The present invention relates to pharmaceutical compositions which can be administered orally, allowing the controlled release of pharmaceutically active sub-stances, and to methods of preparing these pharmaceutical compositions.
One of the objectives currently sought in the development of pharmaceutical compositions which can be administered orally is to control the release of pharmaceutically active substances so that they can be administered in a few daily doses, ideally in a single daily dose.
The release of active substances during oral administration can be controlled by means of matrix-type pharmaceutical compositions. Depending on the excipients used, it is possible to identify three types of matrix inert, hydrophilic and lipophilic matrices. Mixed matrices can also be created by combining excipients for these various types of matrix.
The inert matrices comprise excipients essentially belonging to the class of thermoplastic polymers. They are inert towards biological tissues, other excipients in the formulation and the active substance. They are insoluble and indigestible in the fluids of the gastrointestinal tract. Among these, there may be mentioned polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene and the like. They generally use a concentration ranging from 20 to 95%.
The hydrophilic matrices comprise gelling excipients which can be divided into three classes: the cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose and the like), the noncellulose polysaccharides (galactomannans, guar gum, carob gum, gum arabic, sterculia gum, agar, alginates and the like) and the acrylic acid polymers (carbopols 934P and 974P and the like). They are generally used at a concentration of 20 to 700%.
The lipid matrices comprise four types of fatty excipients: glycerides (mono-, di- or triglycerides: stearin, palmitin, laurin, myristin, hydrogenated castor or cottonseed oils, precirol and the like), fatty acids and alcohols (stearic, palmitic or lauric acids; stearyl, cetyl or cetostearyl alcohols, and the like), fatty acid esters (monostearates of propylene glycol and of sucrose, sucrose distearate and the like) and waxes (white wax, cachalot wax and the like). They are generally used at a concentration of 10 to 50%.
The presence of matrix-type exciplents in pharmaceutical compositions makes it possible, in a number of cases, to slow down the release of the active substances by entrapment. However, these matrix-type excipients do not always make it possible to sufficiently slow down the release of the active substance or to obtain the desired ideal release profiles.
For example, when the matrix-type pharmaceutical composition contains a substance which must imperatively be released in the stomach, the release of the active substance over sufficiently long periods depends not only on the type of excipients used in the composition, but also on the residence time of the pharmaceutical composition in the stomach. Accordingly, several documents mention the use of floating matrix tablets.
In particular, patent EP 205336 describes pharmaceutical compositions for the controlled release of active substances comprising a mixed matrix obtained from a mixture of ethers of cellulose and of a polyacrylic acid, of one of its derivatives or of their pharmaceutically acceptable salts, and comprising, in addition, from 10 to 50% by weight, relative to the total weight of matrix excipients, of effervescent foaming agent. The effervescent foaming agent makes it possible to cause the pharmaceutical composition to float in the gastric fluid, thereby increasing the residence time in the stomach. The effervescent foaming agent is an alkali or alkaline-earth metal bicarbonate which is preferably used in combination with an organic acid.
However, the floating in the gastric fluid does not allow other problems observed in the context of the control of the release of active substances from the matrix pharmaceutical compositions to be resolved.
Indeed, the quantities of matrix excipient necessary for adequate prolonged release of the active ingredient can prove to be too high and can make the production of the dosage form impossible or too costly.
Moreover, the release of some active substances greatly depends on the pH. For example, some active substances are not at all released in the stomach, but in other areas of the gastrointestinal tract. In addition, for the same area of the gastrointestinal tract, the release profile will be different depending on whether or not the composition is administered together with a meal. For the active substances whose release depends on the ambient pH, it is therefore desirable to find novel matrix compositions which make it possible to regulate the rate of release so that the active substance can be released at the same rate regardless of the pH of the medium.
Finally, it is very common for the profile of release of an active ingredient from a matrix form to be irregular over time, that is to say that the kinetics of release is not of the zero order but is a function of the square root of the time. A zero order kinetics of release corresponds to a regular and constant release over time and is highly desirable in order to ensure a regular and long-lasting therapeutic effect.
In parallel, it is increasingly therapeutically advantageous to be able to simultaneously administer by the oral route an active substance released immediately after administration, and the same or a second active substance released gradually and regularly after administration. In the case where the same active substance is simultaneously administered for immediate release and for prolonged release, this makes it possible to rapidly release a sufficient dose of active substance to trigger the desired effect and to maintain this effect by a gradual and prolonged release of the same active substance. In the case where an active substance is released immediately and another active substance is released gradually, this makes it possible to obtain combined therapeutic effects by means of two active substances having very different pharmacokinetic profiles.
In this context, international patent application WO 94/09761 describes a slow release oral composition comprising
a) a matrix core comprising
pseudoephedrine sulfate
hydroxypropylmethylcellulose
ethylcellulose
dibasic calcium phosphate
povidone
silicon dioxide
magnesium stearate
and
b) a coating on the matrix core comprising
loratadine
hydroxypropylmethylcellulose
polyethylene glycol 400
polyethylene glycol 3350.
European patent application EP-A-0 396 404 describes a slow release oral composition comprising
a) a matrix core comprising
ibuprofen
pseudoephedrine
swellable hydrophilic polymers, such as hydroxypropylmethylcellulose
excipient such as dibasic calcium phosphate
lubricant such as magnesium stearate,
and
b) a coating on the core comprising
loratadine
hydrophilic polymer
other excipients.
In this context, orally administrable solid pharmaceutical compositions combining, in a single unit, a portion exhibiting immediate release and a portion exhibiting delayed release have been described. However, these compositions require methods of preparation which are technically very sophisticated and/or do not allow the desired release profiles to be obtained for all the active substances.
We have now just discovered, surprisingly, novel pharmaceutical compositions which can be administered orally, allowing the controlled release of pharmaceutically active substances such that a satisfactory therapeutic effect is observed over fairly long periods, for example in only one or even two daily doses.
In particular, the compositions according to the present invention do not require excessive quantities of matrix excipients and allow regular and continuous release of active substances over periods of at least 12 hours.
In addition, we have also just discovered that these new controlled-release pharmaceutical compositions can be used in combination with an immediate-release pharmaceutical composition for the same or for another active substance, in a single unit intended to be administered orally.
The present invention therefore relates to pharmaceutical compositions which can be administered orally, allowing the controlled release of at least one active substance, comprising
a) the said at least one active substance,
b) between 5 and 60% by weight, relative to the total weight of the composition, of at least one excipient, selected from inert matrices, hydrophilic matrices, lipid matrices, mixtures of inert matrices and of lipid matrices, mixtures of hydrophilic matrices and of lipid matrices, mixtures of hydrophilic matrices and of inert matrices, with the exception of mixtures comprising a polyacrylic acid and at least one hydrophilic matrix of the cellulose type;
c) between 5 and 50% by weight, relative to the total weight of the composition, of at least one alkalinizing agent soluble in an aqueous phase under physiological pH conditions, selected from alkali or alkaline-earth metal hydroxides, carbonates, bicarbonates and phosphates, sodium borate as well as the basic salts of organic acids.
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