Sustained release compositions containing ethylcellulose

Abstract

A sustained-release solid composition for oral administration comprises a physiologically active ingredient embedded in a matrix of water-insoluble ethyl cellulose having a DS(ethyl) of at least 1.8, the concentration of the ethyl cellulose being 0.1-20% based on the dry weight of the active ingredient.

Description

[Technical field]

[0001] The present invention relates to a novel sustained release composition comprising a physiologically active ingredient and ethylcellulose. [Background technology]

[0002] Sustained release dosage forms have found a wide range of applications in various technical fields, such as personal care and agricultural applications, water treatment, and especially pharmaceutical applications. Sustained release dosage forms are designed to release a finite amount of active ingredient into an aqueous environment for an extended period of time. Sustained release pharmaceutical forms are desirable because they provide a way to deliver a sustained dose in a single application without overdosing. Known sustained release pharmaceutical forms contain drugs or vitamins, the release of which is controlled by a polymer matrix that may contain, for example, one or more water-soluble cellulose ethers. The water-soluble cellulose ethers hydrate on the surface of the tablet to form a gel layer. The rapid formation of the gel layer is important to prevent internal wetting and disintegration of the tablet core. Once the gel layer is formed, it controls the ingress of additional water into the tablet. The outer layer must be fully hydrated and dissolved, so that the inner layer must replace it, and must be sufficiently cohesive and continuous to retard water influx and control drug diffusion.

[0003] A commonly used cellulose ether to provide sustained release of active ingredients from oral dosage forms is hydroxypropyl methylcellulose (HPMC). For example, U.S. Patent No. 4,734,285 discloses that the release of active ingredients can be prolonged by utilizing fine particle sized HPMC as a solid tablet excipient. HPMC is used in commercial oral pharmaceutical formulations as a component of the polymer matrix, typically at a concentration of 30% to 60% by weight of the oral dosage form, to provide sustained release of the drug.

[0004] EP 1978940 B1 relates to a composition for the controlled release of an active ingredient, comprising at least 25% by weight of ethyl cellulose and at least 10% by weight of polyethylene oxide. The composition is prepared by hot melt extrusion.

[0005] It is a well-known problem in the pharmaceutical art that some patients, especially children or the elderly, or those with swallowing disorders, have difficulty swallowing traditional oral dosage forms such as capsules or tablets. In particular, when the drug administered in such dosage forms is a high-dose drug and the drug is formulated with pharmaceutical excipients in amounts typical of those contained in commercially available dosage forms, each dosage form must be manufactured at great length or the dose must be divided into two or more dosage forms that must be swallowed simultaneously. Summary of the Invention [Problem to be solved by the invention]

[0006] It is therefore desirable to develop sustained release oral dosage forms in which the drug is formulated with reduced amounts of excipients to allow for a reduction in the overall size of the dosage form and to improve swallowability without compromising its sustained release properties. [Means for solving the problem]

[0007] Surprisingly, it has been found that water-insoluble ethylcellulose, when used as an excipient in a mixture with a biologically active ingredient, is capable of forming a stable hydrogel at a temperature of 37° C. and results in sustained release of the active ingredient, even when used at much lower concentrations than those of HPMC used in commercial formulations and in the melt-extruded compositions disclosed in EP 1978940 B1.

[0008] Accordingly, the present invention relates to a sustained release solid composition for oral administration comprising a physiologically active ingredient embedded in a polymer matrix of water-insoluble ethylcellulose having a DS(ethyl) of at least 1.8, wherein the concentration of ethylcellulose is 0.1-20%, based on the dry weight of the active ingredient, and wherein the ethylcellulose constitutes at least 50% by weight of the polymer matrix. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is a graph showing the release of acetaminophen (APAP) over time from compositions of the present invention containing solutions of ETHOCEL Standard 20 Premium (20% solution, shown as -●-), and ETHOCEL Standard 100 Premium (10% and 15% solutions, shown as -▲- and -■-, respectively) when HPMC capsules containing the dry compositions are immersed in 900 ml of 0.1 N HCl (pH 1.1). [Diagram 2] FIG. 1 is a graph showing the release of APAP over time from compositions of the present invention containing 10% and 20% by weight solutions of ETHOCEL Std. 10 FP (shown as -●- and -▲-, respectively) when compressed tablets containing the dry composition are immersed in 900 ml of 0.1 N HCl (pH 1.1). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In the present invention, ethylcellulose is an essential component of the composition in order to form a hydrogel in an aqueous environment, such as the stomach, upon oral administration of the composition and to provide sustained release of the active ingredient, even if the ethylcellulose is present in a very low concentration compared to the active ingredient.

[0011] Ethyl cellulose is composed of anhydroglucose units linked by one to four bonds. 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 cellulose fibers with a caustic solution followed by an ethylating agent yields cellulose ethers substituted with one or more ethoxy groups. If not further substituted with other alkyls, the cellulose derivative is known as ethyl cellulose.

[0012] The inventors have surprisingly found that ethylcellulose, in which the hydroxyl groups of the anhydroglucose units are replaced by ethyl groups up to a DS(ethyl) of 1.8 or higher, can form a stable hydrogel at about 37° C. when included in the composition at a concentration sufficient to embed particles of active ingredient. Although such concentrations can vary within a wide range, and generally, a more sustained release can be obtained when the ethylcellulose is at a higher concentration (e.g., 30-60% by weight), it has surprisingly been found that a low concentration of ethylcellulose, i.e., 20% or less based on the dry weight of the active ingredient, can be sufficient to embed the active ingredient to provide a sustained release of the active ingredient over a 24 hour period. The concentration of ethylcellulose included in the composition is typically 0.2-18%, preferably 0.5-15%, more preferably 1-13%, even more preferably 1.5-10%, and most preferably 2.5-5%, based on the dry weight of the active ingredient. It has been shown that compositions containing about 4.0-4.5% ethylcellulose based on the dry weight of the active ingredient provide about 60%-95% release of the active ingredient over a 22 hour period. See Examples 1-5 below. The resulting sustained release dosage forms, such as tablets or capsules, are smaller in size and therefore easier to ingest. It has further been found that a satisfactory release rate can be obtained without adding any other excipients to the dosage form, although optionally a surfactant may be added during the manufacturing process as an antifoaming agent.

[0013] Ethyl cellulose preferably has a DS(ethyl) of 2.0 to 3.0, more preferably 2.2 to 2.8, even more preferably 2.3 to 2.7, even more preferably 2.4 to 2.65, and most preferably 2.5 to 2.6. The degree of ethyl substitution, DS(ethyl), also indicated as DS(ethoxy), of ethyl cellulose is the average number of OH groups replaced by ethyl groups per anhydroglucose unit.

[0014] Determination of the % ethoxyl in ethyl cellulose is carried out by Zeisel gas chromatography technique as described in ASTM D4794-94 (2003). These are then converted to the degree of substitution (DS) for the ethyl substituent according to the following formula: %Cellulose backbone = 100-[%EtO*[[M(OCH2-CH3)-M(OH)] / M(OCH2-CH3)] DS(ethyl) = [[%EtO / M(OCH2-CH3)] / (%cellulose backbone / M(AGU))] In the formula, EtO is ethoxy and AGU is an anhydroglucose unit.

[0015] Residual amounts of salt were taken into account in the conversion.

[0016] The viscosity of ethyl cellulose is generally 3-110 mPa·sec when measured as a 5% by weight solution in an 80:20 mixture of toluene and ethanol in an Ubbelohde viscometer at 25° C. The viscosity of ethyl cellulose, when measured as set forth above, may be 15-30 mPa·sec, more preferably 18-25 mPa·sec, or alternatively, the viscosity of ethyl cellulose, when measured as set forth above, may be 90-110 mPa·sec.

[0017] In an aqueous environment, ethylcellulose can gel at very low concentrations at 37° C. and form a stable hydrogel in an aqueous environment. The term "stable hydrogel", as used herein, is intended to mean a hydrogel that retains its shape and does not completely dissolve or significantly erode after immersion in 0.1 N HCl (pH 1.1) at 37° C. for 4 hours.

[0018] Examples of ethylcellulose are ETHOCEL Standard 20 Premium ethylcellulose, ETHOCEL Standard 100 Premium ethylcellulose, and ETHOCEL Standard 10 FP (available from DuPont).

[0019] Ethylcellulose is useful as an excipient for sustained release dosage forms, meaning that it has the ability to regulate the release of active ingredients from the dosage form over an extended period of time. The term "sustained release" is used synonymously herein with the term "controlled release". Sustained release is an approach that makes an active ingredient, such as a bioactive compound, available at a rate and for a period of time designed to achieve an intended effect. Ethylcellulose is useful to form all or part of a polymer matrix in which the active ingredient is embedded. The polymer matrix may additionally include one or more other polymers that can provide sustained release of the active ingredient from the dosage form. Ethylcellulose constitutes at least 50% by weight of the polymer matrix, preferably 60-100% by weight, more preferably 70-100% by weight, even more preferably 80-100% by weight, and most preferably 90-100% by weight. The polymer matrix may contain one or more other polymers, such as other cellulose ethers, e.g., hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, hydroxypropylcellulose or carboxymethylcellulose, or it may contain one or more other polysaccharides, such as sodium alginate or calcium alginate. It is generally preferred that ethylcellulose constitutes 100% by weight of the polymer matrix.

[0020] Ethylcellulose may be included in sustained release dosage forms, particularly dosage forms intended for oral administration of drugs or other bioactive ingredients and their release into the gastrointestinal tract to control the rate of absorption of the active ingredient to achieve a desired plasma profile. The combined amount of ethylcellulose and active ingredient in the dosage form is preferably at least 50%, more preferably 70%, most preferably at least 95%, based on the dry weight of the dosage form, and preferably up to 100%, more preferably up to 98%, most preferably up to 95%, based on the dry weight of the dosage form. The dosage form is designed to provide a constant or nearly constant concentration of the active ingredient in plasma with reduced fluctuations through a slow, continuous release of the active ingredient over an extended period of time, such as 4 to 30 hours, preferably 8 to 24 hours, to release all or nearly all of the active ingredient from the dosage form.

[0021] It has been found that sustained release dosage forms such as tablets and capsules in which the polymer matrix is ​​formed partially or completely from ethyl cellulose remain intact for extended periods such as at least 4 hours, preferably at least 6 hours, and under optimized conditions at least 8 hours. Without wishing to be bound by theory, it is believed that ethyl cellulose hydrates and forms a strong swelling layer on the outer surface of the dosage form upon contact with aqueous liquid at body temperature. The strong swelling layer minimizes the release of active ingredients caused by erosion of the dosage form. Since the tablet or capsule contents do not disperse (i.e., do not separate to any significant extent), the release of active ingredients is controlled by slow diffusion from the swelling layer formed by the hydration of ethyl cellulose on the outer surface of the dosage form. The strong swelling layer reduces the ingress of water into the sustained release dosage form, and the release of active ingredients, especially water-soluble active ingredients, into the aqueous environment is slowed down due to the reduced amount of water in the areas of the dosage form into which water diffuses and dissolves the active ingredients. Most surprisingly, it is concluded that ethyl cellulose, which is not soluble in water, can be hydrated in this manner to form a hydrogel.

[0022] In one embodiment, the composition includes an additive that reacts with gastric fluids upon ingestion to generate a gas, such as CO2. The generated gas is trapped in the hydrogel and, as a result, floats to the surface of the stomach contents, resulting in a prolonged gastric retention time. Prolonged gastric retention time improves the bioavailability of the active ingredient, increases the duration of release, and improves the solubility of active ingredients that do not readily dissolve in the high pH environment of the intestine. Examples of additives that generate gas upon contact with gastric fluids are alkali metal or alkaline earth metal carbonates, such as CaCO3 or Na2CO3. The concentration of the additive may be in the range of 1-5% by weight of the composition, preferably 1.5-3% by weight, such as 2% by weight.

[0023] The addition of a surfactant assists in homogeneously distributing low concentrations of liquid diluents and producing a smooth, highly viscous semi-solid paste, possibly by defoaming and emulsifying. The surfactant may be selected from conventional antifoam agents selected from the group consisting of anionic surfactants having an anionic functional group, such as sulfates, sulfonates, phosphates and carboxylates, such as alkyl sulfates, such as 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 having a cationic functional group, 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, such as modified polydimethylsiloxane-based antifoam agents, ethoxylates, fatty acid esters of glycerol, sorbitol and sucrose. The concentration of the surfactant may range from 0.1 to 1.5% by weight of the composition.

[0024] In one embodiment of the present invention, the composition comprising ethylcellulose mixed with an active ingredient is in the form of a dry powder. The dry powder may be prepared in a manner known in the art by preparing a solution of ethylcellulose in an organic solvent such as ethanol, methanol, isopropanol or acetone, or a mixture thereof with water, mixing the solution with the active ingredient and, optionally, one or more solid excipients, and drying at a temperature of 40-100°C until the mixture has a water 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, for example less than 1% by weight, followed by milling or grinding the mixture to granules of the desired particle size. The dry powder will typically contain granules containing the active ingredient partially or completely embedded in ethylcellulose, which promotes the sustained release of the active ingredient as shown above.

[0025] In one embodiment, the present invention relates to a unit dosage form comprising the composition. The unit dosage form is intended for oral administration and may be in the form of a tablet comprising a compressed dry composition, for example in the form of a compressed granule of the dry composition. Alternatively, the unit dosage form may be in the form of a tablet or pellet prepared by extruding a semi-solid paste prepared as described above, cutting the extruded mass into suitable diameters, followed by drying. The tablet may optionally contain one or more other excipients, such as the cellulose derivatives mentioned above, but preferably ethylcellulose is the only polymeric matric forming excipient contained in the dosage form, except that a surfactant may also be optionally included as indicated above. The unit dosage form may also be a capsule comprising the dry composition, preferably in the form of a dry granule containing a mixture of methylcellulose and the active ingredient. The unit dosage form may also be in the form of a syringe or pouch pre-filled with a wet mixture, which may be easily administered by small children.

[0026] The unit dosage form contains one or more bioactive ingredients, preferably one or more pharmaceutical agents, one or more diagnostic agents, or one or more bioactive ingredients that are useful for cosmetic or nutritional purposes. The term "pharmaceutical agent" means a compound that has beneficial prophylactic and / or therapeutic properties when administered to an individual, typically a mammal, especially a human individual. This dosage form is considered to be particularly suitable for administering high-dose drugs, i.e. drugs administered in unit doses of 500 mg or more, since it is possible to provide a unit dose containing the required amount of active ingredient in a size that makes it easier to consume. Examples of high-dose drugs are metformin, metformin hydrochloride, acetaminophen (paracetamol) or acetylsalicylic acid. Thus, each unit dosage form may typically contain 500 to 1000 mg of active ingredient.

[0027] Some embodiments of the present invention will now be described in detail in the following examples.

[0028] All parts and percentages are by weight unless otherwise stated. The following testing procedures were used in the examples.

[0029] Ubbelohde test (ethyl cellulose) In a typical embodiment, the ethyl cellulose has a viscosity of 3-110 mPa·sec in a 5% solution in an 80:20 mixture of toluene and ethanol by weight. Viscosity is determined at 25° C. in an Ubbelohde viscometer. A typical viscosity analysis is performed as follows: 57 g of an 80:20 toluene / ethanol mixture is weighed into a dry 8 oz. bottle and 3 g of ethyl cellulose is added. The bottle is placed in a mechanical shaker and shaken until all the ethyl cellulose is dissolved (approximately 20 minutes). The resulting solution is analyzed within 24 hours of preparation. For viscosity measurements, the solution is filled into an Ubbelohde viscometer, which is then placed in a 25° C. water bath until the solution equilibrates to 25° C. According to the instructions for the Ubbelohde viscometer, the solution is drawn up through a calibrated flow tube and then allowed to flow out. The flow time between the upper and lower calibration marks is stopped and the viscosity is calculated according to the instructions considering the particular capillary used for the measurement. EXAMPLES

[0030] Example 1: Release of Acetaminophen from Dry Gelatin Capsules Containing Ethylcellulose A 20% by weight solution of ethyl cellulose (ETHOCEL Std.20 Premium, available from DuPont) in ethanol was prepared. 7.00 g of finely milled acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 3.00 g of the ethyl cellulose solution until a white, homogeneous, highly viscous paste was obtained. The mixture was immediately filled into a syringe and injected into an HPMC capsule (size 00), which was then closed and sealed. The mixture was carefully dried at 60° C. overnight.

[0031] The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. and drug release was measured in a USP II dissolution apparatus at 243 nm wavelength, 100 rpm, 37° C. for 22 hours with a path length of 0.1 mm.

[0032] The release of APAP from the dry capsules is shown in Figure 1. It is evident from the figure that about 60% of the drug was released after 22 hours (indicated as -●- in the figure).

[0033] Example 2: Release of Acetaminophen from Dry Gelatin Capsules Containing Ethylcellulose A 10% by weight solution of ethyl cellulose (ETHOCEL Std.100 Premium, available from DuPont) in ethanol was prepared. 7.00 g of finely milled acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 3.00 g of the ethyl cellulose solution until a white homogeneous and highly viscous paste was obtained. The mixture was immediately filled into a syringe and injected into an HPMC capsule (size 00), which was then closed and sealed. The mixture was carefully dried at 60° C. overnight.

[0034] The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. and drug release was measured in a USP II dissolution apparatus at 243 nm wavelength, 100 rpm, 37° C. for 22 hours with a path length of 0.1 mm.

[0035] The release of APAP from the dry capsules is shown in Figure 1. It is clear from the figure that about 60% of the drug was released after 22 hours (indicated as -▲- in the figure).

[0036] Example 3: Release of Acetaminophen from Dry Gelatin Capsules Containing Ethylcellulose A 15 wt% solution of ethylcellulose (ETHOCEL Std.100 Premium, available from DuPont) in ethanol was prepared. 7.00 g of finely milled acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 3.00 g of the ethylcellulose solution until a white, homogeneous, highly viscous paste was obtained. The mixture was immediately filled into a syringe and injected into an HPMC capsule (size 00), which was then closed and sealed. The mixture was carefully dried at 60° C. overnight.

[0037] The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. and drug release was measured in a USP II dissolution apparatus at 243 nm wavelength, 100 rpm, 37° C. for 22 hours with a path length of 0.1 mm.

[0038] The release of APAP from the dry capsules is shown in Figure 1. It is evident from the figure that about 80% of the drug was released after 22 hours (indicated as -■- in the figure).

[0039] Example 4: Release of Acetaminophen from Compressed Tablets Containing Ethylcellulose A 10 wt% solution of ethylcellulose (ETHOCEL Std.10 FP, available from DuPont) in ethanol was prepared. 7.00 g of finely milled acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 3.00 g of the ethylcellulose solution until a white homogeneous viscous paste was obtained. The mixture was spread on a plate and dried at 60°C. Once completely dry, the mixture was de-lumped by hand using a pistil and compressed into tablets using a laboratory manual IR tablet press at 2 t pressure. The tablets had a weight of 500 mg and contained 95.89 wt% APAP. The tablets had a tablet hardness of 32 N.

[0040] The tablets were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. and drug release was measured in a USP II dissolution apparatus at 100 rpm, 37° C. for 22 hours at a wavelength of 243 nm with a path length of 0.1 mm.

[0041] The release of APAP from the tablets is shown in Figure 2. It is evident from the figure that about 95% of the drug was released after 22 hours (indicated as -●- in the figure).

[0042] Example 5: Release of Acetaminophen from Compressed Tablets Containing Ethylcellulose A 20 wt% solution of ethylcellulose (ETHOCEL Std.10 FP, available from DuPont) in ethanol was prepared. 7.00 g of finely milled acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 3.00 g of the ethylcellulose solution until a white homogeneous viscous paste was obtained. The mixture was spread on a plate and dried at 60°C. Once completely dry, the mixture was de-lumped by hand using a pistil and compressed into tablets using a laboratory manual IR tablet press at 2 t pressure. The tablets had a weight of 505 mg and contained 92.11 wt% APAP. The tablets had a tablet hardness of 42 N.

[0043] The tablets were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37° C. and drug release was measured in a USP II dissolution apparatus at 100 rpm, 37° C. for 22 hours at a wavelength of 243 nm with a path length of 0.1 mm.

[0044] The release of APAP from the tablets is shown in Figure 2. It is evident from this figure that about 95% of the drug was released after 22 hours (indicated as -▲- in the figure).

Claims

1. 1. A sustained release solid composition for oral administration comprising a physiologically active ingredient embedded in a polymer matrix of water-insoluble ethylcellulose having a DS (ethyl) of at least 1.8, the concentration of said ethylcellulose being 4.0-10% based on the dry weight of said active ingredient, and said ethylcellulose comprising 90-100% by weight of said polymer matrix.

2. The composition of claim 1, wherein the concentration of the ethylcellulose is 4.0 to 5%, based on the dry weight of the active ingredient.

3. The composition of claim 1 or 2, wherein the ethyl cellulose has a DS(ethyl) of 2.0 to 3.

0.

4. 4. The composition of claim 1, wherein the ethyl cellulose has a viscosity of 3 to 110 mPa seconds, measured as a 5 wt. % solution in a mixture of toluene and ethanol in a weight ratio of 80:20 at 25° C. in an Ubbelohde viscometer.

5. The composition according to any one of claims 1 to 4, further comprising a surfactant.

6. The composition according to any one of claims 1 to 5, wherein the concentration of the surfactant is in the range of 0.1 to 1.5% by weight of the composition.

7. The composition according to any one of claims 1 to 6, further comprising an additive capable of reacting with gastric fluids to generate gas.

8. The additive is an alkali metal or alkaline earth metal carbonate, for example CaCO ３ Or Na ２ CO ３ The composition of claim 7, wherein the compound is selected from the group consisting of

9. The composition according to any one of claims 1 to 8, which is in the form of a dry powder.

10. The composition according to any one of claims 1 to 9, wherein the active ingredient is selected from the group consisting of metformin, metformin hydrochloride, acetaminophen and acetylsalicylic acid.

11. A unit dosage form comprising the composition of any one of claims 1 to 10.

12. 11. A unit dosage form, wherein the composition according to any one of claims 1 to 10 is a compressed dry composition, the unit dosage form being a tablet comprising said compressed dry composition.

13. A unit dosage form, wherein the composition according to any one of claims 1 to 10 is a dry composition, the unit dosage form being a tablet comprising compressed granules of said dry composition.

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