WO2014055740A1

WO2014055740A1 - Controlled release solid dose forms

Info

Publication number: WO2014055740A1
Application number: PCT/US2013/063227
Authority: WO
Inventors: Juergen Siepmann; Rina CHOKSHI; Michael SESTRICK; Carine VELGHE
Original assignee: Fmc Corporation
Priority date: 2012-10-04
Filing date: 2013-10-03
Publication date: 2014-04-10

Abstract

The present invention is directed to a solid dose form having a film coating composition encapsulating a core, wherein: (i) the core includes an active ingredient that is at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient; (ii) the film coating composition includes ethylcellulose and locust bean gum; (iii) the dose form provides controlled release of the active ingredient; and (iv) the dose form is ethanol resistant.

Description

CONTROLLED RELEASE SOLID DOSE FORMS

FIELD OF THE INVENTION

[0001] The present invention is directed to controlled release solid dosage forms, controlled release film coating compositions, and methods for reducing the ethanol sensitivity of solid dosage forms.

BACKGROUND OF THE INVENTION

[0002] Controlled release dosage forms are designed to provide prolonged and/or delayed release of an active ingredient after the administration of the dosage form, as compared with the administration of an immediate release dosage form. Such sustained response offers many inherent therapeutic benefits that cannot be obtained with immediate release and short acting dose forms.

[0003] Controlled release dosage forms known in the art include beads, pellets, spheroids, coated capsules, coated tablets and ion exchange resins, wherein the sustained release of the active drug is realized, for example via permeation of the active drug through a coating layer or a matrix formulation to slow down the release of the drug.

[0004] An essential characteristic of all controlled release dosage forms is the stability and consistency of the release profile, which must be documented in regulatory applications. The design of controlled release dosage forms must mitigate the risk of premature release ("dose dumping") leading to overdose. Coadministration of the dosage form with ethanol may accelerate release, so reducing the sensitivity of the dosage form to the effect of ethanol is essential.

[0005] The sensitivity of controlled release dosage forms to ethanol is critical, for example, if the incorporated drug is highly potent, present at higher doses (than would be found in immediate release dose forms) and/or the undesired side effects are potentially severe. The co-ingestion of alcoholic beverages with solid dosage forms can lead to unintended high release rates and potentially fatal side effects. As a result, the sensitivity to ethanol has led to products being withdrawn from the market.

[0006] The object of this invention was to identify a novel polymeric film coating, which has reduced sensitivity to high concentrations of ethanol in the surrounding bulk fluid.

[0007] The inventors have surprisingly found that the addition of small amounts of a locust bean gum to ethylcellulose based film coatings effectively suppresses undesired acceleration of rapid drug release due to high ethanol concentrations. For example, theophylline release from matrix pellets coated with the aqueous ethylcellulose dispersion Aquacoat® ECD containing 10% locust bean gum of the invention was unaffected in the presence of 40% ethanol in the release medium.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to a solid dose form comprising a film coating composition encapsulating a core, wherein: (i) the core comprises an active ingredient comprising at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient; (ii) the film coating composition comprises ethylcellulose and locust bean gum; (iii) the dose form provides controlled release of the active ingredient; and (iv) the dose form is ethanol resistant.

[0009] The present invention is also directed to controlled release film coating compositions for solid dose forms. The film coating compositions of the invention comprise ethylcellulose and locust bean gum. The film coating composition of the invention provides controlled release of and ethanol resistance to a pharmaceutical, veterinary or nutraceutical active ingredient contained within a solid dose form containing the film coating composition.

[0010] In another embodiment, the present invention is also directed to controlled release film coating compositions for solid dose forms, the film coating compositions consisting essentially of ethylcellulose and locust bean gum. The film coating composition of the invention provides controlled release of and ethanol resistance to a pharmaceutical, veterinary or nutraceutical active ingredient contained within a solid dose form containing the film coating composition.

[0011] In yet another embodiment, the present invention is directed to a method of reducing the ethanol sensitivity of a pharmaceutical, nutraceutical or veterinary active ingredient in the core of a solid dosage form comprising coating the core with a film coating composition comprising ethylcellulose and locust bean gum. The film coating composition of the invention provides controlled release of and ethanol resistance to the active ingredient in the solid dose form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows theophylline release from drug matrix pellets coated with a 90: 10 blend of ethylcellulose:locust bean gum (Grindsted® LBG 047 having an apparent viscosity of 56.3 cPs when measured using the stepped flow procedure described herein) (1 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 %).

[0013] Figure 2 shows theophylline release from drug matrix pellets coated with a 90: 10 blend of ethylcellulose:locust bean gum (Grindsted® LBG 147 having an apparent viscosity of 25.9 cPs when measured using the stepped flow procedure described herein) (1 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 %).

[0014] Figure 3 shows theophylline release from drug matrix pellets coated with a 90: 10 blend of ethylcellulose:locust bean gum (Grindsted® LBG 246 having an apparent viscosity of 22.8 cPs when measured using the stepped flow procedure described herein) (1 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 %).

[0015] Figure 4 shows theophylline release from drug matrix pellets coated with a 90: 10 blend of ethylcellulose:locust bean gum (Grindsted® LBG 860 having an apparent viscosity of 459 cPs when measured using the stepped flow procedure described herein) (1 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 %).

[0016] Figures 5 (a) and (b) show theophylline release from drug matrix pellets coated with a (a) 85:15 or (b) 90:10 blend of ethylcellulose:locust bean gum (Polygum 16/1-125 having an apparent viscosity of 573 cPs when measured using the stepped flow procedure described herein) (1 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 ).

[0017] Figure 6 shows theophylline release from drug matrix pellets coated with a 90: 10 blend of ethylcellulose: locust bean gum (Polygum 14/1-85 having an apparent viscosity of 18.4 cPs when measured using the stepped flow procedure described herein) (0.7 % locust bean gum in the total coating dispersion) upon exposure to: (i) 0.1 M HC1 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (filled squares), or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours and phosphate buffer pH 7.4 for the subsequent 6 hours (open squares); (coating level: 20 ).

DETAILED DESCRIPTION OF THE INVENTION

[0018] "Dose dumping," as defined by the FDA, is the unintended, rapid release of a significant portion of a drug from a controlled release dosage form (Meyer, et al, "Awareness Topic: Mitigating the Risks of Ethanol Induced Dose Dumping From Oral Sustained/Controlled Release Dosage Forms," FDA's ACPS Meeting, October, 2005). This phenomenon can, for example, be caused by the consumption of alcoholic beverages, leading to high ethanol concentrations in the contents of the stomach (Roth et al., "Ethanol Effects on Drug Release From Verapamil Meltrex, an Innovative Melt Extruded Formulation," Int. J. Pharm., 368, 72-75, 2009). If drug release is controlled by a polymer, which is insoluble in water and the contents of the stomach under "normal" conditions, but soluble in aqueous media containing significant amounts of ethanol, the co-ingestion of alcoholic beverages can lead to unintended polymer dissolution. Thus, drug release can be rapid, instead of being controlled during prolonged periods of time. This is true for drug reservoirs, which are surrounded by release rate controlling polymeric films, as well as for drug matrix systems, in which the drug is embedded within a polymeric matrix. Surprisingly, the inventors have identified a coating composition containing ethylcellulose and locust bean gum that reduces ethanol sensitivity in a solid dose form containing the film coating.

[0019] The solid dose forms of the present invention are ethanol resistant or, said differently, not sensitive to ethanol. In general, this means that the release kinetics of the active ingredient are not significantly affected by the presence of alcohol. More specifically, as used herein, a solid dosage form is ethanol resistant (or not sensitive to ethanol) if the in vitro drug release data in 0.1 M HC1 is compared with and without 40% ethanol for 2 hours at 37 °C and the difference throughout the two hour period in release profiles between the ethanol free media and ethanol containing media is (i) less than 15%, more preferably, less than 7.5%, when less than 20% of the active is released in the ethanol free media, and (ii) less than 30%, more preferably, less than 15%, when between 20 and 40%, preferably, 20-50%, more preferably, 20-80%, of the active is released in ethanol free media. A typical apparatus for determining the dissolution profile is USP 32 paddle apparatus (900 ml, 37 °C, 100 rpm).

[0020] In addition to being ethanol resistant throughout the two hour period as noted in the foregoing definition, the present invention has also been found to have the ability to maintain a controlled release of the solid dosage form when subsequently and immediately placed (after the two hour period in 0.1 M HC1 with and without 40% ethanol at 37 °C) in phosphate buffer at pH 7.4 at 37 °C for at least three hours, at least four hours, at least five hours, at least six hours, at least seven hours, and at least eight hours; i.e., the difference in release profiles between the ethanol free media and ethanol containing media throughout the two hour period in 0.1 M HC1 (with and without 40% ethanol) at 37 °C and thereafter throughout the at least three hour period (or, the at least four hour period, five hour period, six hour period, seven hour period or eight hour period) in phosphate buffer at pH 7.4 at 37 °C is (i) less than 15%, more preferably, less than 7.5%, when less than 20% of the active is released in the ethanol free media, and (ii) less than 40%, more preferably, less than 20%, when between 20 and 40%, preferably, 20-50%, more preferably, 20-80%, of the active is released in ethanol free media.

[0021] Immediate release of drug is often considered to be greater than 85% of the drug released in less than 15 minutes when measured in vitro in accordance with the following standard test: the dosage form is exposed to 900 mL 0.1 M HC1 in a USP 32 paddle apparatus (37 °C, 100 rpm). At pre-determined time points, samples are withdrawn and their drug contents analyzed using an appropriate analytical technique for the respective drug. Controlled release, as used herein, encompasses any release profile that is not immediate release and includes less than 85% drug released in greater than 15 minutes and 100% drug released in, for example, 2 hours, 4 hours, 6 hours or anywhere from 8 to 12 hours or longer all as measured with the following test: the dosage form is exposed to 900 mL 0.1 M HC1 in a USP 32 paddle apparatus (37 °C, 100 rpm). At pre-determined time points, samples are withdrawn and their drug contents analyzed using an appropriate analytical technique for the respective drug. Optionally, the release medium is partially or completely replaced after more than 1 h, e.g., completely replaced by phosphate buffer pH 7.4 (USP 32, 37 °C, 100 rpm) after 2 hours. Controlled release, as used herein, includes delayed release, enteric release, pulsatile release, sustained release, programmed release rates, and extended release.

[0022] In one embodiment, the present invention is directed to a solid dose form comprising a film coating composition encapsulating a core, wherein: (i) the core comprises an active ingredient comprising at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient; (ii) the film coating composition comprises ethylcellulose and locust bean gum; (iii) the dose form provides controlled release of the active ingredient; and (iv) the dose form is ethanol resistant.

[0023] In the present invention, the ethylcellulose is used in an aqueous dispersion. Typical aqueous dispersions can contain 20-40 wt ethylcellulose. Commercially available ethylcellulose aqueous dispersions are, for example, available from FMC Corporation and sold under the name Aquacoat® ECD and from Colorcon sold under the name Surelease®. Aquacoat® ECD is an aqueous dispersion containing 30% by weight ethylcellulose.

[0024] Locust bean gum is a natural polysaccharide extracted from the seeds of the carob tree (Certonia siliqua). Locust bean gum is capable of being soluble in water. Consequently, pure locust bean gum coatings of insufficient thickness when ingested may not allow for controlled oral drug delivery. Various embodiments of the present invention are produced by blending locust bean gum dissolved in water with an aqueous dispersion containing ethylcellulose.

[0025] The apparent viscosity of the locust bean gum as provided herein is measured at a shear rate of 50 s^"1 in a 1% aqueous gum solution measured rotationally at 20°C after 5 minute equilibration using a 4 cm acrylic cone (2°) on a cone-plate viscometer, wherein the shear is ramped up linearly from 1 to 50 s^"1 over 5 minutes. A typical example of such a cone-plate viscometer is an AR1000N rheometer (TA Instruments, New Castle, DE USA). This procedure is often referred to as a stepped flow procedure. Unless otherwise indicated, all viscosities referred to herein are apparent viscosities obtained using this specific stepped flow procedure.

[0026] Locust bean gums, and mixtures thereof, within a wide range of apparent viscosities have been found to be useful in the present invention. While not critical to the invention, various embodiments of the present invention may include locust bean gums having an apparent viscosity of from 0.1 to 2000 cps, more particularly, from 10 to 1000 cps, and, more particularly, from 15 to 600 cps.

[0027] The 1) ratio of ethylcellulose to locust bean gum in the coating composition, and 2) locust bean gum concentration in the coating dispersion, used in the invention are determined based on the composition which provides optimal processing and results in a coating that is ethanol resistant. If the coating dispersion is too viscous, it is difficult to spray or apply, resulting in an increase in processing time. If the coating dispersion is highly diluted (exhibiting low viscosity), processing time also increases due to the need for continuous coating to achieve the acceptable polymer weight gain. Thus, the 1) optimum ratio of ethylcellulose to locust bean gum in the coating composition, and 2) optimum locust bean gum concentration in the coating dispersion, will be those that will impart ethanol resistance and provide a minimum processing time which may be easily determined using procedures known to one of ordinary skill in the art. The weight % ratio of the ethylcellulose to locust bean gum typically used in the present invention may be any one of the following including any and all ranges by and between the following: 60:40; 61:39; 62:38; 63:37; 64:36; 65:35; 66:34; 67:33; 68:32; 69:31; 70:30; 71:29; 72:28; 73:27; 74:26; 75:25; 76:24; 77:23; 78:22; 79:21; 80:20; 81:19; 82:18; 83:17; 84: 16; 85:15; 86:14; 87:13; 88:12; 89: 11; 90:10; 91:9; 92:8; 93:7; and 94:6; all weight % ratios are ethylcellulose to locust bean, respectively. For example, the weight % ratio of the ethylcellulose to locust bean gum typically used in the present invention is from 85:15 to 90: 10, respectively.

[0028] The film coating composition of the invention may contain a plasticizer. The plasticizer may reduce the glass transition temperature (Tg) so that films formed at a suitable film forming temperature are softer, more ductile, and have increased mechanical stress. Examples of suitable plasticizers include dibutyl sebacate, diethyl phthalate, acetyltriethyl citrate, triethyl citrate, tibutyl citrate, triacetin, acetylated monoglycerides, phthalate esters, castor oil, etc. Triethyl citrate and dibutyl sebacate are especially preferred plasticizers for use in the aqueous dispersions of this invention. When used, the plasticizer is typically added to the ethylcellulose aqueous dispersion after the ethylcellulose dispersion is prepared, unless the ethylcellulose aqueous dispersion is pre-plasticized, using known techniques and is present in a typical amount of about 1 to about 50 % by weight of the ethylcellulose.

[0029] The film coating composition may also contain a stabilizer that decreases the surface energy of the aqueous ethylcellulose dispersion. Examples include surfactants such as sodium dodecyl sulfate and cetyl alcohol. [0030] The film coating composition may also contain an anti-tacking agent, such as talc, to reduce sticking during coating.

[0031] Typically, the active ingredient is present in the solid dosage form in an amount of from 1 μg to 1 g.

[0032] The coating of the present invention may be coated on a wide variety of cores, such as pellets, tablets, soft capsules, hard capsules, powders, granules, beads, films and film-enrobed dosage forms, microspheres, seeds, ion-exchange resin beads, and other single unit or multi-particulate systems, in order to obtain a desired controlled release of the therapeutically active agent. Granules, spheroids, or pellets, etc., prepared in accordance with the present invention can be presented in a capsule or film-enrobed dosage form or in any other suitable dosage form. They can be mixed with other drug preparations, or they can be mixed with other vehicles and drugs or particles that contain drugs or particles that have been subjected to film coating, after which they can be compressed into tablets or filled into capsules.

[0033] A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, sulindac), gastro-intestinals and anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. theophylline), anti-spasmodics (e.g. atropine, scopolamine), hormones (e.g., insulin, leparin), diuretics (e.g., eltacrymic acid, bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), bronchodilators (e.g., albuterol), anti-inflammatory steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and mixtures thereof. The above list is not meant to be exclusive.

[0034]In certain preferred embodiments, the therapeutically active agent comprises hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing, and the like. In one preferred embodiment, the therapeutically active agent comprises aspirin, ibuprofen, or acetaminophen and their mixtures with other pharmaceutically compatible, therapeutically active agents.

[0035] When the controlled release coating of the present invention is to be applied to tablets, the tablet core (e.g. the substrate) may comprise the active agent along with any pharmaceutically accepted inert pharmaceutical filler (diluent) material, including, but not limited to, sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures thereof and the like. Also, an effective amount of any generally accepted pharmaceutical lubricant, including calcium or magnesium salts may be added to the above-mentioned ingredients of the excipient prior to compression of the tablet core ingredients. Most preferred is magnesium stearate in an amount of about 0.5-3% by weight of the solid dosage form.

[0036] In another embodiment, the present invention is also directed to the controlled release film coating compositions described herein.

[0037] In a further embodiment, the present invention is directed to a method of reducing the ethanol sensitivity of a pharmaceutical, nutraceutical or veterinary active ingredient in the core of a solid dosage form comprising coating the core with the film coating composition described herein. The film coating composition provides controlled release of and ethanol resistance to the active ingredient.

[0038] The process for making, using and coating the film coating composition on the solid dosage form can be any of those known in the field. An example of film coating preparations and coating processes are disclosed in US 7,829,148 (incorporated herein by reference). The dispersion containing the ethylcellulose and locust bean gum is typically coated on a dry solids basis in an amount of 1 to 60%, preferably 10-40%, more preferably, 10-20%, by weight of the total dose form.

[0039] The present invention is now described in more detail by reference to the following examples, but it should be understood that the invention is not construed as being limited thereto. Unless otherwise indicated herein, all parts, percents, ratios and the like are by weight.

EXAMPLES

Materials

[0040] Theophylline matrix pellets (70 % drug content, diameter: 0.71-1.25 mm; FMC BioPolymer, Philadelphia, PA, USA); Ethylcellulose Aqueous Dispersion NF (Aquacoat® ECD 30D; FMC BioPolymer); locust bean gum: Grindsted® LBG 047 (Danisco, Paris, France; apparent viscosity of a 1 % aqueous solution = 56.3 cPs), Grindsted® LBG 147 (apparent viscosity of a 1 % aqueous solution = 25.9 cps), Grindsted® LBG 246 (apparent viscosity of a 1 % aqueous solution = 22.8 cps), Grindsted® LBG 860 (apparent viscosity of a 1 % aqueous solution = 459 cPs), Polygum 16/1-125 (Polygal, Maerstetten, Switzerland; apparent viscosity of a 1 % aqueous solution = 573 cPs), Polygum 14/1-85 (apparent viscosity of a 1 % aqueous solution = 18.4 cPs); dibutyl sebacate (DBS; Morflex, Greensboro, NC, USA); ethanol (Fisher Bioblock Scientific, Illkirch, France). All apparent viscosities were measured using an AR1000N rheometer at a shear rate of 50 s^"1 in a 1% aqueous locust bean gum solution measured rotationally at 20°C after 5 minute equilibration using a 4 cm acrylic cone (2°), wherein the shear was ramped up linearly from 1 to 50 s^"1 over 5 minutes. All coating levels, unless otherwise indicated, refer to the amount of the coating (wt%) on a dry solids basis by weight of the uncoated dose form.

Pellet coating

[0041] Theophylline matrix cores were coated with different Aquacoat® ECD:locust bean gum blends. Aquacoat® ECD was plasticized for 1 day with 25 % DBS (w/w, based on the ethylcellulose content). Locust bean gum was dissolved in purified water (0.7 % or 1 % w/w, as indicated). In all cases, the 100 % reference value was the total coating formulation and the stirring time was 2 h. The two liquids (plasticized Aquacoat® ECD dispersion and aqueous solution of locust bean gum) were blended and stirred for 30 min prior to use. The coating dispersions were sprayed onto theophylline pellets using a fluidized bed coater (Strea 1, Wurster insert; Niro; Aeromatic-Fielder, Bubendorf, Switzerland). The process parameters were as follows: inlet temperature = 38 °C, product temperature = 38 + 2 °C, spray rate = 2g/min, atomization pressure = 1.2 bar, nozzle diameter = 1.2 mm. After coating the pellets were further fluidized for 10 minutes and subsequently cured for 24 hours at 60 °C in an oven.

Drug release measurements

[0042] Theophylline release from coated pellets was separately measured in each of 0.1 M HC1 and 0.1 M HC1: ethanol 60:40, followed by phosphate buffer pH 7.4 (USP 32) using the USP 32 paddle apparatus (Sotax, Basel, Switzerland) (900 mL, complete medium change after 2 h; 37 °C, 100 rpm; n = 3). At pre-determined time points, 3 mL samples were withdrawn and analyzed UV-spectrophotometrically (λ = 270.4 nm in 0.1 N HC1, λ = 272.2 nm in 0.1 M HCl:ethanol 60:40 and phosphate buffer pH 7.4) (UV 1650 PC, Shimadzu, Champs-sur-Marne, France). The ethanol concentration was intentionally high to simulate "worst case" conditions in vivo (consumption of beverages with significant ethanol content).

EXAMPLE 1

[0043] Theophylline release was measured from drug matrix pellets coated with ethylcellulose:locust bean gum 90: 10 blends (coating level: 20 ) into (i) 0.1 M HC1 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HC1: ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum had an apparent viscosity of 56.3 cPs.

[0044] The percent of theophylline released over 8 hours in the solutions of 0.1 M HC1 and 0.1 M HCl:ethanol followed by phosphate buffer is provided below in Table 1 and illustrated in Figure 1 : Table 1

% drug % drug

released in released in

HCI HC!:E|OH difference in time, h + PBS 7.4 * PBS 7.4 drug release

0.00 0.00 0.00 0.00

0.25 0.34 2.27 1.92

0.50 2.11 4,86 2.75

0.75 4.09 7.59 3.50 1 .00 5.88 9.19 3.32

1.50 9.38 14.26 ■4.88

2.00 12.22 19.92 7.70

3..00 15..08 25.39 10.31

4 00 22.39 31.95 9.56

5.00 29.02 3-8.48 8.57

^■6.00 37 62 43.78 6.15

7.00 46.41 50.13 3.78

8.00 53.37 55.77 2.40

[0045] As demonstrated in Table 1, at no time is the difference between the release profiles for the coated drug matrix pellet in 0.1 M HQ and 0.1 M HQ:ethanol greater than 15%, thus demonstrating ethanol resistance.

EXAMPLE 2

[0046] Theophylline release was measured from drug matrix pellets coated with ethylcellulose:locust bean gum 90:10 blends (coating level: 20 %) into (i) 0.1 M HQ for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HQ: ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum had an apparent viscosity of 25.9 cPs.

[0047] The percent of theophylline released over 8 hours in the solutions of 0.1 M HQ and 0.1 M HQ:ethanol followed by phosphate buffer is provided below in Table 2 and illustrated in Figure 2: Table 2

% drug % drug

rei eased: irs released in

HCS HCt:EtOH difference in

+ PBS 7.4 + PBS 7. drug release

0.00 0.00 0.00 0.00

0.25 1.47 2 79 1.32

0,50 4.16 6. 3 1.97

0.75 6.40 8. Θ4 165

100 7.65 9.Θ1 2.17

150 11.16 14.67 3.51

2.00 15.30 2s.es 5.58

3.00 18.52 26.43 7 91

4.00 25.24 31 29 6.05

5.00 31.20 37.4 6:21

6.00 39.35 43.23 3,88

7.00 46.55 48.96 2.41

8 00 53.93 53.99 0 01

[0048] Similar to Example 1, the coating composition of Example 2 is ethanol resistant because at no time is the difference between the release profiles for the coated drug matrix pellet in 0.1 M HQ and 0.1 M HCl:ethanol greater than 15%.

EXAMPLE 3

[0049] Theophylline release was measured from drug matrix pellets coated with ethylcellulose:locust bean gum 90:10 blends (coating level: 20 %) into (i) 0.1 M HQ for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HQ: ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum had an apparent viscosity of 22.8 cPs.

[0050] The percent of theophylline released over 8 hours in the solutions of 0.1 M HQ and 0.1 M HQ:ethanol followed by phosphate buffer is provided below in Table 3 and illustrated in Figure 3 : Table 3

% drug % drug

released in released in

HCI:E¾Oj| difference

+ PBS 7,4 + PBS 7.4 drug release

0.00 0.00 0.00 0.00 0,25 o.?s 138 0.61

0,50 2,51 4.22 170

0.75 3,44 5.78 2 33

100 4 65 7.38 3.23

150 6.63 11,63 5,01

2,00 9,08 15.99 6.91

3.00 12.32 22,56 10.24

4.00 20.66 25,82 5 17

5.00 24.47 3159 7.11

6.00 29.35 35,96 6.61

7.00 35.55 4127 5.72

3 OQ 41,33 46.57 5.25

[0051] Again, similar to Examples 1 and 2, the coating composition of Example 3 is ethanol resistant because at no time is the difference between the release profiles for the coated drug matrix pellet in 0.1 M HCl and 0.1 M HCl:ethanol greater than 15%.

EXAMPLE 4

[0052] Theophylline release was measured from drug matrix pellets coated with ethylcellulose:locust bean gum 90:10 blends (coating level: 20 %) into (i) 0.1 M HCl for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HCl: ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum had an apparent viscosity of 459 cPs.

[0053] The percent of theophylline released over 8 hours in the solutions of 0.1 M HCl and 0.1 M HCl: ethanol followed by phosphate buffer is provided below in Table 4 and illustrated in Figure 4: Table 4

% drug % drug

released in released in

HCl HCl: EtOH difference in time, h * PBS 7.4 + PBS 7.4 drug release

a oo 0.00 0.00 0.00

0.25 3.57 ■4.2 0.65

0.50 7.75 8.60 0.85

0.75 11.65 14.28 2.63

1.00 15.56 19.95 4.40

1.50 23.18 27,66 4,48

2.00 32.35 38.28 5.93

2.50 35.09 ■43.37 8.27

3..00 40 35 ■48. 7 7,82

4.00 54.11 60.26 6.16

5.00 bb.32 71.41 4.59

6.00 79.31 81.13 1.82

7.00 87.27 87.99 0.71

8.00 92.02 92.37 0.35

[0054] The coating composition of Example 4, similar to Examples 1-3 is ethanol resistant because at no time is the difference between the release profiles for the coated drug matrix pellet in 0.1 M HCl and 0.1 M HCl:ethanol greater than 15%.

EXAMPLE 5

[0055] Theophylline release was measured from drug matrix pellets coated with two different compositions, ethylcellulose:locust bean gum 90:10 and 85:15 blends (coating level: 20 %), into (i) 0.1 M HCl for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HCl: ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum for both blends had an apparent viscosity of 573 cPs.

[0056] The percent of theophylline released over 8 hours in the solutions of 0.1 M HCl and 0.1 M HCl:ethanol followed by phosphate buffer for the drug matrix pellet coated with a composition having a 85:15 ethylcellulose:locust bean gum blend is provided below in Table 5a and illustrated in Figure 5a:

Table 5 a

% drug % drug

released in released in

HCl HCLEtOH difference in time, h + PBS 7. + PBS 7,4 drug release

0.00 0.00 9.00 0 00

0.25 11.59 10 46 1.13

0 50 21.37 22 19 0.82

0.75 29,08 32.45 3 37

1.00 35.94 49.35 14.00

1.50 46.07 70.80 24.73

2.GG 53.88 S2.78 28.30

2,50 60.62 91.94 31.32

3.00 64.12 32.76 28,64

4.00 76.98 98.26 2 .28

D. Γ' ίΓU! EJD.U t O SO3 R DOQ t f R Do<¾

6:00 93,60 100.84 7.25

7.00 36 81 99.70 2.89

[0057] At 2.00 hours, the percent of theophylline released in the 0.1M HCl solution was 53.88%. Therefore, in order to qualify as ethanol resistant, the difference in the release profiles between the theophylline released in the 0.1M HCl solution with and without ethanol should be less than 30% throughout the 2 hour period, which was exhibited. Thus, the composition is ethanol resistant.

[0058] The percent of theophylline released over 8 hours in the solutions of 0.1 M HCl and 0.1 M HCl:ethanol followed by phosphate buffer for the drug matrix pellet coated with a composition having a 90:10 ethylcellulose:locust bean gum blend is provided below in Table 5b and illustrated in Figure 5b: Table 5b

% drug % drug

released in released in

HCi HCI:EtOH difference in time, h + PB S 7.4 ÷^■ PBS 7.4 drug release

0.00 0.00 0.00 0.00

0.25 3 20 3.80 0.50

0,50 5,30 7.98 2.69

u. o . ^■ί Ϊ Ζ Λ ΠΟ

. Ο ί 4. s

100 9 48 17.56 8.37

150 13.17 26.55 13.37

2.00 1S.35 37,07 20.71

2.50 18.07 38,43 20:36

3.00 20 54 41.50 20.96

4.00 30.20 50.17 19.88

5,00 37.99 57,5 19,52

6. 0 46.36 65,40 19.04

7.00 55,55 73,86 1830

8.00 62.91 79.77 16,86

[0059] At 2.00 and 2.50 hours, the percent of theophylline released in the 0.1M HCl solution in Table 5b was less than 20%; however, the difference in the release profiles between the theophylline released in the 0.1M HCl solution with and without ethanol at those times exceeded 15%. At 3.00 hours, when the percent of theophylline released in 0.1 M HCl increased above 20%, the difference in the release profiles remained below 30%. Therefore, the 90:10 blend exhibited a brief period for approximately 1 hr in which the amount of theophylline released in a HCl:ethanol solution was not consistent with an ethanol resistant coating. This indicates that for this locust bean gum obtained from Polygal, the preferred ethylcellulose:locust bean gum blend in a coating composition would contain more than 10 % locust bean gum.

EXAMPLE 6 [0060] Theophylline release was measured from drug matrix pellets coated with ethylcellulose:locust bean gum 90:10 blends (coating level: 20 ) into (i) 0.1 M HCl for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours, or (ii) 0.1 M HCl:ethanol 60:40 for 2 hours, followed by phosphate buffer pH 7.4 for 6 hours. The locust bean gum had an apparent viscosity of 18.4 cPs.

[0061] The percent of theophylline released over 8 hours in the solutions of 0.1 M HCl and 0.1 M HCl:ethanol followed by phosphate buffer is provided below in Table 6 and illustrated in Figure 6:

Table 6

% drug % drag

re teased in released in

HCl: HCtrEtOH dfffererace in time, h + PBS 7,4 + PBS 7.4 drug release

0 00 0.00 0.00 0.00

025 1 .09 3,48 2.39

0.50 2.60 5.55 2.75

0.75 4 68 764 2.96

1.00 8.63 9.26 2.63

2.00 12.51 19.6» 7,18

3.00 14,88 23.84 8.96

4 00 20.08 31.28 10.30

5.00 27.52 37.05 9.52

6.00 36.05 43.21 7.16

7..00 43.67 48.53 4,86

8.00 51.08 53.83 2.76:

[0062] The coating composition of Example 6, similar to Examples 1-4 is ethanol resistant because at no time is the difference between the release profiles for the coated drug matrix pellet in 0.1 M HCl and 0.1 M HCl:ethanol greater than 15%.

Claims

WHAT IS CLAIMED IS:

1. A solid dose form comprising a film coating composition encapsulating a core, wherein:

(i) said core comprises an active ingredient comprising at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient;

(ii) said film coating composition comprises ethylcellulose and locust bean gum;

(iii) said dose form provides controlled release of said active ingredient; and

(iv) said dose form is ethanol resistant.

2. The solid dose form of claim 1, wherein the difference between the release profile of said active ingredient in (i) 0.1M HC1 for two hours at 37 °C and subsequently in phosphate buffer at pH 7.4 for three hours at 37 °C and (ii) 0.1M HC1 and 40% ethanol at 37 °C for two hours and subsequently in phosphate buffer at pH 7.4 for at least three hours at 37 °C is less than 15% when less than 20% of the active is released in ethanol free media and less than 30% when greater than 20 to 40% of the active is released in the ethanol free media.

3. The solid dose form of claim 1, wherein said viscosity of said locust bean gum is from 15 cps to 600 cps.

4. The solid dose form of claim 1 , wherein a wt % ratio of said ethylcellulose to locust bean gum is from 60:40 to less than 95:5, respectively.

5. The solid dose form of claim 4, wherein said ratio is 70:30 to 93:7, respectively.

6. The solid dose form of claim 4, wherein said ratio is 80:20 to 92:8, respectively.

7. The solid dose form of claim 4, wherein said ratio is 85:15 to 90:10, respectively.

8. The solid dose form of claim 4,wherein said ratio is 90: 10, respectively.

9. The solid dose form of any preceding claim, wherein said coating composition further comprises a plasticizer.

10. The solid dose form of any preceding claim, wherein said film coating composition further comprises at least one of a surfactant or anti-tack agent.

11. The solid dose form of any preceding claim, wherein said core comprises pellets, tablets, soft capsules, hard capsules, powders, granules, beads, films and film-enrobed dosage forms, microspheres, seeds, ion-exchange resin beads, and other single unit or multi-particulate systems.

12. The solid dose form of claim 1, wherein said locust bean gum has an apparent viscosity greater than 15 cps.

13. A film coating composition comprising ethylcellulose and locust bean gum, wherein said film coating composition provides controlled release of and ethanol resistance to a pharmaceutical, veterinary or nutraceutical active ingredient contained within a solid dose form containing said film coating composition.

14. The film coating composition of claim 13, wherein said viscosity of said locust bean gum is from 15 cps to 600 cps.

15. The film coating composition of claim 13, wherein a wt % ratio of said ethylcellulose to locust bean gum is from 70:30 to 93:7, respectively.

16. The film coating composition of claim 13 further comprising a plasticizer.

17. The film coating composition of claim 13, wherein said locust bean gum has an apparent viscosity greater than 15 cps.

18. A method of reducing the ethanol sensitivity of a pharmaceutical, nutraceutical or veterinary active ingredient in the core of a solid dosage form comprising coating said core with a film coating composition comprising the film coating composition of claim 13, wherein said film coating composition provides controlled release of and ethanol resistance to said active ingredient.

19. A film coating composition consisting essentially of ethylcellulose and locust bean gum, wherein said film coating composition provides controlled release of and ethanol resistance to a pharmaceutical, veterinary or nutraceutical active ingredient contained within a solid dose form containing said film coating composition.