Patent Description:
Sustained release dosage forms have found wide application in a variety of technology areas such as in personal care and agricultural applications, water treatment and in particular pharmaceutical applications. Sustained release dosage forms are designed to release a finite quantity of an active ingredient into an aqueous environment over an extended period of time. Sustained release pharmaceutical dosage forms are desirable because they provide a method of delivering a long-lasting dose in a single application without overdosing. Known sustained release pharmaceutical dosage forms contain a drug or a vitamin whose release is controlled by a polymeric matrix which, for instance, may comprise one or more water-soluble cellulose ethers. Water-soluble cellulose ethers hydrate on the surface of a tablet to form a gel layer. A fast formation of the gel layer is important to prevent wetting of the interior and disintegration of the tablet core. Once the gel layer is formed, it controls the penetration of additional water into the tablet. As the outer layer fully hydrates and dissolves, an inner layer must replace it and be sufficiently cohesive and continuous to retard the influx of water and control drug diffusion.

A commonly used cellulose ether for providing sustained release of an active ingredient from an oral dosage form is hydroxypropyl methylcellulose (HPMC). For instance, <CIT> discloses that the release of an active ingredient can be prolonged by employing a fine particle sized HPMC as an excipient in a solid tablet. HPMC is used in commercial oral pharmaceutical formulations as a component of a polymeric matrix providing sustained release of a drug usually at a concentration of <NUM>% to <NUM>% by weight of the oral dosage form.

<CIT> relates to a composition for controlled release of an active ingredient, the composition comprising at least <NUM>% by weight of ethylcellulose and at least <NUM>% by weight of polyethylene oxide. The composition is prepared by hot melt extrusion. <NPL> disclose swellable sustained release tablets comprising metformin and ethyl cellulose. Patent document <CIT> discloses sustained release formulations comprising ranolazine and ethyl cellulose.

It is a well-known problem in the pharmaceutical art that some patients, especially children or the elderly, or patients with dysphagia, find it difficult to swallow conventional oral dosage forms such as capsules or tablets. In particular, this is the case if the drug administered in the dosage form is a highly dosed drug which, when the drug is formulated with pharmaceutical excipients in the typical amounts included in commercial dosage forms, either makes each dosage form very large or requires the dose to be divided among two or more dosage forms that have to be swallowed at the same time.

It would therefore be desirable to develop a sustained release oral dosage form where a drug is formulated with a reduced amount of excipient(s) to permit a reduction in the overall size of the dosage form and improve the swallowability without compromising the sustained release properties thereof.

It has surprisingly been found that when a water-insoluble ethylcellulose is used as an excipient in a mixture with a physiologically active ingredient, it is capable of forming a stable hydrogel at a temperature of <NUM> and provide sustained release of the active ingredient. This is the case even when it is used at much lower concentrations that the concentrations of HPMC used in commercial formulations and at much lower concentrations than in the melt-extruded compositions disclosed in <CIT>.

Accordingly, the present invention relates to a sustained release solid composition for oral administration comprising a physiologically active ingredient embedded in a polymeric matrix of a water-insoluble ethylcellulose which has a DS(ethyl) of at least <NUM>, wherein the concentration of ethylcellulose is <NUM>-<NUM>% by dry weight of the active ingredient, and wherein the ethylcellulose constitutes <NUM>-<NUM>% by weight of the polymeric matrix.

In the present invention, ethylcellulose is an essential component of the composition to form a hydrogel in an aqueous environment such as the stomach and provide sustained release of the active ingredient on oral administration of the composition even when the ethylcellulose is present in a very low concentration relative to the active ingredient.

The ethylcellulose is composed of anhydroglucose units joined by <NUM>-<NUM> linkages. Each anhydroglucose unit contains hydroxyl groups at the <NUM>, <NUM> and <NUM> positions. Partial or complete substitution of these hydroxyls creates cellulose derivatives. For example, treatment of cellulosic fibers with caustic solution, followed by an ethylating agent, yields cellulose ethers substituted with one or more ethoxy groups. If not further substituted with other alkyls, this cellulose derivative is known as ethylcellulose.

The present inventors have surprisingly found that ethylcellulose wherein hydroxy groups of the anhydroglucose units are substituted with ethyl groups to a DS (ethyl) of more than <NUM> can form a stable hydrogel at about <NUM> when included in the composition at concentrations that are sufficient to embed particles of the active ingredient. While such concentrations may vary between wide limits, and while generally more sustained release may be obtained at higher concentrations of ethylcellulose (e.g. <NUM>-<NUM>% by weight), it has surprisingly been found that ethylcellulose at low concentrations, i.e. concentrations of <NUM>-<NUM>% by dry weight of the active ingredient, may be sufficient to cause the active ingredient to become embedded to an extent providing sustained release of the active ingredient over <NUM> hours. The concentration of ethylcellulose included in the present composition is <NUM>-<NUM>% and most preferably <NUM>-<NUM>% by dry weight of the active ingredient. Compositions containing about <NUM>-<NUM>% of ethylcellulose by dry weight of the active ingredient have been shown to provide a release of the active ingredient of between about <NUM>% and <NUM>% over a period of <NUM> hours, cf. Examples <NUM>-<NUM> below. The resulting sustained release dosage form, such as tablet or capsule, is smaller in size and therefore easier to ingest. It has furthermore been found that a satisfactory release rate may be obtained without adding any other excipients to the dosage form, though a surfactant may optionally be added during the manufacturing process as a defoaming agent.

The ethylcellulose preferably has a DS(ethyl) of from <NUM> to <NUM>, more preferably from <NUM> to <NUM>, even more preferably from <NUM> to <NUM>, still more preferably from <NUM> to <NUM> and most preferably from <NUM> to <NUM>. The degree of the ethyl substitution, DS(ethyl), also designated as DS(ethoxyl), of an ethylcellulose is the average number of OH groups substituted with ethyl groups per anhydroglucose unit.

The determination of the % ethoxyl in ethylcellulose is carried out by a Zeisel gas chromatographic technique as described in ASTM D4794-<NUM>(<NUM>). These are subsequently converted into degree of substitution (DS) for ethyl substituents according to the formulas below: <MAT> wherein EtO is ethoxy and AGU is anhydroglycose unit.

Residual amounts of salt have been taken into account in the conversion.

The viscosity of the ethylcellulose is generally from <NUM> to <NUM> mPa. s when measured as a <NUM> wt. % solution in a mixture of toluene and ethanol in a weight ratio of <NUM>:<NUM> at <NUM> in an Ubbelohde viscometer. The viscosity of the ethylcellulose may be from <NUM> to <NUM> mPa. s and more preferably from <NUM> to <NUM> mPa. s when measured as indicated above. Alternatively, the viscosity of the ethylcellulose may be from <NUM> to <NUM> mPa. s when measured as indicated above.

In an aqueous environment, the ethylcellulose is capable of gelling at <NUM> at very low concentrations, forming stable hydrogels in an aqueous environment. The term "stable hydrogels", when used in this context is intended to mean hydrogels that retain their shape and are not completely dissolved or significantly eroded after immersion in <NUM> N HCl, pH <NUM>, for <NUM> hours at <NUM>.

Examples of ethylcelluloses are ETHOCEL Standard <NUM> Premium ethylcellulose, ETHOCEL Standard <NUM> Premium ethylcellulose and ETHOCEL Standard <NUM> FP ( available from DuPont).

The ethylcellulose is useful as an excipient for a sustained release dosage form which means that it has the function to regulate the release of an active ingredient from the dosage form over an extended period of time. The term "sustained release" is used herein synonymously with the term "controlled release". Sustained release is an approach by which active ingredients such as physiologically active compounds are made available at a rate and duration designed to accomplish an intended effect. The ethylcellulose is useful for forming all or part of a polymeric matrix in which the active ingredient is embedded. The polymeric matrix may additionally comprise one or more other polymers capable of providing sustained release of the active ingredient from the dosage form. The ethylcellulose constitutes <NUM>-<NUM>%, and most preferably <NUM>-<NUM>% by weight of the polymeric matrix. The polymeric matrix may include one or more other polymers such as other celluloseethers, e.g. hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, methylcellulose, hydroxypropyl cellulose or carboxymethyl cellulose, or it may include one or more other polysaccharides such as sodium alginate or calcium alginate. It is generally preferred that ethylcellulose constitutes <NUM>% by weight of the polymeric matrix.

The ethylcellulose may be included in sustained release dosage forms, in particular dosage forms intended for oral administration of drugs or other physiologically active ingredients and release thereof into the gastrointestinal tract so as to control the absorption rate of the active ingredient to achieve a desired blood plasma profile. The combined amount of ethylcellulose and active ingredient in the dosage form is preferably at least <NUM>%, more preferably <NUM>% and most preferably at least <NUM>% by dry weight of the dosage form, and preferably up to <NUM>%, more preferably up to <NUM>% and most preferably up to <NUM>% by dry weight of the dosage form. The dosage form is designed to provide a constant or nearly constant level of the active ingredient in plasma with reduced fluctuation via a slow, continuous release of the active ingredient over an extended period of time such as a period of between <NUM> and <NUM> hours, preferably between <NUM> and <NUM> hours to release all or almost all of the active ingredient from the dosage form.

It has been found that sustained release dosage forms such as tablets and capsules wherein the polymer matrix is formed partially or completely from ethylcellulose remains intact over an extended time period such as at least <NUM> hours, preferably at least <NUM> hours and under optimized conditions at least <NUM> hours. Without wanting to be bound by theory, it is believed that the ethylcellulose is hydrated to form a strong swollen layer on the outer surface of the dosage form upon contact with an aqueous liquid at body temperature. The strong swollen layer minimizes the release of the active ingredient caused by erosion of the dosage form. Since the tablets or capsule contents do not disintegrate (i.e. do not fall apart to any significant degree), the release of the active ingredient is controlled by the slow diffusion from the swollen layer that has been formed by hydration of the ethylcellulose on the outer surface of the dosage form. A strong swollen layer reduces the penetration of water into the sustained release dosage form, which delays the release of the active ingredient, particularly a water-soluble active ingredient, into an aqueous environment due to a reduced amount of water in the zone of the dosage form into which water diffuses and dissolves the active ingredient. It is considered most surprising that ethylcellulose, which is not soluble in water, is capable of being hydrated and forming a hydrogel in this manner.

In an embodiment, the composition comprises an additive which on ingestion reacts with gastric fluid to generate a gas such as CO<NUM>. The developing gas is trapped in the hydrogel which, as a result, floats to the surface of the gastric contents resulting in prolonged gastric retention time. The prolonged gastric retention time improves the bioavailability of the active ingredient, increases the duration of release and improves the solubility of active ingredients that are not readily soluble in the high pH environment of the intestine. Examples of additives which generate gas in contact with gastric fluid are alkali metal or alkaline earth metal carbonates such as CaCO<NUM> or Na<NUM>CO<NUM>. The concentration of the additive may be in the range of <NUM>-<NUM>% by weight, preferably <NUM>-<NUM>% by weight, such as <NUM>% by weight of the composition.

Addition of a surfactant helps to distribute a low level of liquid diluent homogenously and produce a smooth highly viscous semi-solid paste, possibly due to defoaming and emulsification. The surfactant may be selected from conventional defoaming agents selected from the group consisting of anionic surfactants with anionic functional groups such as sulfates, sulfonates, phosphates and carboxylates such as alkyl sulfates, e.g. ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and alkyl-ether sulfates, such as sodium laureth sulfate (sodium lauryl ether sulfate or SLES), and sodium myreth sulfate; cationic surfactants with cationic functional groups such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB); zwitterionic surfactants such as cocamidopropyl betaine; and nonionic surfactants such as siloxane surfactants like modified polydimethylsiloxane-based defoamer, ethoxylates, fatty acid esters of glycerol, sorbitol and sucrose. The concentration of surfactant may be in the range of <NUM>-<NUM>% by weight of the composition.

In one embodiment of the invention, the composition comprising ethylcellulose admixed with the active ingredient is in the form of a dry powder. The dry powder may be prepared by preparing a solution of ethylcellulose in an organic solvent such as ethanol, methanol, isopropanol or acetone or a mixture thereof with water, and mixing the solution with an active ingredient and optionally one or more solid excipients, and drying the mixture at a temperature of <NUM>-<NUM> until the mixture has a moisture content of less than <NUM>% by weight, preferably less than <NUM>% by weight, more preferably less than <NUM>% by weight, in particular less than <NUM>% by weight, such as less than <NUM>% by weight, followed by milling or grinding the mixture to granules of a desired particle size in a manner known in the art. The dry powder will typically contain granules comprising the active ingredient partially or completely encased by ethylcellulose which facilitates sustained release of the active ingredient as discussed above.

In one embodiment, the invention relates to a unit dosage form comprising the present composition. The unit dosage form is intended for oral administration and may be in the form of a tablet comprising the compressed dried composition, for instance in the form of compressed granules of the dried composition. Alternatively, the unit dosage form may be in the form of a tablet or pellet prepared by extruding the semi-solid paste prepared as described above and cutting the extruded mass into pieces of an appropriate size followed by drying. The tablet may optionally comprise one or more other excipients, such as a cellulose derivative as described above, though preferably ethylcellulose is the only polymeric matric forming excipient included in the dosage form, except that a surfactant may optionally also be included as indicated above. The unit dosage form may also be a capsule including the dried composition, preferably in the form of dry granules containing the mixture of methylcellulose and active ingredient. The unit dosage form may also be in the form of a syringe or pouch pre-filled with the wet mixture: this dosage form may more readily be administered to young children.

The unit dosage form contains one or more physiologically active ingredients, preferably one or more drugs, one or more diagnostic agents, or one or more physiologically active ingredients which are useful for cosmetic or nutritional purposes. The term "drug" denotes a compound having beneficial prophylactic and/or therapeutic properties when administered to an individual, typically a mammal, especially a human individual. The dosage form is believed to be particularly suited for administering highly dosed drugs, i.e. drugs administered in unit doses of <NUM> or more, as it is possible to provide a unit dose that includes the requisite amount of the active ingredient in a size that makes it easier to ingest. Examples of highly dosed drugs are metformin, metformin hydrochloride, acetaminophen (paracetamol) or acetylsalicylic acid. Thus, each unit dosage form may typically include <NUM>-<NUM> of the active ingredient.

Some embodiments of the invention will now be described in detail in the following Examples.

Unless otherwise mentioned, all parts and percentages are by weight. In the Examples the following test procedures are used.

In typical embodiments, the ethylcellulose has a viscosity of from <NUM> to <NUM> mPa. s in a <NUM>% solution in a mixture of toluene and ethanol at a weight ratio of <NUM>:<NUM>. The viscosity is determined at <NUM> in an Ubbelohde viscometer. A typical viscosity analysis is performed as follows: <NUM> of a <NUM>:<NUM> toluene/ethanol mixture is weighed into a dry <NUM> ounce (ca. <NUM>) bottle and <NUM> of ethylcellulose is added. The bottle is placed on a mechanical shaker and shaken until all the ethylcellulose is dissolved (approximately for <NUM> minutes). The resulting solution is analyzed within <NUM> of preparation. For viscosity measurement, the solution is filled into an Ubbelohde viscometer which is then placed in a water bath at <NUM> until the solution has equilibrated to <NUM>. Following the instructions for the Ubbelohde viscometer, the solution is sucked up through the calibration flow tube and then allowed to drain. The time of the flow between the upper and lower calibration mark is stopped and the viscosity is calculated according to the instructions taking into account the specific capillary used for the measurement.

A <NUM> % by weight solution of ethylcellulose (ETHOCEL Std. <NUM> Premium, available from DuPont) in ethanol was prepared. <NUM> of finely ground acetaminophen (abbreviated herein to APAP) was intimately mixed with <NUM> of the ethylcellulose solution until a white homogenous and highly viscous paste was obtained. The mixture was immediately filled into a syringe and injected into HPMC capsules (size <NUM>) which were subsequently closed and sealed. The mixture was carefully dried overnight at <NUM>.

The dried capsules were placed in <NUM> of <NUM>. 1N HCl pH <NUM> at <NUM> and drug release was measured in a USP II dissolution apparatus at <NUM>, <NUM> rpm, for <NUM> hours at a wavelength of <NUM> with a path length of <NUM>.

The release of APAP from the dried capsules is shown in <FIG> from which it appears that about <NUM>% of the drug was released after <NUM> hours (shown as -• - in the figure).

A <NUM>% by weight solution of ethylcellulose (ETHOCEL Std. <NUM> Premium, available from DuPont) in ethanol was prepared. <NUM> of finely ground acetaminophen (abbreviated herein to APAP) was intimately mixed with <NUM> of the ethylcellulose solution until a white homogenous and highly viscous paste was obtained. The mixture was immediately filled into a syringe and injected into HPMC capsules (size <NUM>) which were subsequently closed and sealed. The mixture was carefully dried overnight at <NUM>.

The release of APAP from the dried capsules is shown in <FIG> from which it appears that about <NUM>% of the drug was released after <NUM> hours (shown as -▲- in the figure).

The release of APAP from the dried capsules is shown in <FIG> from which it appears that about <NUM>% of the drug was released after <NUM> hours (shown as -■ - in the figure).

A <NUM>% by weight solution of ethylcellulose (ETHOCEL Std. <NUM> FP, available from DuPont) in ethanol was prepared. <NUM> of finely ground acetaminophen (abbreviated herein to APAP) was intimately mixed with <NUM> of the ethylcellulose solution until a white homogenous and viscous paste was obtained. The mixture was spread out onto a plate and dried at <NUM>. When completely dry, the mixture was de-agglomerated by hand using a pistil and compressed into tablets by using a lab manual IR tablet press at a pressure of 2t. The tablets had a weight of <NUM> and contained <NUM>% by weight of APAP. The tablets had a tablet hardness of <NUM> N.

The tablets were placed in <NUM> of <NUM>. 1N HCl pH <NUM> at <NUM> and drug release was measured in a USP II dissolution apparatus at <NUM>, <NUM> rpm, for <NUM> hours at a wavelength of <NUM> with a path length of <NUM>.

The release of APAP from the tablets is shown in <FIG> from which it appears that about <NUM>% of the drug was released after <NUM> hours (shown as -• - in the figure).

Claim 1:
A sustained release solid composition for oral administration comprising a physiologically active ingredient embedded in a polymeric matrix of a water-insoluble ethylcellulose which has a DS(ethyl) of at least <NUM>, wherein the concentration of ethylcellulose is <NUM>-<NUM>% by dry weight of the active ingredient, and wherein the ethylcellulose constitutes <NUM>-<NUM>% by weight of the polymeric matrix.