosage units are generally administered twice daily.

Known antibiotic dosage regimes for the treatment of G.I. tract infections include more frequent administrations, or higher dosages of antibiotic. Known antibiotic treatment regimes generally involve the administration of 125 to 250 mg antibiotics four times daily.

Generally treatment includes administration of the pharmaceutical dosage units of the present invention for 10 to 20 days, typically 10 to 14 days.

The patient is generally a human or animal, in particular a mammal. According to one embodiment the patient is a human, cat, dog, horse, pig or camel. Preferably the patient is a human.

In general the pharmaceutical dosage form of the present invention is administered orally.

According to a further aspect of the present invention there is provided the dosage unit as described above for use in therapy.

According to a further aspect of the present invention there is provided the dosage unit as described above for use in the treatment or prevention of a G.I. tract infection.

Method of Manufacture According to a ftirther aspect of the present invention, there is provided a method of preparing a dosage unit as described above comprising the steps of: forming an inner housing, housing a second antibiotic composition, coating the inner housing with a colonic coating, in particular, a colonic coating susceptible to attack by colonic bacteria and/or has a pH threshold of about pH 5 or above, forming an outer housing, placing the inner housing within the outer housing, providing a first antibiotic composition within the housing, closing the outer housing, coating the outer housing with an enteric coating, in particular, an enteric coating susceptible to attack by bacteria of the small intestine and/or has a pH threshold of about pH 6 or above.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other moieties, additives, components, integers or steps.

Generally the term "approximately" is intended to encompass a range of 10% or less of any numerical value to which it is applied.

Further aspects and embodiments of the invention are set forth in the following description and claims.

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should instead be defined only in accordance with the following claims and their equivalents. All documents, including webpages, cited herein are incorporated in their entirety by reference.

The present invention will now be described by way of example only with reference to the accompanying figures in which: Table 1 details micro-organisms of the GI tract and their location; Table 2 details the degradation of Vancomycin under different pH conditions; Table 3 compares the release profiles of different Vancomycin compositions, including immediate release and sustained release of Vancomycin compositions, in a phosphate buffer at apH of 6.8.

Example 1

A vancomyein composition was prepared and its impurity level was calculated. The composition was subjected to contact with acid having a pH of 1.0 to 2.5 to simulate the conditions of the stomach. The composition was then subjected to contact with a pH of 6.8 for a further 4 hours to simulate gastro intestinal transit. The results summarised in Table 2 evidence that the rate of degradation of Vancomycin is far faster under gastric conditions than intestinal conditions.

Binomial name. LoeationLt AcJ2romoLlacier spp -1.arge intestine. small intestine leon Large intestine 4 ctneiobacier eucotwe us Large intestine Aeromonas spp Large intestine, small intestine (Ileon) cgJjggnesfqeca/R Large intestine, small intestine (ileon) figjy.cpp Large intestine /$Jfiththacwriwn spp Large intestine, feces Thyyr,vihczinjthrosoivei&s Large intestine çuinpviobac 1ev spp Large intestine Usrna.an Si),) Large intestine, small intestine (Ileon) civtridn4n*!d!qIllE Large intestine (Ioswithum_sorde/Ih Stomach. small intestine, large intestine, rectus. anus channel Havobcwternan spp Large intestine, small intestine (lleon %k'cobacterw spp I 2rge intestine, small intestine Uleon) L:iy.'I?4?.:»=.?ll.c.cpp Large intestine, small intestine (Ileon) P2LQ.cocc4Li.cpp Mouth, large intestine hiQpLomOacLenl.un.cpp Large intestine Pseudomonas aerugmosa I arge intestine, small intestine leon) Large intestine &m inococcus spp Cecum. large intestine rcjna.cpp Large intestine 5/apin.'iocccczss aureus Mouth, large intestine, small intestine (Ileon) Mouth, large intestine, small intestine (Ileon) i*L'iI/one/Ia.spp Mouth, amygdala, large Intestine F7hria spp Large intestine, Small intestine (Ileon) Yes stnw twierocoiiuica Large intestine

Table I

Condition Total Impurities Total Degradation Input Material 3.58% - 2hrAcid 8.13% 4.55% 2hr Acid + 2hr pH6.8 8.97% 5.39% 2hr Acid + 4hr pH6.8 10.39% 6.81%

Table 2

Vancomycin (125mg) Number + Absorbance Percentage _______ Excipient (375mg) TIME/Minutes ________ -TIME/Minutes ____ __________ 10 20 60_ 10 20 60 I Peg 6000 0.08 0.205 0.639 14 35 110 _______ ___________________ 0.335 0.583 0.653 58 100 112 2 Gelucire 44/14 0.06 0.12 0.327 -10 21 56 ________ ___________________ 0.066 0.125 0.289 -11 21 50 3 Poloxamer 188 0.06 0.232 0.624 -10 40 107 _______ ___________________ 0.031 0.146 0.611 5 25 105 4 Gelucire 50/02 0.017 0.024 0.032 3 4 5 _______ __________________ 0.022 0.031 0.042 4 5 7 Gelucire 50/13 0.011 0.021 0.062 2 4 11 _______ __________________ 0.019 0.035 0.093 -3 6 16 6 Miglyol 0.032 0.063 0.173 5 11 30 _______ __________________ 0.026 0.054 0.161 -4 9 28 7 Poloxamer 407 0.014 0.039 0.185 2 7 32 8 PEG 400 0.16 0.573 0.643 27 98 110 _______ ___________________ 0.328 0.596 0.67 -56 102 115 9 Sterotex 0.014 0.02 0.024 2 3 4 _______ __________________ 0.011 0.018 0.025 2 3 4 Hydrokote 0.012 0.018 0.026 -2 3 4 _______ __________________ 0.013 0.021 0.034 2 4 6 Vancomycin 13.89mg in reference lOOmI _______ 0.582 Standard 0.1389 mg/mI _______

Table 3

Claims

Claims 1. A pharmaceutical dosage unit comprising an outer housing defined by an outer wall, one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall is adapted to disintegrate or partially disintegrate within the small intestine of a mammal, releasing the first antibiotic compositions and wherein said inner wall(s) are adapted to disintegrate or partially disintegrate within the large intestine of a mammal, in particular the colon of the mammal, releasing the second antibiotic composition.
2. A dosage unit of claim 1 wherein the outer wall comprises an enteric coating and the inner wall(s) comprise a colonic coating.
3. A dosage unit of either one of claims 1 and 2 wherein the outer wall is adapted to disintegrate or partially disintegrate at a pH of 5 to 8, preferably 5 to 7.5, and/or comprises a time-delayed erodible coating.
4. A dosage unit of any preceding claim wherein the inner wall is adapted to disintegrate or partially disintegrate at a pH of 6 to 7.5, preferably 6.4 to 7.5, and/or upon contact with colonic micro-organisms.
5. A dosage unit of any preceding claim wherein the first and second antibiotic compositions comprise the same antibiotic or mixture of antibiotics.
6. A dosage unit as claimed in any preceding claim wherein the first and second antibiotic compositions are in the form of a fluid have a melting point of less than 40 degrees Celsius.
7. A dosage unit as claimed in any preceding claim wherein the first and second antibiotic compositions are available for immediate release upon disintegration or partial disintegration of the outer and inner walls respectively.
8. A dosage unit as claimed in any one of claims 1 to 6 wherein the first and second antibiotic compositions are available for sustained release upon disintegration or partial disintegration of the outer and inner walls respectively.
9. A dosage unit as claimed in any one of claims 1 to 6 wherein one of the first and second antibiotic compositions is available for sustained release upon disintegration or partial disintegration of the outer and inner walls respectively, and one of the first and second antibiotic compositions is available for immediate release upon disintegration or partial disintegration of the outer and inner walls respectively.
10. A dosage unit as claimed in any preceding claim wherein the weight ratio of first antibiotic composition: second antibiotic composition is 10:1 to 1:10.
11. A dosage unit as claimed in any preceding claim wherein the outer housing comprises to 150 mg Vancomycin composition and the inner housing comprises 50 to 100 mg vancomycin composition.
12. A pharmaceutical dosage unit comprising an outer capsule housing a first antibiotic composition, one or more inner capsules within the outer capsule, said inner capsules housing a second antibiotic composition, wherein said outer capsule includes an enteric coating allowing disintegration or partial disintegration of the outer capsule in the small intestine of a mammal and said inner capsule(s) include a colonic coating allowing disintegration or partial disintegration of the inner capsule(s) in the colon of the mammal.
13. A method of treating or preventing an infection of the gastrointestinal tract (GI tract) comprising the steps of administering one or more pharmaceutical dosage units as claimed in any preceding claim to a patient in need thereof 14. A method as claimed in claim 13, wherein the G.I. tract infection is an infection of the colon.15. A method as claimed in either one of claims 13 and 14, wherein the G.I. tract infection may be associated with Escherichia coli or Clostridium micro-organisms, in particular Clostridium difficile micro-organism.16. A method as claimed in any one of claims 13 to 15 wherein the G.1. tract infection is selected from the group consisting of gastroenteritis, diarrhoea (including antibiotic associated diarrhoea), pseudo membranous colitis (PMC), haemolytic-uremic syndrome iaflammatory bowel disease, irritable bowel syndrome, constipation, diarrhoea, ulcerative colitis and colonic inflammation.17. A dosage unit as claimed in any one of claims I to 12 for use in therapy.18. A dosage unit as claimed in any one of claims 1 to 12 for use in the treatment or prevention of a G.1. tract infection.19. The use of a dosage unit as claimed in any one of claims 1 to 12 for use in the manufacture of a medicament for the treatment of a G.I. tract infection.Claims 1. A pharmaceutical dosage unit comprising an outer housing defined by an outer wall, one or more inner housings within the outer housing defined by one or more inner walls, a first antibiotic composition housed within the outer housing, a second antibiotic composition housed within the or one of the inner housing(s) wherein said outer wall is adapted to disintegrate or partially disintegrate within the small intestine of a mammal, releasing the first antibiotic compositions and wherein said inner wall(s) are adapted to disintegrate or partially disintegrate within the large intestine of a mammal, in particular the colon of the mammal, releasing the second antibiotic composition.2. A dosage unit of claim 1 wherein the outer wall comprises an enteric coating and the inner wall(s) comprise a colonic coating.3. A dosage unit of either one of claims 1 and 2 wherein the outer wall is adapted to V" disintegrate or partially disintegrate at a pH of 5 to 8, preferably S to 7.5, and/or LI') comprises a time-delayed erodible coating.1'"' 4. A dosage unit of any preceding claim wherein the inner wall is adapted to disintegrate or partially disintegrate at a pH of 6 to 7.5, preferably 6.4 to 7.5, and/or upon contact with colonic micro-organisms.S. A dosage unit of any preceding claim wherein the first and second antibiotic compositions comprise the same antibiotic or mixture of antibiotics.6. A dosage unit as claimed in any preceding claim wherein the first and second antibiotic compositions are in the form of a fluid have a melting point of less than 40 degrees Celsius.7. A dosage unit as claimed in any preceding claim wherein the first and second antibiotic compositions are available for immediate release upon disintegration or partial disintegration of the outer and inner walls respectively.8. A dosage unit as claimed in any one of claims 1 to 6 wherein the first and second antibiotic compositions are available for sustained release upon disintegration or partial disintegration of the outer and inner walls respectively.9. A dosage unit as claimed in any one of claims 1 to 6 wherein one of the first and second antibiotic compositions is available for sustained release upon disintegration or partial disintegration of the outer and inner walls respectively, and one of the first and second antibiotic compositions is available for immediate release upon disintegration or partial disintegration of the outer and inner walls respectively.10. A dosage unit as claimed in any preceding claim wherein the weight ratio of first antibiotic composition: second antibiotic composition is 10:1 to 1:10.11. A dosage unit as claimed in any preceding claim wherein the outer housing comprises to 150 mg Vancomycin composition and the inner housing comprises 50 to 100 mg vancomycin composition. ro 12. A pharmaceutical dosage unit comprising an outer capsule housing a first antibiotic composition, one or more inner capsules within the outer capsule, said inner capsules 0 housing a second antibiotic composition, wherein said outer capsule includes an enteric coating allowing disintegration or partial disintegration of the outer capsule in the small intestine of a mammal and said inner capsule(s) include a colonic coating allowing disintegration or partial disintegration of the inner capsule(s) in the colon of the mammal.13. A dosage unit as claimed in any one of claims ito 12 for use in therapy.
14. A dosage unit as claimed in any one of claims 1 to 12 for use in the treatment or prevention of a G.I. tract infection.
15. A dosage unit as claimed in claim 14 wherein the G.I. tract infection is an infection of the colon.
16. A dosage unit as claimed in either one of claims 14 and 15 wherein the G.I. tract infection may be associated with Escherichia coli or Clostridium micro-organisms, in particular Clostridium difficile micro-organism.
17. A dosage unit as claimed in any one of claims 14 to 16 wherein the G.I. tract infection is selected from the group consisting of gastrocnteritis, diarrhoea (including antibiotic associated diarrhoea), pseudo membranous colitis (PMC), haemolytic-uremic syndrome inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhoea, ulcerative colitis and colonic inflammation. c\J rLU r