KR20150136081A - Pharmaceutical compositions for rectal administration - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for rectal administration comprising pidacomycin and a method for preparing the pharmaceutical composition for rectal administration. The present invention also relates to an aerosol canister comprising a foam-formable pharmaceutical composition comprising a pidacomycin for rectal administration and a method for the treatment or alleviation of an infection such as diarrhea with Clostridium difficile will be.

Description

[0001] PHARMACEUTICAL COMPOSITIONS FOR RECTAL ADMINISTRATION [0002]

The present invention relates to a pharmaceutical composition for rectal administration comprising pidacomycin, a method for preparing said pharmaceutical composition for rectal administration, and its use in the treatment of infection by Clostridium difficile .

Clostridium difficile is a gram-positive toxin-producing bacterium. This is due to treatment with broad-spectrum antibiotics that invade the intestinal tract of a patient whose normal intestinal flora fails to function. Bacterial toxins cause varying degrees of damage to the large intestine (ie, colon) epithelium and also cause a variety of ailments, from mild diarrhea to severe colitis. Because antibiotic therapy causes the onset of Clostridium difficile disease, the associated syndrome is referred to as antibiotic-associated diarrhea and colitis. This is an increasing problem with the emergence of hyper-virulent bacterial species and the elderly most affected by them. According to the Centers for Disease Control, this causes about 15,000 deaths in the United States each year. Furthermore, Clostridium difficile is a spore forming bacteria that enters the vegetative stage if it does not die but maintains spore formation when attacked. In the absence of intestinal gut flora, the spore production is accelerated and the chances of re-emergence increase.

A variety of therapies have been developed to treat or specifically attack Clostridium difficile , for example, US Pat. No. 6,969,952 discloses a method of prophylactic and / or therapeutic treatment of Clostridium difficile infection And a passive immunization method comprising administering a subcutaneous administration of a Clostridium difficile toxin-neutralizing polyclonal immunoglobulin, a Clostridium difficile modified toxoid, or a combination thereof, .

US20130004561 provides an antibody composition comprising an ovine antibody for use in the prevention or treatment of Clostridium difficile infection wherein said antibody binds to a Clostridium difficile toxin And the prevention or treatment is by oral transport of the antibody composition.

US20130022575 discloses one or more systems for treating diseases including Clostridium difficile and Crohn's disease by introducing a mixture of pure cultures of viable bacteria into the gastrointestinal tract and ≪ / RTI >

Oral administration is not always possible or desirable, although administration via the oral route is the most commonly pursued goal of new and new type research and development. In addition, some patients, especially children, elderly patients, and patients with dysphagia, are often difficult to treat with oral tablets or capsules. In addition, the treatment of certain diseases, particularly those associated with colon or anal rectal tissue, is best accomplished by direct administration near the affected site. Although oral administration can be used for drugs targeting some of these disease tissues, exposure of the entire body compartment to the administered drug can lead to side effects. Several animal test data from pidacomaxin demonstrate that oral administration of pidacomycin reaches the site of action and produces the desired effect, producing dark red discoloration of the lungs and lymph nodes and distribution to other essential organs such as the lungs .

However, rectal drug administration may be possible for both local and systemic drug delivery. Rectal drug administration has not only been used for systemic delivery of drugs in place of oral administration, but has also been effectively used for the treatment of topical diseases of the anal rectal region. Some of the advantages of this targeted transport, including but not limited to the long residence time as well as the ability to treat large surface areas and avoid first-pass metabolism, Thus making the administration route more promising.

Pidacomacin, formerly referred to as OPT-80, is the first experimental drug in a new series of narrow spectrum macroscopic antibiotic drugs. While many antibiotics are aimed at halting the growth of infectious bacteria, pidacomycin induces the death of Clostridium difficile by inhibiting bacterial enzymes, referred to as RNA polymerases. Pidacomaxin has a narrow-spectrum activity believed to selectively kill Clostridium difficile and has a minimal disruption to normal intestinal bacteria and harmful to healthy flora .

Pidak Soma who is oxa cyclooctadiene big -3,5,9,13,15- penta sold as ^® Dificid en-2-one, 3 - [[[6-deoxy -4-O- (3,5- 2-ethyl-4,6-dihydroxybenzoyl) -2-O-methyl-bD-mannopyranosyl] oxy] methyl] 18 - [(1R) -1-hydroxyethyl] -9, 8-dihydroxy- It is chemically known as 13,15-trimethyl (3E, 5E, 8S, 9E, 1S, 12R, 13E, 15E, 18S) and has the following structure.

US 3978211 discloses pidacomycin and its preparation method which are characterized by physical and chemical properties.

US7378508 discloses crystalline polymorphic forms and compositions of pidacomycin for use in the treatment of diarrhea by Clostridium difficile .

US 7863249 discloses a pharmaceutical composition comprising a crystalline polymorphic form of a therapeutically effective amount of pidacomycin in the form of a film-coated tablet.

US 7906489 discloses a method for the treatment of diarrhea caused by Clostridium difficile gastrointestinal tract infection by administering to a patient in need thereof a therapeutically effective amount of Pidacomycin in a Clostridium difficile gastrointestinal tract infection Lt; RTI ID = 0.0 > diarrhea < / RTI >

Pidacomaxine has a high molecular weight (1,058 g / mol) and exhibits low aqueous solubility (10-20 g / mL at neutral pH), which contributes to overall low bioavailability (~ 1%) after oral administration.

In general, topical delivery of the active ingredient via the rectal route can be achieved using suppositories, enema, ointments, creams, or foams. Suppositories are the most common form of rectal administration. The suppository base is generally inherently fatty, but a water-soluble or water-miscible base may also be used. In order to achieve the desired bioavailability, the active ingredient must be in contact with the rectal or colon mucosa.

Rectal forms such as ointments and creams create an environment unfavorable to the wound's breathing. Furthermore, there may be the possibility of experiencing pain and irritation in the application of rectal ointments and creams to mucous membranes, especially in the rectum or colon where peeling, scarring or inflammation has occurred. Rectal foams are usually less preferred than other rectal administration forms. However, rectal preparations and foams exhibit better spreadability, so that the drug can reach distant parts of the intestinal tract.

Rectal enema and foam among the known rectal administration forms exhibit a better spreading effect, thus allowing them to reach the remote site. However, rectal enuresis can be uncomfortable to the patient because it can stimulate the bowel to be compulsorily forcibly and can cause a discomfort and discomfort to the patient in combination with the need for enema retention . Complications may include leakage, bloating, irritation, bleeding, swelling, or prolapse of the intestinal tissue. In addition, rectal enema is difficult for patients to self-administer.

These formulations require a specific balance between the foam-forming additives, although rectal foams provide a variety of advantages such as better spreading to surrounding tissue compared to other rectal dosage forms. Particularly when the administration takes place through a applicator nozzle having a small diameter, any slight variation in this form-forming additive can lead to unstable foam or no foam at all.

Rectal foams have been designed to transport fungicides, antifungal agents, anti-inflammatory agents, topical anesthetics, emollients, and protectants, although most rectal forms are known to contain corticosteroids. However, this prior art does not disclose a rectal foam formulation or composition specifically for the treatment of infection by Clostridium difficile .

Thus, there is a need to develop topical pharmaceutical compositions of pidacomycin suitable for rectal administration.

Object of the invention:

It is an object of the present invention to provide a pharmaceutical composition suitable for rectal administration in the form of a foam comprising pidacomycin.

Another object of the present invention is to provide a foam-formable pharmaceutical composition for rectal administration comprising pidacomycin.

It is another object of the present invention to provide a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin exhibiting even better spreadability.

It is another object of the present invention to provide a stable pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin.

Another object of the present invention is to provide a pharmaceutical composition for rectal administration in the form of a foam containing pidacomycin which remains effective even after intestinal evacuation by the patient.

It is a further object of the present invention to provide a process for the preparation of a pharmaceutical composition comprising pidacomycin suitable for rectal administration in the form of a foam.

It is another object of the present invention to provide an apparatus comprising a pharmaceutical composition comprising pidacomycin, which is capable of forming a foam.

It is yet another object of the present invention to provide a method of treating a patient suffering from Clostridium difficile infection by administering a pharmaceutical composition for rectal administration in the form of a foam containing pidacomycin to a patient in need of such treatment or maintenance of Clostridium difficile infection, And to provide a method of maintaining or alleviating the treatment of Clostridium difficile infection.

It is yet another object of the present invention to provide a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin for use in the treatment of diarrhea associated with Clostridium difficile .

Summary of the invention:

According to one aspect of the present invention there is provided a pharmaceutical composition in the form of a foam for rectal administration comprising pidacomycin and optionally one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a foam-formable pharmaceutical composition for rectal administration comprising pidacomycin and optionally one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a stable foam-formable pharmaceutical composition for rectal administration comprising pidacomycin.

According to another aspect of the present invention there is provided a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin, wherein the total daily dose of the pidacomycin is less than 400 mg.

According to another aspect of the present invention there is provided a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin for once or twice daily administration.

According to a further aspect of the present invention there is provided a method for preparing a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin, the method comprising heating the vehicle and optionally adding the emulsifying agent together with other pharmaceutically acceptable additives Adding to the vehicle, and then adding the pidacomycin to obtain a mixture; Optionally filling the vessel with the mixture and filling the vessel with a propellant.

According to another aspect of the present invention there is provided an aerosol canister for a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin, said canister comprising a housing containing said pharmaceutical composition under pressure; Means for measuring a metered dose of the composition from the canister for administration to a patient; An aerosol canister is provided, optionally including an applicator device for rectal administration.

According to a further aspect of the present invention there is provided a method of treating a patient suffering from a Clostridium difficile infection by administering a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin to a patient in need thereof, Methods of maintaining or alleviating the treatment of Clostridium difficile infection are provided.

According to another aspect of the present invention there is provided a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin for use in the treatment of infection by Clostridium difficile .

According to still another aspect of the present invention, there is provided a method for treating or alleviating anal diseases, comprising administering a pharmaceutical composition for rectal administration for administering pidacomycin in foam form to a subject in need of treatment or relief of anal disease / RTI >

DETAILED DESCRIPTION OF THE INVENTION [

Some medications require local or topical administration. Therefore, some medicines require administration by oral route or rectal route, and the latter is applied when it is intended to treat pathological conditions such as rectum.

Pidacomycin is an 18-membered macrocyclic (also known as OPA-80), also known as Tiacumicins (almost all of which are composed of R-Tiacumicin B) It is a microbial agent. Currently, pidak Soma who is commercially available as oral tablets (Diffie seed ^® (Dificid ^®) tablets, 200 mg / 1 twice a day) administered for 10 days. Pidacomaxin is minimally absorbed from the gastrointestinal tract after oral (PO) administration, which is due to the low permeability and solubility properties of the pidacomycin. In addition, oral administration of pidacomaiicin causes side effects such as hives, dyspnea, facial, lips, edema of the tongue or throat.

Thus, in order to solve the problem of permeability and solubility, it is necessary to search for the release of pidacomycin at the actual site of action through the rectal route.

It is also desirable to maintain a balance between the foam-forming additives in the formulation of such rectal foams, and also that some of the differences in these foam-forming additives may lead to unstable foams, It is believed that it can cause results.

Accordingly, the present invention provides a pharmaceutical composition suitable for rectal administration comprising pidacomycin and optionally one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition exhibits optimal stability.

The present invention also provides a pharmaceutical composition suitable for rectal administration in the form of a foam comprising pidacomycin.

The present invention also provides foam-formable pharmaceutical compositions for rectal administration comprising pidacomycin.

The term "fidaxomicin" or "active agent ", as used herein, is used in its broad sense to include not only" pidacomycin "itself, but also its pharmaceutically acceptable derivatives. Suitable derivatives include, but are not limited to, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable anhydride, a pharmaceutically acceptable enantiomer, a pharmaceutically acceptable ester , Pharmaceutically acceptable isomers, pharmaceutically acceptable crystalline polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes (e. ) And the like.

The amount of pidacomycin in the pharmaceutical composition for rectal administration according to the present invention is preferably in the range of about 0.01% to about 30% by weight based on the total weight of the pharmaceutical composition, more preferably about 0.5% To about 25% by weight.

The pharmaceutical composition according to the present invention refers to a foam-formable pharmaceutical composition for rectal administration comprising pidacomycin, and also refers to a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin.

The present invention provides a pharmaceutical composition for rectal administration comprising pidacomycin and at least one pharmaceutically acceptable excipient which is filled in a compressed gas container such that during operation of the valve the concentration of liquid and / And emits a fine dispersion.

The pharmaceutical composition for rectal administration of the present invention is easy to apply, less dense, has direct contact with the mucosa without latency time, has a longer retention time at the site of action, Have the advantage of being adapt to contours, less irritating, and exhibiting better spreadability compared to other rectal dosage forms. Another advantage is ease of use and patient compliance.

The pharmaceutical compositions for rectal administration of the present invention may be formulated with suitable additives to provide an emollient or drying effect on the rectal mucosa.

The pharmaceutical composition is suitable for rectal and / or colon administration and / or terminal ileum administration of a patient for the treatment or relief of infection by Clostridium difficile .

A preservative, a chelating agent, an emollient and / or a humectant, a permeation enhancer, a suspending agent, a preservative, a surfactant, an emulsifier, a mineral oil, a propellant, thickening agents, Suitable additives such as suspension-forming agents or mucoadhesives or combinations thereof may be used to formulate pharmaceutical compositions for rectal administration according to the present invention, but are not limited thereto.

The vehicle may comprise an aqueous, non-aqueous or hydro-alcoholic vehicle. Suitable aqueous vehicles compatible with rectal and colonic mucosa may include water-soluble alkanols selected from ethanol, propylene glycol, glycerol, polyethylene glycol, polypropylene glycol, polyalcohols such as propylene glycol glyceryl ester, and combinations thereof, But is not limited thereto. Non-aqueous vehicles that may be used in the pharmaceutical rectal foam compositions of the present invention include vegetable oils such as olive oil; But are not limited to, injectable organic esters such as ethyl oleate, and combinations thereof.

The vehicle may also contain a high hydrophilic organosiloxane such that the surfactant performs its foam forming action, but preferably is not inhibited by other ingredients present in the composition, such as the active ingredient and stabilizers thereof. , While certain adjuvants (such as foam consistency correctors) are preferably selected from those having strong hydrophilic and lipophilic properties.

The vehicle is preferably present in an amount ranging from about 10% to about 95% by weight relative to the total weight of the pharmaceutical composition, preferably in an amount of from about 10% to about 90% by weight relative to the total weight of the pharmaceutical composition, May be present in an amount of from about 20% to about 85% by weight, based on the total weight of the composition.

Suitable surfactants that may be used in the pharmaceutical compositions for rectal administration of the present invention include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants.

The anionic surfactants include ammonium lauryl sulfate, sodium lauryl sulfate, ammonium laureth sulfate, sodium laureth sulfate, alkyl glyceryl ether sulfonate, triethylamine lauryl sulfate, triethylamine laureth sulfate, triethanolamine lauryl Monoethanolamine lauryl sulfate, diethanolamine lauryl sulfate, diethanolamine laureth sulfate, lauric monoglyceride sodium sulfate, potassium lauryl sulfate, potassium lauryl sulfate, monoethanolamine lauryl sulfate, monoethanolamine lauryl sulfate, Lauryl sulfate, sodium lauroyl sarcosinate, sodium lauroyl sarcosinate, lauryl sarcosine, cocoyl sarcosine, ammonium cocoyl sulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate , Potassium cocoyl sulfate Monoethanolamine cocoyl sulfate, monoethanolamine lauryl sulfate, sodium tridecylbenzene sulfonate, sodium dodecylbenzene sulfonate, coconut alkyl triethanolamine lauryl sulfate, monoethanolamine cocoyl sulfate, monoethanolamine lauryl sulfate, sodium dodecylbenzene sulfonate, sodium dodecylbenzene sulfonate, Sodium and ammonium salts of ethylene glycol ether sulfate; Tallow alkyl triethylene glycol ether sulfate, tallow alkyl hexaoxyethylene sulfate, disodium N-octadecylsulfosuccinate, disodium lauryl sulfosuccinate, diammonium lauryl sulfosuccinate, tetra Sodium dodecyl ester of sodium sulfosuccinic acid, dioctyl ester of sodium sulfosuccinic acid, dioctyl ester of sodium sulfosuccinic acid, sodium dodecyl ester of sodium sulfosuccinic acid, sodium dodecyl ester of sodium sulfosuccinic acid, , And combinations thereof.

The nonionic surfactants include polyoxyethylene fatty acid esters, sorbitan esters, cetyl octanoate, cocamide DEA, cocamide MEA, cocamidopropyldimethylamine oxide, coconut fatty acid diethanolamide, coconut fatty acid monoethanolamide, diglyceryl But are not limited to, diisostearate, diglyceryl monoisostearate, diglyceryl monolaurate, diglyceryl monooleate, ethylene glycol distearate, ethylene glycol monostearate, ethoxylated castor oil, glyceryl monoisostearate , Glyceryl monolaurate, glyceryl monomyristate, glyceryl monooleate, glyceryl monostearate, glyceryl tricaprylate / caprate, glyceryl triisostearate, glyceryl trioleate, glycol dis Tealate, glycol monostearate, Lauric acid diethanolamide, lauric acid monoethanolamide, lauric / myristic acid diethanolamide, lauryldimethylamine oxide, lauryl / di Stearamide DEA, lauryl / myristyl dimethylamine oxide, methyl gluceth, methyl glucosuccinate, oleamide DEA, PEG-distearate, polyoxyethylene butyl ether, polyoxyethylene cetyl ether , Polyoxyethylene lauryl amine, polyoxyethylene lauryl ester, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene octyl ether, polyoxyethylene octyl phenyl ether, polyoxyethylene oleyl amine, poly Oxyethylene oleyl cetyl ether, polyoxyethylene oleyl ester, polyoxyethylene oleyl ether, poly Polyoxyethylene stearyl ether, polyoxyethylene talloamine, polyoxyethylene tridecyl ether, propylene glycol monostearate, sorbitan monolaurate, sorbitan monooleate, polyoxyethylene stearyl ether, Tartrate diethanolamide, stearic acid monoethanolamide, lauryl-4-ene, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearamide DEA, stearic acid diethanolamide, , And combinations thereof. ≪ / RTI >

The zwitterionic surfactants include sodium N-dodecyl-alanine, sodium N-lauryl-iminodipropionate, myristole amphoacetate, lauryl betaine, lauryl sulfobetaine, sodium 3- Aminopropionate, sodium 3-dodecylaminopropane sulfonate, sodium lauroamphoacetate, coco dimethyl carboxymethyl betaine, cocoamidopropyl betaine, coco betaine, laurylamidopropyl betaine, oleyl betaine , Lauryldimethylcarboxymethylbetaine, lauryldimethylcarboxyethylbetaine, cetyldimethylcarboxymethylbetaine, laurylbis- (2-hydroxyethyl) carboxymethylbetaine, stearylbis- (2-hydroxy (2-hydroxypropyl) alpha-carboxyethyl betaine, oleamidopropyl betaine, coco dimethyl betaine, carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, But are not limited to, propyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis- (2-hydroxyethyl) sulfopropyl betaine, and combinations thereof. It is not.

Cationic surfactants include, but are not limited to, behenyl trimethyl ammonium chloride, bis (acyloxyethyl) hydroxyethyl methyl ammonium methosulfate, settimulonium bromide, settimorium chloride, Ammonium chloride, ditallowedimonium chloride, guar hydroxypropyltrimonium chloride, laurethalkonium chloride, lauryldimethylamine oxide, lauryldimethylbenzylammonium chloride, laurylpolyoxyethylenedimethylamine oxide, lauryltrimethylammonium chloride , Rutremumium chloride, methyl-1-oleylamidoethyl-2-oleylimidazolinium methylsulfate, picoline benzylammonium chloride, polyquatemium, stearalkonium chloride, stearyl Dimethylbenzyl But are not limited to, ammonium chloride, stearyltrimethylammonium chloride, trimethylglycine, and combinations thereof.

The surfactant may be present in an amount of about 0.1% to about 15% by weight, more preferably about 0.1% to about 12% by weight, based on the total weight of the pharmaceutical composition, of the total weight of the pharmaceutical composition.

Suitable thickening or viscosity modifying agents that can be used in the pharmaceutical compositions for rectal administration include, but are not limited to, carboxymethylcellulose, polyoxyethylene-polyoxypropylene copolymer, xanthan gum, agar, guar gum, hydroxy Ethylcellulose, hydroxypropylcellulose, methylcellulose, and combinations thereof, but is not limited thereto.

The thickening agent may be present in an amount from about 0.01% to about 3% by weight, based on the total weight of the pharmaceutical composition for rectal administration.

It will be appreciated by those skilled in the art that the surfactant chosen may provide an emulsifying action or provide a foam-stabilizing action. The surfactant (s) are preferably selected to be compatible with the rectal and colonic mucosa, preferably in amounts that achieve the desired pharmaceutical effect but do not cause irritation problems.

Propellants may be used in the pharmaceutical compositions for rectal administration to achieve a foam-forming effect. The propellant may be selected according to known principles for preparing a foam-formable composition in the form of an aerosol which is filled into a pressurized container and is suitable for rectal application. Such propellants include low molecular weight hydrocarbons such as isobutane, n-butane, propane, CFC, hydrocarbons; Chlorofluorocarbons (CFCs); Hydrochlorofluorocarbons (HCFCs); Hydrofluoroalkanes (HFAs) such as HFA 134a and HFA 227; ≪ / RTI > and combinations thereof. Preferably, the propellant comprises a mixture of n-butane, isobutane, and propane.

Propulsion characteristics may vary depending on the type and amount of propellant used and thus the foam may reach the farther site of the large intestine.

The propellant may be present in the composition in an amount from about 0.05% to about 20% by weight, preferably from about 0.5% to about 20% by weight, and most preferably from about 1% to about 10% % ≪ / RTI > by weight.

Additionally, liquefied nitrogen may be present as a pressurizer to obtain the desired number of doses.

In a preferred embodiment, the pharmaceutical composition for rectal administration comprises pidacomycin, at least one propellant, at least one vehicle, at least one emulsifier and / or a surfactant and optionally other pharmaceutically acceptable excipients do.

In addition, the pharmaceutical compositions according to the present invention for rectal administration can be formulated as stable non-aqueous (anhydrous) foams, stable aqueous foams, instantaneous or quick breaking non-aqueous foams, or instantaneous or rapid- have.

In addition, the pharmaceutical composition according to the present invention for rectal administration may comprise at least one additional active ingredient suitable for rectal administration.

Additional active ingredients may be selected from one or more of an anti-inflammatory agent, a steroid (e. G., A corticosteroid), an additional antibiotic, an antifungal agent, an analgesic or an anti-tumor agent, an antiviral agent, It is not.

Examples of suitable antibiotics are: dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradine, erythromycin erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, but are not limited to, cyclicillin, picloxacillin, hetacillin, methicillin, nafcillin, penicillin, polymyxin, tetracycline, amphotericin Amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin (see, for example, lucensomycin, mepartricin, natamycin, But are not limited to, nystatin, pecilocin, perimycin, azaserine, griseofulvin, oligomycins, neomycin undecylenate, but are not limited to, pyrroinitrin, siccanin, tubercidin, viridin, picloxacillin, hetacillin, methicillin, nafcillin, But are not limited to, penicillin, polymyxin, or tetracycline, and combinations thereof.

Examples of suitable antifungal agents include but are not limited to allyl amines such as butenafine, naftifine, bifonazole, butoconazole, chlordantoin, chlormidazole, The use of cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, thioconazole, such as imidazole, fluconazole, itraconazole, saperconazole, terconazole, such as tioconazole, and triazol, such as acrisorcin, amorolfine, Biphenamine, bromosalicylclo < RTI ID = 0.0 > But are not limited to, bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate, But are not limited to, diamantazole dihydrochloride, exalamide, flucytosine, halethazole, hexetidine, Ioflucarban, nifuratel, But are not limited to, potassium iodide, propionates, propionic acid, pyrithione, salicylanilide, sulbentine, tenonitrozole, triacetin triacetin, ujothion, other antifungal agents such as undecylenic acid, and combinations thereof.

Antifungal agents also include, for example, amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin, But are not limited to, such as hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin, azaserine, Griseofulvin, oligomycins, neomycin undecylenate, pyrroinitrin, siccanin, tubercidin, viridin, and the like. Butenafine, allylamines such as naftifine, bifonazole, butoconazole, chlordantoin, chlormidazole, clavulanic acid, Clonazole, clotrimazole, econazole, enilconazole, , Fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole, Such as imidazole, fluconazole, itraconazole, saperconazole, terpenes such as oxiconazole nitrate, sertaconazole, sulconazole, and tioconazole, But are not limited to, triazole such as terconazole, acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide, But are not limited to, calcium propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazole dihydrochloride, exalamide, , It has been found that it can be used in combination with other drugs such as flucytosine, halethazole, hexetidine, Ioflucarban, nifuratel, potassium iodide, propionates, propionic acid, pyrithione, salicylanilide, sulbentine, tenonitrozole, triacetin, ujothion, or undecylenic acid. And combinations thereof.

Other therapeutic agents may include steroids or non-steroidal anti-inflammatory agents. Useful non-steroidal anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, Flophene, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, and the like, But are not limited to, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, ), Indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, penty- Fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flu, Flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, intercostal, Isoxicam; Aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, sulfasalazine, ), And salicylic acid derivatives including olsalazin; Para-aminophenol derivatives including acetaminophen and phenacetin; Indole and indene acetic acid including indomethacin, sulindac, and etodolac; Heteroaryl acetic acids including tolmetin, diclofenac, and ketorolac; Anthranilic acids (phenamates) including mefenamic acid and meclofenamic acid; Enol acids including oxycarboxylic acid (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyphenthartazone); And alkanones, including nabumetone, and pharmaceutically acceptable salts thereof, and combinations thereof.

Examples of suitable corticosteroids include: hydrocortisone, i.e., 11-17-21-trihydroxypregn-4-ene-3 (11-17-21-trihydroxypregn- , 20-dione or Cortisol, Cortisol acetate, hydrocortisone phosphate, hydrocortisone 21-sodium succinate, hydrocortisone tebutate, Corticosterone acetate, cortisone, cortisone acetate, cortisone 21B-cyclopentanepropionate, cortisone phosphate, corticosterone acetate, corticosterone acetate, cortisone acetate, cortisone 21B-cyclopentanepropionate, cortisone phosphate, Triamcinolone hexacetonide, dexamethasone phosphate, desonide, betamethasone dipropionate, But are not limited to, betamethasone dipropionate, mometasone furoate, and combinations thereof.

Corticosteroids and topical anesthetics may be used in combination with pidacomycin in the pharmaceutical rectal foam formulations.

For inflammation, preferred therapeutic agents for use in combination therapy with the compositions of the present invention include naproxen sodium, flurbiprofen, diclofenac sodium, misoprostil, Valdecoxib, diclofenac potassium, celecoxib, sulindac, oxaprozin, salsalate, diflunisal, naproxen sodium, and the like. ), Piroxicam, indomethacin and indocin SR, etodolac, meloxicam, ibuprofen, naproxen, ketoprofen, but are not limited to, ketoprofen, nabumetone, tolmetin sodium, choline magnesium trisalicylate, and rofecoxib.

The antitumor agent may also be included in the pharmaceutical rectal foam composition of the present invention together with pidacomycin. Suitable antineoplastic agents include, but are not limited to: vincristine, vinblastine, vindesine, busulfan, chlorambucil, spiroplatin, cisplatin, But are not limited to, carboplatin, methotrexate, adriamycin, mitomycin, bleomycin, arabinosyl adenine, mercaptopurine, mitotane, Procarbazine, dactinomycin (antinomycin D), daunorubicin, doxorubicin hydrochloride, taxol, plicamycin, , Aminoglutethimide, estramustine, flutamide, leuprolide, megestrol acetate, tamoxifen, testolactone, and the like. , Trilos 2a, and 2b (interferon a-2a and 2b), asparaginase (L-asparaginase), etoposide, ), And combinations thereof.

The antiviral agent may also be included in the topical foam composition of the present invention together with the pydacomycin. Suitable antiviral agents include, but are not limited to: acyclovir, amantadine, azidothymidine, ribavirin or vidarabine. If the component of the target disease is painful, the other therapeutic agent may be an analgesic agent. Useful analgesic agents include, but are not limited to, phenacetin, butacetin, acetaminophen, nefopam, acetoamidoquinone, and combinations thereof.

Local anesthetics may be present in the pharmaceutical rectal foam formulations of the present invention. For example, the topical anesthetic may include, but is not limited to, dibucaine, lidocaine, pramoxine, benzocaine, tetracaine, and combinations thereof . Generally, the topical anesthetic may be present in an amount effective in the practice of treatment of infection by Clostridium difficile , i.e. diarrhea.

The pharmaceutical composition for rectal administration of the present invention may also contain the active ingredient in nanoscale form.

The term "nanosize ", as used herein, refers to particles of the active ingredient having an average particle size of about 2000 nm or less, preferably about 1000 nm or less.

The pharmaceutical composition for rectal administration according to the present invention is preferably packaged in a pressurized dispensing canister in the form of an aerosol, which is well known in the art, such as an aluminum canister. Each canister is sealed with a suitable foam dispensing valve. Any valve or nozzle / valve assembly that provides a means for discharging foam from the canister and that provides a foam suitable for use in the present invention may also be used. The pharmaceutical rectal foam exhibits excellent properties. An advantage associated with the pharmaceutical rectal foam composition according to the present invention is that better results can be obtained in combating the disease and lower doses of the active ingredient or lower daily dose result in similar results compared to prior art compositions It may be necessary to obtain. For example, increased spreadability of the foam with longer exposure times to the drug results in optimal local effects at the target site. It is also expected that the rectal foam of the present invention will not cause extra stimulation of the inflamed target mucosa. Because of these excellent properties of the foam, the present invention can provide a valuable alternative to previously known dosage forms used in the treatment of infections by Clostridium difficile .

The pharmaceutical compositions of the invention for rectal administration are provided in a suitable dispensing canister equipped with a suitable metering or non-metering valve, for example an aluminum aerosol canister. The canister is well known in the art. If desired, the canister may be provided with, or provided with, an applicator device for insertion into the rectum to ensure more efficient administration of the rectal foam.

The dispensing canister may be in the form of an aluminum can, coated to prevent corrosion, such as an epoxy-coated can. In application, the mixing of the components with the propellant can be ensured by shaking, or by using a mixing bead together. The can is arranged in the form of an " upside down "spray with a valve on the bottom, or the can is arranged in a dip tube (dip) so that the foam can be sprayed using the top valve while the can stands upright tube.

Additionally, the dispensing canister may include a metered pump dome, which may be fixed, preferably on top of the canister, to dispense the optimal amount of dose.

In use, the dosing valve of the can expands the propellant rapidly, which causes and enhances the foaming action of the surfactant, thus bringing the lyophilized liquid out in the form of a rectal foam.

The propellant expansion energy is mainly absorbed in forming the foam, thus enabling rectal application without risk.

According to the present invention, a rectal foam may be created at the moment of therapeutic application. Thus, in the field applicable to foam cans, known formulation and dispensing techniques used, for example, in cosmetics may be suitable for obtaining a rectal foam.

In addition, the main disadvantage of rectal foams is the low density, typically on the order of 0.1 g / l, which prevents the administration of higher amounts of the active ingredient. This low density necessitates the administration of large amounts of foam, which is problematic in view of the limited volume of the rectum (between about 50 ml and 400 ml).

The inventors of the present invention have optimized the ability to achieve the desired efficacy using a minimum volume of 0.5 to 10 g of rectal foam according to the present invention.

The present invention also relates to a method for preparing a pharmaceutical composition for rectal administration comprising a pydacomycin, said method comprising the steps of 1) heating the vehicle and adding an emulsifier to the heated vehicle, 2) adding a preservative and a chelating agent 3) adding the active ingredient pidacomycin under agitation to obtain a suspension; And optionally 4) filling the canister with the solution and filling it with propellant.

The vehicles, emulsifiers, preservatives, chelating agents and propellants defined hereinabove herein may be used in the process according to the invention.

The active ingredient is dissolved or suspended in a suitable liquid vehicle containing an emulsifying agent. The liquid containing the active ingredient and the emulsifier is placed in a spray can, sealed by a dispensing valve, and then pressurized by supplying an appropriate amount of propellant through the valve.

A pharmaceutical rectal foam composition comprising a pydacomaiicin is selected from the group consisting of emollients or humectants, pH adjusting agents, emulsifiers, foaming agents, fatty alcohols, preservatives, chelating agents, antioxidants It may further comprise one or more pharmaceutical excipients selected from, but not limited to, suspending agents, thickening agents, permeation enhancers, occlusive agents, colorants and fragrances or combinations thereof Will be understood by those skilled in the art.

Examples of suitable pH adjusting agents are sodium hydroxide, citric acid, hydrochloric acid, acetic acid, phosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicate, malic acid, But are not limited to, sodium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butanetetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, And combinations thereof, but are not limited thereto; Preferably, triethanolamine is used.

The pharmaceutical compositions for rectal administration according to the present invention may comprise suitable pH adjusting agents to adjust the pH in the range of about 4 to 8.

Examples of emulsifiers which can be used in the pharmaceutical compositions of the invention for rectal administration include polysorbate (Tween ^® 20, Tween ^® 40, Tween ^® 60, Tween ^® 80), nonylphenol polyethylene glycol ethers, (alkylphenol-hydroxy polyoxyethylene), poly (oxy-1, 2-ethanediyl), alpha- (4-nonylphenol) omega-hydroxy-ethoxy, nonylphenol polyethylene glycol ether mixture, phenoxy poly, such as Triton ^® and ethanol It includes a polymer thereof, poloxamer ^®, span ^®, tile lock sapol ^®, Brij, sodium dodecyl sulfate and the like, or combinations thereof of different grades. Preferably, the emulsifying agent used in the pharmaceutical compositions of the present invention for rectal administration is selected from the group consisting of cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cetomacrogols, and the like, or combinations thereof, as described in US National Formulary , USNF, and " Martindale ". The emulsifying wax may be incorporated into the pharmaceutical rectal composition of the present invention to fortify the foam.

The content of the emulsifier in the composition is preferably 0.5% by weight to 10% by weight based on the total weight of the pharmaceutical composition.

Examples of suitable skin conditioners and / or moisturizers that may be used in the pharmaceutical compositions of the present invention for rectal administration include polyhydric alcohols such as glycols and polysaccharides such as ethylene glycol, propylene glycol, butylene glycol , Diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, , Esters such as octyldodecanol, myristyl alcohol, myristyl lactate, urea, lanolin, lactic acid, isopropyl stearate, isopropyl myristate, isopropyl palmitate, light liquid paraffin, Cetearyl alcohol, lanolin derivatives, mineral oil, petrolatum, cetyl esters, Scotland, cholesterol, glycerol monostearate, lecithin, isopropyl laurate, etc., and a combination thereof, without being limited thereto.

Permeation enhancers may be incorporated into the pharmaceutical compositions of the present invention for rectal administration for delivery to the mucosal surface of the active ingredient. Most forms of the promoter are detergents including: sodium glycocholate, sodium taurocholate, polysorbate 80, sodium lauryl sulfate, lauric acid, and various alkyl glycosides or combinations thereof. Other examples of accelerators are: dextrins (cyclodextrin, dextran sulfate), fatty acids (phosphatidylcholine, lysophosphatidylcholine), heterocyclic compounds (azone), and small molecules (benzalkonium chloride, cetyltrimethylammonium bromide ), And combinations thereof.

Suitable mucoadhesives may be used in the pharmaceutical compositions of the present invention for rectal administration to enhance the local retention of the active ingredient delivered to the mucosa.

Mucoadhesive adhesion compounds are synthetic or natural polymers that can be attached primarily to wet mucosal surfaces. These include, but are not limited to, synthetic polymers such as monomeric alpha-cyanoacrylates, polyacrylic acid, hydroxypropylmethylcellulose, and polymethacrylate derivatives or combinations thereof. The adhesive-like polymers include epoxy resins and polyurethanes. Mucoadhesives present in nature include chitosan, hyaluronic acid and xanthan gum, and combinations thereof.

Suitable emulsifying agents include, but are not limited to, linear or branched chain fatty acids, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, propylene glycol stearate, glyceryl stearate, polyethylene glycol, fatty alcohols, polymeric ethylene oxide-propylene oxide block copolymers , And combinations thereof.

Suitable suspending agents include, but are not limited to, alginic acid, bentonite, carbomer, carboxymethylcellulose and salts thereof, colloidal oatmeal, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum , Xanthan gum, kaolin, magnesium aluminum silicate, maltitol, triglyceride, methylcellulose, polyoxyethylene fatty acid ester, polyvinylpyrrolidone, propylene glycol alginate, sodium alginate, sorbitan fatty acid ester, tragacanth, and combinations thereof But is not limited thereto.

Suitable antioxidants include but are not limited to butylated hydroxytoluene, alpha tocopherol, ascorbic acid, fumaric acid, malic acid, butylated hydroxyanisole, propyl gallate, sodium ascorbate, sodium metabisulfite, Ascorbyl phosphate, vitamin A, folic acid, flavones or flavonoids, histidine, glycine, tyrosine, tryptophan, carotenoids, carotenoids, alpha-carotene, beta-carotene, uric acid ), Their pharmaceutically acceptable salts, derivatives thereof, and combinations thereof. The antioxidant is preferably present in an amount from about 0.01% to about 10% by weight, based on the total weight of the pharmaceutical composition.

Suitable chelating agents include EDTA, disodium edetate, trans-1,2-diaminocyclohexane-N, N, N ', N'-tetraacetic acid monohydrate, N, N, N ', N'-tetraacetic acid, 1,3-diaminopropane-N, N, N', N'-tetra N, N'-bis (methylenephosphonic acid), N- (2-hydroxyethyl) ethylenediamine, ethylenediamine-N, N'-diacetic acid, (Methylenephosphonic acid), O, O'-bis (2-aminoethyl) ethyleneglycol-N, N ', N'-triacetic acid, ethylenediamine- N, N ', N'-tetraacetic acid, N, N'-bis (2-hydroxybenzyl) ethylenediamine- N, N ', N'-tetraacetic acid, nitrilotriacetic acid, iminodiacetic acid, 1,2-diaminopropane-N, Nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitrilotriphosphoric acid, ] Pentatriacontane hexahydrobromide, triethylenetetramine-N, N, N ', N' ', N' '', N '' '- hexaacetic acid, or combinations thereof no. The chelating agent is preferably present in an amount from about 0.01% to about 5% by weight relative to the total weight of the pharmaceutical composition.

Preservatives may be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include benzoic acid, sorbic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, But are not limited to, cetylpyridinium chloride, chloro butanol, phenol, phenylethyl alcohol, thimerosal, or combinations thereof. The preservative is preferably present in an amount from about 0.01% to about 2.0% by weight, based on the total weight of the pharmaceutical rectal foam composition.

The invention Clostridium difficile silane (Clostridium difficile) to a patient in need of treatment or maintenance of the relief of the associated infections due to administration of a pharmaceutical composition for rectal administration containing pidak Soma who, Clostridium difficile silane (Clostridium Difficile ) in the treatment or relief of infection.

The present invention also provides a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin for use in the treatment of Clostridium difficile- associated infection.

Preferably, the invention also relates to a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin for use in the treatment of Clostridium difficile- associated infection, wherein said infection is a pharmaceutical composition comprising diarrhea .

Preferably, the present invention also relates to a method of treating a patient suffering from Clostridium difficile- associated infection by administering a pharmaceutical composition for rectal administration in the form of a foam comprising pidacomycin to a patient in need thereof, , A method of maintaining or alleviating an infection by Clostridium difficile , wherein the infection comprises diarrhea.

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example

Example  One

Manufacturing method:

(1) Propylene glycol was heated to dissolve the emulsified wax.

(2) Sodium metabisulfite and disodium edetate were dispersed in the solution obtained in step (1).

(3) Pidacomycin was dispersed in the solution obtained in step (2) to form a uniform suspension.

(4) The suspension obtained in step (3) was filled into a vessel and filled with propellant.

It will be apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit of the invention. It is therefore to be understood that changes and variations of the concepts disclosed herein may be made by those skilled in the art, even if the invention is specifically disclosed by preferred and optional features, which modifications and variations are within the scope of the present invention Are considered to be included.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of " including ", " comprising ", or " having ", and variations thereof, are intended to encompass the items and equivalents listed, as well as additional items.

It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise do. Thus, for example, "propellant" includes not only a single propellant but also two or more different propellants; "Co-solvent" means a single co-solvent or a combination of two or more co-solvents.

Claims (29)

A pharmaceutical composition for rectal administration in the form of a foam comprising pydacomaiicin. A form-forming pharmaceutical composition for rectal administration comprising a pydacomycin. 3. The pharmaceutical composition according to claim 1 or 2, wherein the pydacomycin is in the form of a pharmaceutically acceptable derivative thereof. 4. The composition of claim 3 wherein the pharmaceutically acceptable derivative of pidacomycin is a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydride, enantiomer, crystalline polymorph or prodrug A pharmaceutical composition. 5. The composition of any one of claims 1 to 4 wherein the pidacomycin is present in an amount from about 0.01% to about 10% by weight, and optionally from about 0.5% to about 8% % ≪ / RTI > by weight of the composition. 6. The composition according to any one of claims 1 to 5, further comprising at least one additive selected from the group consisting of propellants, vehicles, skin softeners and / or moisturizers, pH adjusting agents, surfactants, emulsifiers, formulating agents, fatty alcohols, preservatives, chelating agents, Wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable additive selected from the group consisting of thickeners, lubricants, permeation enhancers, suspending agents, mucoadhesives, mineral oils or combinations thereof. 7. The pharmaceutical composition according to claim 6, wherein the vehicle comprises an aqueous, non-aqueous or hydro-alcoholic vehicle. The pharmaceutical composition according to claim 7, wherein the aqueous vehicle comprises a water-soluble alkanol, ethanol, polyalcohol, propylene glycol, glycerol, polyethylene glycol, polypropylene glycol, propylene glycol glyceryl ester or a combination thereof. 8. The pharmaceutical composition according to claim 7, wherein the non-aqueous vehicle comprises vegetable oil, olive oil, injectable organic ester, ethyl oleate or a combination thereof. 10. A composition according to any one of claims 6 to 9, wherein the vehicle is present in an amount from about 10% to 95% by weight, based on the total weight of the composition; Preferably in an amount of about 20% to 85% by weight, based on the total weight of the composition. 7. The pharmaceutical composition of claim 6, wherein the emulsifier is present in an amount of from about 0.5% to about 10% by weight relative to the total weight of the composition. 7. The method of claim 6, wherein the propellant is selected from the group consisting of isobutane, n-butane, propane, CFC, hydrocarbons, Chlorofluorocarbons (CFCs); Hydrochlorofluorocarbons (HCFCs); A hydrofluoroalkane (HFAs), HFA 134a and HFA 227 or a combination thereof. 13. The composition of claim 6 or 12, wherein the propellant is present in an amount from about 0.05% to 20% by weight, and optionally in an amount from about 1% to 10% by weight, based on the total weight of the composition ≪ / RTI > The pharmaceutical composition according to claim 6, wherein the surfactant comprises an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a combination thereof. 15. The composition of claim 6 or 14, wherein the surfactant is present in an amount from about 0.1% to about 10.0% by weight, based on the total weight of the composition; Optionally present in an amount of from about 0.1% to about 8% by weight relative to the total weight of the composition. 16. The pharmaceutical composition according to any one of claims 1 to 15, further comprising at least one additional active ingredient selected from at least one of an anti-inflammatory agent, a steroid, an antibiotic, an antifungal agent, an analgesic agent, an antineoplastic agent, an antiviral agent and an anesthetic agent ≪ / RTI > 17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pH of the rectal foam is in the range of about 4 to 8. 18. A method according to any one of claims 1 to 17, characterized in that the foam is in the form of a stable non-aqueous foam, a stable aqueous foam, a non-aqueous foam of instantaneous or rapid cracking or an instantaneous or quick- ≪ / RTI > Claims 1. A method of preparing a pharmaceutical composition for rectal administration in the form of a foam comprising a pseudosomaline, said method comprising heating the vehicle, optionally adding an emulsifier together with other pharmaceutically acceptable additives to the vehicle, Adding an acetic acid to obtain a mixture; Optionally filling the vessel with the mixture and filling the vessel with a propellant. 20. The method according to claim 19, wherein the vehicle is defined in claims 7 to 10. 20. The process according to claim 19, wherein the emulsifier is as defined in claim 11. 20. The method according to claim 19, wherein the propellant is as defined in claims 12 and 13. 18. An aerosol canister for the pharmaceutical composition as defined in any one of claims 1 to 18, comprising: a housing containing said pharmaceutical composition under pressure; Means for measuring a metered dose of the composition from the canister for administration to a patient; Optionally an applicator device for rectal administration. 24. An aerosol canister according to claim 23, wherein the means for measuring the metered dose of the pharmaceutical composition from the canister is a valve or pump dome. The pharmaceutical composition as defined in any one of claims 1 to 18 for the rectal, colon and / or distal ileum administration of a patient for the treatment or maintenance of infection by Clostridium difficile . A pharmaceutical composition as defined in any one of claims 1 to 18 for administration to the rectum, colon and / or distal ileum of a patient for the treatment or alleviation of infection by Clostridium difficile Use of. Comprising administering an effective amount of a pharmaceutical composition according to any one of claims 1 to 18 to a patient in need of treatment or alleviation of an infection by Clostridium difficile , A method for the treatment or alleviation of infection by Clostridium difficile . 28. A pharmaceutical composition according to any one of claims 25 to 27, characterized in that the infection comprises diarrhea. The pharmaceutical composition substantially as hereinbefore described with reference to the Examples.