ETHYLCELLULOSE

FIELD

The present invention relates to novel sustained release compositions comprising a physiologically active ingredient and an ethylcellulose.

INTRODUCTION

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, US 4,734,285 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 30% to 60% by weight of the oral dosage form. EP 1978940 B1 relates to a composition for controlled release of an active ingredient, the composition comprising at least 25% by weight of ethylcellulose and at least 10% by weight of polyethylene oxide. The composition is prepared by hot melt extrusion.

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.

SUMMARY OF THE INVENTION

It has surprisingly been found that when a cold water-soluble 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 about 37°C 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 EP 1978940 Bl.

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 cold water-soluble ethylcellulose which has a DS(ethyl) of 1.7 or less, wherein the concentration of ethylcellulose is 0.1-20% by dry weight of the active ingredient.

In another aspect, the invention relates to use of a cold water-soluble ethylcellulose with a DS(ethyl) of 1.5 or less as an excipient of a polymeric matrix providing sustained release of a physiologically active ingredient from an oral solid dosage form. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. l is a graph showing the release over time of acetaminophen (APAP) from compositions of the invention containing solutions of cws ethylcellulose (3% solution, shown in the figure as -·-) when HPMC capsules containing the dried compositions are immersed in 900 ml of 0.1 N HC1, pH 1.1.

Fig. 2 is a graph showing the release over time of acetaminophen (APAP) from compositions of the invention containing solutions of cws ethylcellulose (3% solution, shown in the figure as -·-) and calcium carboante when HPMC capsules containing the dried compositions are immersed in 900 ml of 0.1 N HC1, pH 1.1.

DESCRIPTION OF EMBODIMENTS

Ethylcellulose with a DS(ethyl) of 1.7 or less is soluble in water as a 2% by weight solution at a temperature of about 10°C or less and is therefore termed“cold water-soluble” (abbreviated to“cws” in the following). At 2°C the ethylcellulose can generally be dissolved in water as a 0.5-20% by weight solution.

In the present invention, the cws ethylcellulose is an essential component of the composition to form a hydrogel at about 37°C 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 low concentration relative to the active ingredient.

Ethylcellulose is composed of anhydroglucose units joined by 1-4 linkages. Each anhydroglucose unit contains hydroxyl groups at the 2, 3 and 6 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 cws ethylcellulose wherein hydroxy groups of the anhydroglucose units are substituted with ethyl groups to a DS(ethyl) of 1.5 or less can form a stable hydrogel at about 37°C 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, it has surprisingly been found that cws ethylcellulose at low concentrations, i.e. concentrations of 20% or less 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 24 hours. The

concentration of cws ethylcellulose included in the present composition is typically 0.2- 18%, preferably 0.5-15%, more preferably 0.7-10%, even more preferably 1.0-7.5% and most preferably 1.5-5% by dry weight of the active ingredient. Compositions containing about 1.7% by weight of cws ethylcellulose by dry weight of the active ingredient have been shown to provide a release of the active ingredient of about 80% over a period of 22 hours, cf. Example 1 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 cws ethylcellulose preferably has a DS(ethyl) of 1.4 or less, preferably 1.3 or less and more preferably between 0.8 and 1.2. 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 D4794-94(2003). These are subsequently converted into degree of substitution (DS) for ethyl substituents according to the formulas below:

% cellulose backbone = 100-[%EtO*[[M(OCH2-CH3)-M(OH)]/M(OCH2-CH3)] DS(ethyl) = [[%EtO/M(OCH2-CH3)]/(%cellulose backbone/M(AGU))]

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 cws ethylcellulose is generally least 2.4 mPa ^» s, preferably at least 3 mPa _* s, and most preferably at least 10 mPa _* s, when measured as a 2 wt. % aqueous solution at 5 °C at a shear rate of 10 s-1. The viscosity of the methylcellulose is preferably up to 10,000 mPa _* s, more preferably up to 5000 mPa _* s, and most preferably up to 2000 mPa _* s, when measured as a 2 wt. % aqueous solution at 5 °C at a shear rate of 10 s-1. Methods of making cws ethylcellulose are described in more detail in the Examples. Generally, cellulose pulp is treated with a caustic, for example alkali metal hydroxide. Preferably, about 1.5 to about 3.0 mol NaOH per mol anhydroglucose units in the cellulose is used. Uniform swelling and alkali distribution in the pulp is optionally controlled by mixing and agitation. The rate of addition of aqueous alkaline hydroxide is governed by the ability to cool the reactor during the exothermic alkalization reaction. In one embodiment, an organic solvent such as dimethyl ether is added to the reactor as a diluent and coolant. Likewise, the headspace of the reactor is optionally purged with an inert gas (such as nitrogen) to minimize unwanted reactions with oxygen and molecular weight losses of the cws ethylcellulose. In one embodiment, the temperature is maintained at or below 45°C.

An ethylating agent such as ethyl chloride is also added by conventional means to the cellulose pulp either before or after or concurrently with the caustic, generally in an amount of 2.0 to 6 mol ethylating agent per mol anhydroglucose units in the cellulose. Preferably, the ethylating agent is added after the caustic. Once the cellulose has been contacted with caustic and ethylating agent, the reaction temperature is increased to about 100°C and reacted at this temperature for about three and half an hour.

The cws ethylcellulose is washed to remove salt and other reaction by-products. Any solvent in which salt is soluble may be employed, but water is preferred. The cws ethylcellulose may be washed in the reactor, but is preferably washed in a separate washer located downstream of the reactor. Before or after washing, the cws ethylcellulose may be stripped by exposure to steam to reduce residual organic content. The cellulose ether may subsequently be subjected to a partial depolymerizing process. Partial depolymerizing processes are known in the art and described in e.g. EP 1141029, EP 210917, EP 1423433 and US 4316982. Alternatively, partial depolymerization can be achieved during the production of the cellulose ether, for example by the presence of oxygen or an oxidizing agent.

The cws ethylcellulose is dried to a reduced moisture and volatile content of preferably 0.5 to 10.0% by weight of water and more preferably 0.8 to 5.0% by weight of water and volatiles based on the weight of cws ethylcellulose. The reduced moisture and volatiles content enables the cws ethylcellulose to be milled into particulate form. The cws ethylcellulose is milled to particulates of a desired size. If desired, drying and milling may be carried out simultaneously.

In an aqueous environment, the cws ethylcellulose is capable of gelling at 37°C at 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 0.1 N HC1, pH 1.1, for 4 hours at 37°C.

The cws 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 cws ethylcellulose is useful for forming all or part of a polymeric matrix in which the active ingredient is embedded. The polymeric matrix may include one or more other polymers capable of providing sustained release of the active ingredient from the dosage form. The cws ethylcellulose typically constitutes at least 50%, preferably 60-100%, more preferably 70- 100%, even more preferably 80-100%, and most preferably 90-100% by weight of the polymeric matrix. When one or more other polymers are included in the polymeric matrix, they may be selected from celluloseethers, e.g. hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, methylcellulose, hydroxypropyl cellulose or carboxymethyl cellulose, although it is generally preferred that the cws ethylcellulose constitutes 100% by weight of the polymeric matrix.

The cws 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 cws ethylcellulose and active ingredient in the dosage form is preferably at least 50%, more preferably at least 70%, and most preferably at least 90% by dry weight of the dosage form, and preferably up to 100%, more preferably up to 98% and most preferably up to 95% 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 4 and 30 hours, preferably between 8 and 24 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 cws ethylcellulose remain intact over an extended time period such as at least 4 hours, preferably at least 6 hours and under optimized conditions at least 8 hours. Without wanting to be bound by theory, it is believed that the cws 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 where the cws ethylcellulose is not soluble. 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 cws 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.

In an embodiment, the composition comprises an additive which on ingestion reacts with gastric fluid to generate a gas such as CO2. 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 CaCCb or Na2CCb. The

concentration of the additive may be in the range of 1-5% by weight, preferably 1.5-3% by weight, such as 2% 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 0.1-1.5% by weight of the composition.

In one embodiment of the invention, the composition comprising cws ethylcellulose admixed with the active ingredient is in the form of a dry powder. The dry powder may be prepared by preparing an aqueous solution of cws ethylcellulose in cold water (i.e. water with a temperature of 10°C or less), and mixing the solution with an active ingredient in the form of particles until a semi-solid paste is formed, and drying the mixture at a temperature of 40-100°C until the mixture has a moisture content of less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, in particular less than 2% by weight, such as less than 1% 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 particles of the active ingredient partially or completely encased by cws 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 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 cws ethylcellulose is the only polymer matrix 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 500 mg 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 500-1000 mg 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.

Production of a 2 % aqueous solution of the cws ethylcellulose

To obtain a 2 % aqueous solution of cws ethylcellulose, 3 g of milled, ground, and dried cws ethylcellulose (under consideration of the water content of the cws ethylcellulose) were added to 147 g of water (temperature 20 - 25 °C) at room temperature while stirring with an overhead lab stirrer at 750 rpm with a 3-wing (wing = 2 cm) blade stirrer. The solution was then cooled to about 1.5 °C. After the temperature of 1.5 °C was reached the solution was stirred for 180 min at 750 rpm. Prior to use or analysis, the solution was stirred for 15 min at 100 rpm in an ice bath.

Determination of the gelation temperature of aqueous cws ethylcellulose

Aqueous cws ethylcellulose solutions were subjected to small-amplitude oscillatory shear flow (frequency = 2 Hz, strain amplitude = 0.5%) while warming from 5 to 85 °C at 1 K/min in a rotational rheometer (Anton Paar, MCR 501, Peltier temperature-control system). The oscillatory shear flow was applied to the sample placed between 5 parallel- plate fixtures (type PP-50; 50-mm diameter, 1-mm separation [gap]). Water loss to the sheared material was minimized during the temperature ramp by (1) covering the fixtures with a metal ring (inner diameter of 65 mm, width of 5 mm, height of 15 mm) and (2) placing a water-immiscible paraffin oil around the sample perimeter. The storage modulus G', which is obtained from the oscillation measurements, represents the elastic properties of the solution (during the gelation process of methylcellulose, G' increases). The loss modulus G", which is obtained from the oscillation measurements, represents the viscous properties of the solution. The gelation temperature, Tgel, is identified as the temperature when G’and G” are equal (e.g. Tgel = T(G’=G”).

Determination of the viscosity of aqueous cws ethylcellulose

The steady-shear-flow viscosities h (5 °C, 10 s-1, 2 wt.% MC) of aqueous 2-wt.% CE solutions were measured at 5 °C from 0,1 - 1000 s-lwith an Anton Paar Physica MCR 501 rheometer and cup -and-bob sample fixtures (CC-27)

The value of 10 s-1 was used as the viscosity values for these solutions.

Production of cws ethylcellulose

Cws ethylcellulose were produced according to the following procedure. Finely ground wood cellulose pulp was loaded into a jacketed, agitated reactor. The reactor was evacuated and purged with nitrogen to remove oxygen, and then evacuated again. The reaction is carried out in two stages. In the first stage, a 50% by weight aqueous solution of sodium hydroxide was sprayed onto the cellulose until the level reached 1.5 mol of sodium hydroxide per mol of anhydroglucose units of the cellulose, and then the temperature was adjusted to 40 °C. After stirring the mixture of aqueous sodium hydroxide solution and cellulose for about 30 minutes at 40 °C, 3.5 mol of ethyl chloride per mol of

anhydroglucose units were added to the reactor. The contents of the reactor were then heated in 60 min to 100 °C. After having reached 100 °C, the reaction was allowed to proceed for 210 min.

After the reaction, the reactor was vented and cooled down to about 50 °C. The contents of the reactor were removed and transferred to a tank containing hot water. The crude cws ethylcellulose was then neutralized with formic acid and washed chloride free with hot water (assessed by AgNCb flocculation test), cooled to room temperature and dried at 55 °C in an air-swept drier, and subsequently ground. The cws ethylcellulose had a DS(methyl) of 0.9, a viscosity of 1090 mPas (2-wt-%) and a gelation temperature of 35.2 °C.

Example 1: Release of Acetaminophen from dried gelatin capsules comprising ethylcellulose

A 4% by weight solution of cws ethylcellulose in water was prepared on an ice bath. 3.5 g of finely ground acetaminophen (abbreviated herein to APAP) was added to 1.5 g of the cws ethylcellulose solution followed by addition of 0.111 g of a modified

polydimethylsiloxane-based defoamer (available from BASF under the tradename Foamstar SI 2210) and thorough mixing until a white homogenous and highly viscous paste was obtained. The mixture was transferred into HPMC capsules (size 00) which were subsequently closed and sealed. The mixture was carefully dried overnight at 50°C.

The dried capsules were placed in 900 ml of 0.1N HC1 pH 1.1 at 37°C and drug release was measured in an USP II dissolution apparatus at 37°C, 100 rpm for 22 hours with a wavelength of 243 nm and a path length of 0.1 mm.

The release of APAP from the dried capsules is shown in Fig. 1 from which it appears that about 80% of the drug was released after 22 hours (shown as -·- in the figure).

Example 2: Release of Acetaminophen from dried gelatin capsules comprising ethylcellulose and calcium carbonate

A 4% by weight solution of cws ethylcellulose in water was prepared on an ice bath.

i t 6.863 g of finely ground acetaminophen (abbreviated herein to APAP) together with 0.196 g of calcium carbonate was added to 2.941 g of the cws ethylcellulose solution followed by a thorough mixing until a white homogenous and highly viscous paste was obtained. The mixture was transferred into HPMC capsules (size 00) which were subsequently closed and sealed. The mixture was carefully dried overnight at 50°C.

The dried capsules were placed in 900 ml of 0.1N HC1 pH 1.1 at 37°C and drug release was measured in an USP II dissolution apparatus at 37°C, 100 rpm for 22 hours with a wavelength of 243 nm and a path length of 0.1 mm.

The release of APAP from the dried capsules is shown in Fig. 2 from which it appears that about 80% of the drug was released after 22 hours (shown as -·- in the figure).