Mucoadhesive granules of carbomer suitable for oral...

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Reexamination Certificate

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C424S487000

Reexamination Certificate

active

06306789

ABSTRACT:

The present invention relates to mucoadhesive granules of carbomer and in particular to such granules containing pharmaceutical active agents suitable for sustained release into the gastrointestinal tract or for targeted delivery to the gastrointestinal mucosa.
The problems associated with conventional oral administration of drugs are well known. For example following oral administration of a drug, peak blood level concentrations are attained which then decline until there is a repeat administration. To maintain the mean blood level concentrations at a therapeutic level either frequent dosing or less frequent dosing but at a higher level is generally required. The former can result in poor patient compliance while with the latter there may be an unacceptable level of side effects, which depend upon the drug being used.
Therefore various attempts have been made to produce sustained release dosage forms for orally administered drugs. There have been a number of different approaches. One of the most commonly used is the application of polymers to coat particles of drug substance. Commonly used coating polymers include those which are insoluble or slowly soluble but are permeable, so allowing gradual release of dissolved drug from the particles as they pass through the gastrointestinal tract. The disadvantages of this system include the possibility of sudden drug release when the coat is breached and dependence upon gastrointestinal transit time (which varies greatly between individuals)
A further method of improved drug delivery that has been suggested is to combine the active agent with a mucoadhesive agent. Various mucoadhesive agents are known which are believed to bind to the mucus layers coating the stomach and other regions of the gastrointestinal tract. It is believed that using such agents in combination with an active agent will result in the active agent also being bound to the mucus layer, leading either to slow release into the gastrointestinal tract or direct delivery to the gastrointestinal mucosa.
Carbomers and their salts are particularly useful agents for such drug delivery as they have good mucoadhesive activity. Furthermore carbomers are themselves known to produce beneficial effects in the gastrointestinal tract and on the gastrointestinal mucus.
One disadvantage of mucoadhesive powders is the possibility that they may form large aggregates on arrival in the stomach, leading to poor release of the active agents or to uneven application to the mucus layers. Thus granular forms of mucoadhesives are considered to be preferential. It would also be preferable if the active agent could be mixed as closely as possible with the granular mucoadhesive i.e, if they were mixed in the same granules. A simple method for preparing such granules requiring as few process steps as possible and as few expensive excipients (for example complex binding agents) would therefore be very valuable.
In a first aspect of the invention there are therefore provided mucoadhesive granules comprising
a) carbomer and/or a salt thereof (hereinafter component a); and
b) an inert filler (hereinafter component b).
Carbomers are synthetic high molecular weight polymers of acrylic acid cross linked with either alkyl esters of sucrose or pentaerythritol. Suitable commercially available grades of carbomer include Carbopol 910, Carbopol 934P, Carbopol 940, Carbopol 941, Carbopol 971P, Carbopol 974P, Carbopol 980, Carbopol 981, Carbopol 1342, Rheogic 252L and Rheogic 250H (both available from Nikon Junyaku)and Hostacerin PN73 (available from Hoechst UK).
Salts of carbomer may be complete salts (where all of the acid groups have been neutralised) or partial salts (in which only a proportion of the acid groups have been neutralised). Where salts of carbomer are referred to it will be understood that this includes complete salts, partial salts or mixtures thereof.
Preferred salts of carbomer are mono or divalent salts, most preferably sodium or potassium salts.
Suitable inert fillers include carbohydrates (for example dextrose, sucrose, mannitol, lactose, starch or microcrystalline cellulose) or inorganic salts (for example dicalcium phosphate, tricalcium phosphate or magnesium carbonate)
Preferably the inert filler is microcrystalline cellulose.
The mucoadhesive granules of the invention preferably comprise from 5 to 50% w/w carbomer and/or a salt thereof, more preferably 10 to 45% w/w and most preferably 15 to 40% w/w.
The mucoadhesive granules of the invention preferably comprise from 5 to 94% w/w inert filler, more preferably 15 to 75% w/w.
The mucoadhesive granules of the invention may also comprise an active agent suitable for sustained release into the gastrointestinal tract or for targeted delivery to the gastrointestinal mucosa.
There are therefore further provided mucoadhesive granules comprising
a) carbomer and/or a salt thereof;
b) an inert filler; and
c) a pharmaceutically active agent (hereinafter component c) suitable for sustained release into the gastrointestinal tract or for targeted delivery to the gastrointestinal mucosa.
Pharmaceutically active agents suitable for sustained release into the gastrointestinal tract (component c1) are well known and include antimicrobial agents, analgesics, local anaesthetics, cardiovascular drugs, antacids, antiinflamatories, antitussives, H2-receptor antagonists and antidepressants. Preferably component c1) is either a compound having poor solubility in the gastrointestinal lumen, or it is combined with release retarding components to delay its release from the mucoadhesive granules of the invention.
Pharmaceutically active agents suitable for targeted delivery to the gastrointestinal mucosa (component c2) include antimicrobial agents (for example antibiotics or antiseptic agents), proton pump inhibitors (for example omeprazole), prokinetic/gastric emptying agents (e.g. cisapride), H2-receptor antagonists, local anaesthetics, antacids or ulcer healing agents. Preferably component c2) has poor solubility in the gastrointestinal lumen.
It is preferred that the solubility of component c2) is greater in neutral or basic conditions than in acid conditions. An example of a compound having the preferred properties of component c2) is triclosan.
It will be appreciated that many compounds may be equally suitable for use as component c1) or component c2).
Preferably component c) is an antimicrobial agent, more preferably triclosan or a derivative thereof.
The term “triclosan or a derivative thereof” as used herein is intended to encompass the use of an amount of an ester of triclosan or a derivative thereof, a cationic salt or an ester of triclosan or a derivative thereof which will provide the equivalent amount of triclosan or the said derivative thereof.
Examples of esters of triclosan or esters of the derivatives thereof for use in the present invention are the phosphate, phosphonate, sulfate, glucuronide, succinate and glutamate esters. Particularly preferred esters are the phosphate esters of triclosan.
The phosphate esters may be prepared by the phosphorylation of triclosan or a derivative thereof, using methods well known in the art.
The esters may be present in the form of the cationic salts thereof, for example the sodium, potassium, calcium or magnesium salts.
The cationic salts of triclosan may also be used in the present invention, for example, the sodium or potassium salts.
Derivatives of triclosan which may be used in the present invention further include those compounds in which one or both of the phenyl groups is/are substituted by one or more substituent groups in addition to the chloro substituents already present on the phenyl rings. Examples of suitable substituents are alkyl groups containing 1 to 4 carbon atoms, haloalkyl groups containing 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, cyano, allyl, amino and acetyl groups. Preferred substituents are methyl, methoxy and trifluoromethyl groups. It will be understood that if triclosan is substituted by more than one substituent, then the substituents may be the same or dif

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