ZA200400192B - Pharmaceutical compositions containing terbinafin and use thereof. - Google Patents

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING TERBINAFIN AND USE THEREOF

The invention relates to pharmaceutical compositions of terbinafine, in particular solid . dosage forms for oral administration, and their use, in particular in the intermittent treatment of fungal infections, especially onychomycosis.

Terbinafine is known from e.g. EP-A-24587. It belongs to the class of allylamine anti-mycotics. It is commercially available under the trademark Lamisil. Terbinafine is effective upon both topical and oral administration, in a wide range of fungal infections.

Terbinafine is particularly useful against dermatophytes, contagious fungi that invade dead tissues of the skin or its appendages such as stratum corneum, nail, and hair.

Terbinafine may be in free base form or in e.g. pharmaceutically acceptable salt form, e.g. the hydrochloride, lactate, ascorbate or malate, e.g. L.(+)-hydrogen malate form.

It preferably is in the hydrochloride acid addition salt form. An acid addition salt form may be prepared from the free base form in conventional manner and vice-versa.

Nail fungi make their home in the nail bed, shielded by the hard outer nail. Thus once the infection is established under the nail, the nail itself provides the fungus with a protective environment that allows it to grow. The effects of these fungi on the nails may be unsightly, seriously complicate foot-care, have a deleterious impact on patients’ overall quality of life and well-being and impair the patients’ ability to work. If left untreated, the fungi can deform toenails permanently and lead to pain on walking. Additionally the fungi can lead to fissures in the skin, encouraging bacterial infection. Serious complications as a result of these infections may occur in people suffering from diabetes such as diabetic foot syndrome, including primary disease-related complications, e.g. gangrene that, ultimately, can be life-threatening or require amputations. Other high-risk patient sub-groups include patients infected with human immunodeficiency virus (HIV), patients with acquired immunodeficiency . syndrome (AIDS), and patients with other types of immunosuppression, e.g. transplant recipients and patients on long-term corticosteroid therapy. * There is an increased prevalence of onychomycosis in the elderly (up to 30 % by age sixty). Microsporum, Trichophyton such as Trichophyton rubrum or Trichophyton mentagrophytes, and Epidermophyton such as Epidermophyton floccosum are those microorganisms commonly involved. These infections are conveniently discussed according . to the sites of the body involved. Diagnosis is confirmed by demonstrating the pathogenic fungus in scrapings of the lesions, either by microscopic examination or by culture. Across : medical disciplines, onychomycosis is well recognized as being arduous both to diagnose and to manage, particularly in the aged.

Terbinafine is particularly useful to treat toenail and fingernail onychomycosis due to dermatophytes (e.g. tinea unguium). Indeed terbinafine has opened up treatment for tinea unguium caused by Trichophyton. For example The Merck Manual [1987] states that treatment of toe-nails should be discouraged with the previously used standard griseofulvin, because 1 to 2 years treatment is required, recurrence is usual and complete cure unlikely.

For the treatment of onychomycosis and other uses, terbinafine is normally administered as an immediate release tablet form containing 125 mg or 250 mg terbinafine (base equivalent) once daily. Such a tablet sold under the trademark Lamisil® releases terbinafine to the extent of at least 80 % over a 30-minute period as measured by standard in vitro dissolution studies, e.g. at pH 3 using the paddle method. This is an example of an immediate release form.

Terbinafine treatment over 12 weeks is required (hereinafter referred to as the “original treatment period”). The progress of its clinical effectiveness may be seen with growth of the healthy nail, pushing out and replacing the diseased unsightly nail-containing debris and dead fungus. About 10 months is needed for a totally new toe-nail to form.

Although terbinafine is generally regarded as safe like any prescription drug, adverse events associated with its use have been reported. As described in the Physicians’ Desk

Reference, there have been a number of adverse events recorded, e.g. headaches, gastrointestinal symptoms (including diarrhea, dyspepsia, abdominal pain, nausea and flatulence), liver test abnormalities, €.g. enzyme abnormalities, dermatological symptoms such as pruritis, urticaria and rashes, and taste disturbances, e.g. loss of taste. These adverse events : are in general mild and transient. Further adverse events include symptomatic idiosyncratic hepatobiliary dysfunction (e.g. cholestatic hepatitis), severe skin reactions such as Stevens- ) Johnson syndrome, neutropenia and thrombocytopenia. Yet further adverse events may include visual disturbances such as changes in the ocular lens and retina, as well as allergic reactions including anaphylaxis, fatigue, vomiting, arthralgia, myalgia and hair loss.

Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions . when co-administered with substrates of this isoform such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. Hereinafter any and all these events are ) referred to as “Adverse Events”.

Various pharmacokinetic and biopharmaceutical properties of terbinafine are known.

Thus terbinafine is well absorbed. Peak drug plasma concentrations (Cmax) of about 1 pg/ml appear within 2 hours after administration of a single 250 mg terbinafine dose. The area under the curve over 24 hours (hereinafter AUC) is about 4.56 pg.hour/ml. A moderate increase in

AUC is apparent when terbinafine is administered with a meal. In patients with renal impairment (e.g. creatinine clearance up to 50 ml/min) or hepatic cirrhosis the clearance of terbinafine is reduced by approximately 50 %. In the steady state, e.g. when the troughs and peaks are constant after dosing extending over several days, in comparison to the single dose, the peak terbinafine blood concentration (Cra) is 25 % higher and the AUC increases by a factor of 2.5. This is consistent with an effective half-life for terbinafine of about 36 hours.

Pharmacokinetic and absorption properties have been disclosed in e.g. J. Faergemann et al., Acta Derm. Venereol. (Stockh.) 77 [1997] 74-76 and earlier articles. Little has been disclosed on steady-state pharmacokinetics and pharmacokinetics on cessation of steady-state treatment. Although some low aborption was found to occur in the lower gastrointestinal tract, the main site of absorption of terbinafine is not precisely known and as indicated above there is no clinically proven correlation of effect with pharmacokinetic profile.

Further, despite the very major contribution to antimycotic therapy which terbinafine has brought, the reported occurrence of undesirable Adverse Events has been an impediment to its wider oral use or application. The particular difficulties encountered in relation to oral dosing with terbinafine have inevitably led to restrictions in the use of terbinafine therapy for the treatment of relatively less severe or endangering disease conditions, e.g. tinea pedis.

While numerous pharmaceutical compositions for topical and oral administration have * been proposed, there still exists a need for commercially acceptable terbinafine formulations for oral administration with good patient convenience and acceptance, especially for children ’ and the elderly. One particular difficulty in the formulation of terbinafine in oral pharmaceutical compositions is its unpleasant, e.g. bitter taste, and/or low physical integrity in free base form. Further, some patients may suffer from taste disturbance or taste loss.

It has now been found that, surprisingly, terbinafine has a beneficial . pharmacodynamic profile even in situations of high dosage load. It may therefore be administered without untoward effect on e.g. the liver in higher daily dosage used " intermittently and for a shorter duration of time than previously contemplated for the treatment of fungal infections such as onychomycosis or fungal sinusitis, yielding the unexpected result of equal or improved therapeutic outcomes from less total drug exposure, thus resulting in an overall dose of less drug than with previously known, e.g. continuous treatments, e.g. of about % less. Thus the present invention enables reduction of terbinafine treatment times and overall dosing over the full treatment period required to achieve effective therapy, thereby reducing the exposure time to terbinafine and improving the global safety profile.

In addition it permits closer standardization as well as optimization of on-going daily dosage requirements for individual subjects receiving terbinafine therapy as well as for groups of patients undergoing equivalent therapy. By closer standardization of individual patient therapeutic regimens, dosaging parameters for particular patient groups, as well as monitoring requirements, may be reduced, thus substantially reducing the cost of therapy. Further, the antifungal activity of terbinafine being not just fungistatic but fungicidal, it may be used intermittently and administered for a short duration of time while nevertheless being curative, thus largely avoiding the need for prophylactic repeat treatment once mycological cure has been obtained and achieving increased efficacy without corresponding side effects.

The beneficial pharmacodynamic profile of terbinafine appears e.g. from tolerability studies upon high dosage over a short time duration. This is shown in e.g. standard tolerability or pharmacokinetic studies wherein terbinafine in immediate release form, such as a tablet, is administered at dosages higher than usual, namely tolerability studies in beagle dogs effected perorally (p.o.). Pharmacokinetic parameters (toxicokinetics), e.g. tmax, Cmax,

Ca/dose and AUC are measured. The following parameters are also monitored: alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, calcium, " chloride, total cholesterol, creatine kinase, creatinine, glucose, inorganic phosphorus, magnesium, potassium, sodium, total bilirubin, total protein, triglycerides and urea, as well as gamma glutamyltransferase (GGT). It was found that after a single peroral administration to male dogs of one standard tablet of terbinafine hydrochloride (125 mg base equivalent) at a mean dose of 12.0 + 0.3 mg/kg terbinafine (base equivalent), the values determined for tax, . Conax and Cpp/dose were, respectively: 1h; 199 + 85 ng/ml; and 16.6 + 7.2 (ng/ml)/(mg/kg)-

Further, it could now be surprisingly determined in extensive computer modeling studies > that e.g. in the treatment of onychomycosis, an intermittent dosing of e.g. 350 mg/day terbinafine (base equivalent) administered in 3 cycles, of 14 days on and 14 days off, would result in concentrations in the nail falling between the concentrations achieved with a continuous daily therapy over 12 weeks of, respectively, 125 mg/day, which is known to be less efficacious, and 250 mg/day, which is known to be highly efficacious, in onychomycosis treatment (see Figure). Therefore, it can be concluded that intermittent treatment in the above regimen, or variants thereof, would be expected to produce efficacy in patients.

Figure 800 700 5 250 mg/day

E 600 ! 2) § 500 = \ £400 A NE OB 350 mg/day (week 1+2) 5 I AN ¢ \ g§ 300 J: \ 3 200 I 100 125 mg/day . 0 ¢ 01 2 3 4 5 6 7 8 9 10111213 14 1516 17 18 19 20 21 22 23 24

Time [weeks]

The modeling is effected based on the following principles: a) Terbinafine plasma concentrations following multiple oral administration is simulated on . the basis of known population pharmacokinetic parameters upon continuous therapy [J. Nedelman et al., J.Clin.Pharmacol. 36 (1996) 452-456; J. Nedelman et al., - Biopharm.Drug Dispos. 18 (1997) 127-138; and J. Nedelman et al.,

Eur.J.Drug Metab.Pharmacokinet. 22 (1997) 179-184]. The model incorporates a central, a rapidly equilibrating (shallow) and a slowly equilibrating (deep) peripheral compartment.

Drug input into the central compartment is described as a zero order absorption process.

Elimination is, as is usual, assumed to occur from the central compartment; and . b) a linear relationship is then established between observed nail concentrations [J. Faergemann et al., Acta Derm.Venereol. 73 (1993) 305-309] and the model-predicted drug : amount in the deep peripheral compartment. Hence the drug amount in the deep compartment is a suitable predictor for terbinafine nail concentrations.

Accordingly the invention provides a novel method of treatment of fungal infection with terbinafine by administration of high doses over a short period of time, preferably in a cyclical manner, thereby reducing total overall drug intake and further, it has now also become possible to devise corresponding oral galenical formulations for delivering high drug loads in a short time span which would not usually be readily contemplated, such as appropriate coated and/or multiparticulate formulation systems.

In one embodiment, the invention therefore provides a novel terbinafine dosing regimen method which meets or substantially reduces difficulties in terbinafine therapy hitherto encountered in the art. In particular it allows the use of pharmaceutical compositions which deliver terbinafine in sufficiently high concentrations to permit convenient oral once-a-day administration, while at the same time achieving improved safety and tolerability in terms of fewer Adverse Events. Specifically, in one aspect of this embodiment the present invention provides a method of administering terbinafine to a subject in need of terbinafine treatment which comprises administering to the subject terbinafine in an intermittent cycle wherein the terbinafine is administered for more than one-third of the cycle, hereinafter briefly named “the method of the invention”.

For example, the cyclically-administered terbinafine in a cycle may be administered daily or less frequently than daily, preferably daily, e.g. once a day. Preferably terbinafine is administered for a period of from more than one-third to two-thirds, preferably for about : one-half of the cycle. A cycle may be e.g. from about 10 to about 50 days. Preferably a cycle is 28 days or a calendar month. Preferably terbinafine is administered daily for 14 consecutive days in a 28 days or monthly cycle, namely, for a 14-day period extending over roughly half a cycle. Preferably there are 3 or 4, especially 3 cycles. Oral administration is preferred. :

It is to be appreciated that effective administration of terbinafine takes place during a . time period extending over just a part, which is exceeding a third, of a cycle. The selection of the exact duration of a cycle, in particular, 28 days or a calendar month, is essentially based on > considerations of convenience, taking into account, for example, the patient’s gender.

If desired terbinafine may be administered every second or third day. Conveniently the total number of cycles is two or more, preferably 2 to 5, for example 4, especially 3.

Preferably the intermittent dose of terbinafine is elevated as compared to daily dosages conventionally used, it is from about 300 mg to about 700 mg terbinafine (base equivalent), preferably from about 300 mg to about 450 mg, especially 350 mg per day. The safety of terbinafine at such a dose in the method of the invention is surprising. Especially preferred is a method of administering terbinafine to a subject in need of terbinafine treatment in three 28 days or monthly cycles of once daily oral administration of 350 mg/day of terbinafine (base equivalent) for 14 consecutive days of each cycle, thus resulting in about 30 % less total drug exposure (14.7 g) as compared with current dose/dose regimen (12 weeks, 250 mg/day; 21 g).

In a further aspect of this embodiment the invention provides for the use of terbinafine as an active agent in the manufacture of a medicament for use in the method of the : invention.

For convenience such medicament, e.g. in the form of capsules, or stored in bottles, may be packaged into an appropriate box with instructions for use, e.g. for use in the above novel dosage regimen method. For example, the package may be a box containing three or four sets of 28 capsules containing 175 mg terbinafine (base equivalent), together with instructions for administration of 2 capsules per day for 14 consecutive days of the first 2 weeks of three or four successive 28-days periods or months.

In a further aspect of this embodiment the invention provides a dosage pack containing a plurality of terbinafine compositions arranged to be dispensed in the method or use of the invention, e.g. in non-continuous manner, e.g. where convenient together with instructions : for use, preferably a calendar pack, optionally, for improved compliance, together with similarly-looking placebo compositions to be dispensed during the remaining part of each cycle when terbinafine is not administered.

Preferably the treatment period is for 3 or 4, especially 3 cycles in onychomycosis. This . period represents the shortest treatment duration to date for treating this chronic infection. Itis surprising that terbinafine in the method of the invention is at least as effective as with the

N original treatment but exhibits fewer Adverse Events than expected.

The above cyclical treatment may conveniently be used in combination with topical treatment with e.g. a cream containing terbinafine, e.g. 1 % by weight.

While pulse therapies with terbinafine have been envisaged in the past, they had either led to negative results (A. Tosti et al., J.Am.Acad. Dermat. 34 [1996] 595-600), and/or each proposed pulse was for a shorter duration with lower initial load and with more repeats (DE 100°17°996-A1) than with the present invention.

The above novel cyclical terbinafine dosing regimen method may be effected using conventional galenical forms, e.g. uncoated immediate release or sustained-release tablets (see e.g. Examples A and B hereafter).

However, in another embodiment, the invention further provides novel galenical formulations of terbinafine which may advantageously be administered in e.g. the method of the invention and allow particularly favourable systemic delivery of high once daily drug dosages in coated and/or multiparticulate form, resulting in low pharmakokinetic variability and few Adverse Events.

This follows from the further unexpected finding, in a study in dogs, of even lower pharmacokinetic variability when the standard 125 mg immediate release tablet is compared with an equivalent dose of terbinafine in a multiparticulate system (the coated minitablets of

Example 4); it was found that the already low variability of the immediate release tablet is even further reduced in the multiparticulate system: while, as described above, at a mean dose of 12.0 + 0.3 mg/kg terbinafine (base equivalent), after a single peroral administration of the standard tablet to male beagle dogs the values determined for mean tmax, Cmax, Cmax/dose and ! AUC were, respectively: 1h; 199 + 85 ng/ml; 16.6 + 7.2 (ng/ml)/(mg/kg); and 526 = 171 ng.hour/ml, with dogs receiving the coated minitablets at the same dosage of ' terbinafine, the values obtained were, respectively: 0.75 h; 246 + 48 ng/ml; 20.5 + 4.3 (ng/ml)/(mg/kg); and 644 + 161 ng.hour/ml.

Thus a similar mean AUC [644 + 161 v. 526 + 171 ng.hour/ml] and a similar mean . Cmax [246 + 48 v. 199 + 85 ng/ml] were found for both galenical forms, but a much lower inter-subject variability of Cray [+ 48 v. + 85 ng/ml standard deviation in Crux] for the : multiparticulate form v. the standard tablet. Furthermore, median tay values were found to be 0.75 h and 1 h, respectively, for the multiparticulate and the standard form, with single values ranging from only 0.5 to 1 h for the multiparticulate form, but from 0.5 to 2 h for the standard form.

The pharmacokinetic parameters of both formulations were obtained using the same dog individuals and a crossover study design, hence possible period and inter-animal variability effects can be excluded. Plasma containing EDTA as anticoagulant was collected up to 48 hours post-dose, and bioanalysis was performed using HPLC with UV detection (measurement at 224 nm) after liquid-liquid extraction of the sample. The lower limit of quantification of the bioanalytical method was 1.00 ng/ml plasma. The dogs were fasted before administration. The washout period was one week between two administrations in the same dog. Feeding was performed 6 hours or more after dosing.

In one aspect of this other embodiment, the invention thus provides a novel terbinafine solid dosage form for oral administration which is suitable for minimizing effects associated with e.g. a high dosage load and which is coated and/or muitiparticulate, e.g which comprises coated tablets providing less adverse events/side effects, and/or multiple, easily dispersed particles providing e.g. a reproducible and mainly food-independent transit through the gastrointestinal tract and a high surface area for reproducible dissolution of the drug substance, such as optionally coated minitablets or pellets in capsules, hereinafter briefly named “the compositions of the invention”.

Intermittent dosing allows administration of less total dose, but it involves administration of high daily doses: thus, the potential for transient adverse effects is enhanced, namely, y - at the systemic level, the higher plasma concentrations achieved (AUC, Cpa) are leading to higher risk of adverse effects associated with pharmacokinetic variability or ’ of e.g. centrally-induced taste disturbance; and - at the local level, e.g. in increased risk of sensation of the bitter taste of terbinafine and/or of locally-induced taste disturbance.

The first concern above has now been found to be favourably addressed with . multiparticulate systems, the second concern with appropriate coating, whereby these two aspects may advantageously be combined.

Taste disturbance or taste loss after terbinafine intake is a relatively rare and reversible

Adverse Event that may, however, in single cases continue over an extended period, e.g. for longer than 12 weeks after cessation of treatment. Drug-induced taste disturbances can be divided into taste perversion (dysgeusia) and loss of acuity of taste (hypogeusia) or complete loss of taste (ageusia). In addition the sense of smell may be affected (hyposmia or anosmia).

These changes, apart from their unpleasantness, can impair appetite, causing weight loss. Many drugs have been reported to cause taste disturbances or taste loss, including the antifungal agents griseofulvin and amphotericin B. AT, receptors may be involved in their pathogenesis.

Terbinafine can also cause taste disturbances in a small number of patients: thus, in one large post-marketing surveillance study conducted in Austria, Germany, the Netherlands and United

Kingdom in which patients were given 250 mg Lamisil® (terbinafine) daily for a mean duration of 13.2 weeks, 186 instances of taste disturbances occurred altogether during the period of oral administration, representing a total incidence of 0.72 %, of which 0.37 % (97 patients) concerned primary dysgeusia (taste perversion) and 0.32 % (84 patients) ageusia (complete taste Toss). All the patients recovered fully on discontinuing treatment.

In 7 further studies involving 959 Lamisil®- and placebo-treated patients in 4 placebo- controlled and 3 dose-duration studies, the frequencies of reports of taste disturbance were 3.2 % in patients given Lamisil" in the placebo-controlled studies, 1.2 % in those given Lamisil® in dose-duration studies, and 0.6 % in placebo patients. Three of the patients had ageusia, the others had a variety of dysgeusia: salty, metallic, bland and bitter tastes. All patients made a complete recovery, with an average recovery time of 10.2 weeks. While annoying, none of the reported taste disturbances was considered to be harmful. ) In rare instances the disturbances last longer than 12 weeks. The longest duration reported after discontinuation of drug was 2.5 years.

Therefore, while taste disturbances after terbinafine intake are rare and innocuous, they ] can be unpleasant and thus there is still a so far unmet need for novel means allowing treatment of fungal infection with terbinafine which eliminate or mitigate taste-related Adverse y Events. The present invention also addresses this issue and provides a novel approach thereto.

The compositions of the invention are adapted for release of the active substance terbinafine in the stomach; for example, in 0.04 M citrate buffer pH 3.0 at 37°C, terbinafine is released from the composition and dissolves within 30 minutes to the extent of at least 50 %, e.g. at least 70 %, preferably at least 80 %.

The constituent particles of the multiparticulate system have a size ranging from about 0.5 mm to about 4 mm in diameter. They are not granules (typically of a particle size of up to about 0.5 mm) and include e.g. tablets, pellets or minitablets. Tablets, pellets or minitablets may be filled into capsules, e.g. hard gelatin capsules, or into sachets. Typically, one administration comprises a plurality of pellets or minitablets to achieve the desired overall dose of terbinafine per day.

The particles preferably are minitablets or pellets, i.e. they are presented formulated in a form that allows easy administration of a high load of active substance. The term "minitablets” denotes small tablets with an overall weight in their uncoated form of from about 3 to about 10mg, e.g. from about 4 to about 7 mg, e.g. about 6 mg. The minitablets may have any shape convenient to the skilled person for tablets, e.g. spherical, e.g. with a diameter of from about 0.5 to about 4 mm, e.g. 1 to 4 mm or 2 to 4 mm; or cylindrical, e.g. having a convex upper face and convex lower face and e.g. with a cylindrical diameter and height which are, independently of each other, of from about 0.5 to about 4 mm, e.g. 1 to 3 mm; or they may be biconvex round minitablets, e.g. whose height and diameter are approximately equal and are from about 0.5 to about 4 mm, e.g. 1.5 to 4 mm, preferably 1.8 to 2.3 mm.

The minitablets may be uncoated, or coated with one or more layers of coating. : In one variant the minitablets are uncoated. In a further variant they are coated with only hydroxypropylmethyl cellulose (HPMC), e.g. HPMC 603 available as e.g. Pharmacoat® 603 ) (see H.P. Fiedler, loc.cit. hereafter, p. 1172). In a further variant the coating(s) include(s) a taste-masking material, e.g. a polyacrylate, preferably an Eudragit® such as Eudragit®-E or

Fudragit®-RD100 or -RS/RL (see Handbook of Pharmaceutical Excipients, loc.cit. hereafter,

p. 362), especially Eudragit®-E. In a further variant they are coated with a 3rd coating, e.g. . with HPMC or polyethyleneglycols (PEG) to minimize further any interaction between minitablet and e.g. capsule. In a further variant the coating is devoid of plasticizer such as ’ dibutyl sebacate, or the plasticizer is a fatty acid such as stearic acid, e.g. stearic acid NF (National Formulary, USP). In a further variant they are unencapsulated. In a further variant in the encapsulating material gelatin is replaced with alternative hard capsule materials, e.g.

HPMC or starch.

Similar considerations apply mutatis mutandis for pellets as set out hereabove for minitablets; pellets preferably have a diameter of from about 0.5 to about 2 mm.

The compositions of the invention are formulated in a manner allowing optimal delivery, e.g. they are uncoated or, preferably, coated as appropriate. Accordingly, the invention also provides a terbinafine solid dosage form for oral administration which is coated, e.g. dragées, or coated tablets, pellets or minitablets. It further provides a terbinafine solid dosage form for oral administration which is multiparticulate, e.g. optionally coated minitablets or pellets, e.g. in capsules. It further provides a novel terbinafine solid coated and/or multiparticulate dosage form for oral administration which has taste-masking properties and/or prevents taste disturbance or taste loss and associated adverse effects such as impaired appetite and weight loss.

Suitable coating materials for the compositions of the invention include: i) pharmaceutically acceptable cellulose derivatives such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP); ii) polyacrylates, especially polymethacrylates, preferably: a) a copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters; ; b) a copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate; or ¢) a copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride; e.g. those available from R6hm GmbH under the trademark Eudragit®;

iii) polyvinyl acetate phthalate (PVAP); “ iv) polyvinyl alcohols; v) polyvinylpyrrolidones (PVP); ’ vi) sugar such as saccharose or glucose, or sugar alcohols such as xylit or sorbit; vii) shellac; and viii) mixtures thereof.

Preferred cellulose derivatives 1) are e.g. modified celluloses, e.g. hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, e.g. hydroxypropyl cellulose having a hydroxypropyl content of about 5 to 16 % by weight and of viscosity for 2 % w/w aqueous solutions of from about 2.0 to about 20 cps (= mPa.s), preferably from about 2.0 to about 6.0, e.g. 3.0 cps, e.g. hydroxypropyl methylcellulose (HPMC) (e.g. USP type 2910, 3 cps), available as e.g. Pharmacoat® 603.

Especially preferred polyacrylic polymers ii) are: 1) the 1:1 copolymers formed from monomers selected from methacrylic acid and methacrylic acid lower alkyl esters, such as the 1:1 copolymers formed from methacrylic acid and methyl methacrylate available under the trademark Eudragit® L, e.g. Eudragit® 1.100, and the 1:1 copolymer of methacrylic acid and acrylic acid ethyl ester available under the trademark Eudragit® 1100-55; 2) the 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)- methacrylate and methyl methacrylate available under the trademark Eudragit® E; and 3) the 1:2:0.2 copolymer formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride available under the trademark

Eudragit® RL; or the corresponding 1:2:0.1 copolymer available under the trademark

Eudragit® RS; or the 1:2:0.2 copolymer formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride which is in combination with carboxymethyl cellulose and available under the trademark Eudragit® RD. ’ The polyacrylates of group 3) above normally contain cationic ester groups. Examples of such cationic groups include dialkylaminoalkyl groups, e.g. dimethylaminoalkyl groups.

Especially preferred cationic groups include quaternary ammonium groups, preferably a tri(alkyl)aminoalkyl group. Examples of such groups are trimethylaminoethyl ester groups.

The polyacrylate may contain some carboxylic acid groups in free form or salt anions,

e.g. chloride anions in order to balance the cationic groups. The ratio of cationic groups to , neutral groups is preferably from 1:10 to 1:50, e.g. from 1:10 to 1:30.

The polyacrylates of group ii) above have a mean molecular weight of about 50000 ! to about 500°000, e.g. about 150°000.

Preferably, the coating materials comprise HPMC, Eudragits or sugar. It has been found that polyacrylates ii), especially Eudragit® E, are particularly suitable for coating solid dosage forms comprising terbinafine in the form of the free base as well as in form of its salts, e.g. terbinafine hydrochloride, e.g. since a coating with Eudragit® E does not easily dissolve at the neutral pH of the mouth, but only at pH values below 5, and thereby prevents the dissolution of the bitter tasting terbinafine until transfer to the stomach.

Coating materials as hereinabove defined may be used in admixture with further excipients conventional in coating formulations, for example talcum, magnesium stearate or silicon dioxide, for example synthetic amorphous silicic acid of the Syloid® type (Grace), for example Syloid® 244 FP, or colloidal silicon dioxide, e.g. Aerosil®, e.g. Aerosil® 200, or wetting agents, for example sodium dodecyl sulfate or the aforementioned polyethyleneglycols or polysorbates.

The coating materials may comprise additional excipients, for example plasticisers : such as: triethyl citrate, e.g. Citroflex® (e.g. from Morflex); triacetin; various phthalates, e.g. diethyl or dibutyl phthalate; diethyl or dibutyl sebacate; fatty acids or mixtures thereof, e.g. lauric, myristic, palmitic or stearic acid; alcohols, e.g. lauryl or stearyl alcohol; mixed mono- or diglycerides of the Myvacet® type (Eastman), for example Myvacet® 9-40; the polyethyleneglycols mentioned hereinbefore, for example having a molecular weight of approximately from 6000 to 8000; and also ethylene oxide/propylene oxide block copolymers of the poloxamer type, e.g. Pluronic® (BASF) or Synperonic® (ICI) type, such as

Pluronic” F68 (poloxamer 188) having a melting point of about 52°C and a molecular ) weight of about 6800 to 8975, or Synperonic® PE L144 (poloxamer 124); pulverulent mould release agents, for example magnesium trisilicate; starch; or synthetic amorphous silicic acid of the Syloid® type, for example Syloid" 244 FP.

In one embodiment, the solid dosage forms may be coated by one, or preferably . by two or more coatings which are applied one after the other. In one aspect, the solid dosage forms may be coated by a first (e.g. protective) coating applied directly upon the - solid dosage form, e.g. comprising HPMC, and a second (e.g. taste-masking) coating applied upon the first coating, e.g. comprising Eudragit®, preferably Eudragit® E or

Eudragit® RD100, or ethyl cellulose.

In another aspect the solid dosage forms may comprise a further coating, e.g. a layer of anti-sticking material applied upon one of the above-mentioned coatings, e.g. comprising a colloidal silicon dioxide product, e.g. Aerosil®, which may avoid adhesion of the solid dosage forms to each other or to the walls of the container material, e.g. a capsule.

Typically, overall coating weights for coating materials i) to v) range from about 0.5 to about 10 mg/cm? based on the surface area of the uncoated formulation, e.g. from about 1 to about 4 mg/cm’, e.g. they are about 1.5 mg/cm’. In particularly preferred embodiments, for a 350 mg terbinafine (base equivalent) coated tablet the coat weight is from about 3 to about 14 mg, and for a coated minitablet of about 6.5 mg terbinafine (base equivalent), the coat weight is about from about 0.5 or 1 to about 2 mg.

Typically, overall coating weights for coating materials vi) to vii) range from about to about 200 % of core weight, preferably from about 50 to about 100 % of core weight.

Terbinafine base equivalent may be present in an amount of from about 0.1 to about 95 %, e.g. from about 20 to about 90 %, preferably from about 30 to about 80 %, especially from about 50 to about 60 % by weight based on the total weight of the composition.

The solid dosage forms typically may comprise disintegrants, e.g. such pharmaceutical excipients which facilitate the disintegration of a solid dosage form when placed in an aqueous environment, and may comprise e.g. the following: ’ (i) natural starches, such as maize starch, potato starch, and the like; directly compressible starches, e.g. Sta-rx® 1500; modified starches, e.g. carboxymethyl starches and sodium starch glycolate, available as Primojel®; Explotab®; Explosol®; and starch derivatives such as amylose; (ii) crosslinked polyvinylpyrrolidones, e.g. crospovidones, e.g. Polyplasdone® XL and

Kollidon® CL; (iii) alginic acid and sodium alginate; ) ’ (iv) methacrylic acid/divinylbenzene copolymer salts, e.g. Amberlite® IRP-88; and } (v) cross-linked sodium carboxymethylcellulose, available as e. g. Ac-di-sol®, Primellose®,

Pharmacel® XL, Explocel® and Nymcel® ZSX.

Preferred disintegrants include those from classes (1) and (ii) above, particularly preferred are StarxX, Primojel® and Polyplasdone®.

The disintegrant may be present in an amount of from about 1 to about 50 %, e.g. from about 5 to about 40 % by weight based on the total weight of the uncoated composition.

In a further aspect the invention provides a composition of the invention wherein the ratio of terbinafine (base equivalent) to disintegrant is from about 1 : 0.01 to about 1: 20, e.g. from about 1 : 0.05 to about 1 : 5, preferably from about 1 : 0.05 to about 1 : 1 by weight.

The compositions of the invention may also comprise further components which are commonly employed in the preparation of dosage forms, e.g. solid dosage forms. These components include, among others: binders; filler and Plasticising agents; lubricants, €.g. magnesium stearate; and glidants, e. g. silica, e.g. in particular colloidal silicon dioxide products available under the trademark Aerosil® (see H.P. Fiedler, loc. cit. hereafter, p. 115;

Handbook of Pharmaceutical Excipients, loc. cit. hereafter, p. 424).

Suitable binders include the following: (i) starches, e.g. potato starch, wheat starch or corn starch; (i) gums such as gum tragacanth, acacia gum or gelatin; (iii) microcrystalline cellulose, e. g. products known under the trademarks Avicel?, Filtrak®,

Heweten® or Pharmacell®,; (iv) modified celluloses, e.g. hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, e. g. hydroxypropyl cellulose having a hydroxypropyl ; content of about 5 to 16 % by weight and of viscosity for 2 % w/w aqueous solutions of from about 2.0 to about 20 cps (= mPa.s), preferably from about 2.0 to about 6.0, . e.g. 3.0 cps, e.g. hydroxypropyl methylcellulose (HPMC) (e.g. USP type 2910, 3 cps), available as e.g. Pharmacoat® 603; and (v) polyvinylpyrrolidone, available as e.g. Povidone®, Kollidon® or PlasdoneX.

A particularly preferred binder is HPMC (Pharmacoat™). The binder may be present in ” an amount of from about 0.5 to about 50 %, e.g. from about 1 to about 40 %, e.g. from about 1 to about 25 %, e.g. from about 1 to about 15 %, preferably from about 1 to about 8 % by ‘ weight based on the total weight of the uncoated composition.

In a further aspect the invention provides a composition of the invention wherein the ratio of terbinafine (base equivalent) to binder is from about 1 : 0.01 to about 1: 10, e.g. from about 1: 0.01 to about 1 : 1, preferably from about 1 : 0.01 to about 1 : 0.1, especially about 1 : 0.04 by weight.

Suitable filler and plasticising agents include excipients known for their favourable properties as filler and plasticising agents, and include: (i) substantially water-insoluble excipients such as microcrystalline cellulose (which may also be regarded as a weak disintegrant), e.g. Avicel® , Pharmacel®, Emcocell®, Vivapurl®, preferably Avicel® (FMC Corp.), e.g. of the types Avicel® PH101, 102, 105, RC 581 or

RC 591 (Fiedler, loc.cit. hereafter, p. 216). (ii) substantially water-soluble excipients such as compression sugars, e.g. lactose, sucrose, amylose, dextrose, mannitol and inositol, preferably lactose; and (iii) calcium hydrogen orthophosphate dihydrate, e.g. Emcompress", or anhydrous calcium hydrogen phosphate, e.g. Fujicalin®.

If present, the filler and plasticising agents may be present in an amount of from about 0.1 to about 50 %, e.g. from about 1 to about 40 %, preferably from about 5 to about 30 % by weight based on the total weight of the uncoated composition.

In a further aspect the invention provides a composition of the invention wherein the ratio of terbinafine (base equivalent) to filler or plasticising agent is from about 1: 0.01 to about 1: 100, e.g. from about 1 : 0.01 to about 1 : 20, preferably from about 1: 0.01 to about 1 : 10, especially from about 1 : 0.1 to about 1 : 5, more especially about 1 : 0.2 ’ by weight.

The compositions of the invention may conveniently further comprise a suitable buffering component, e.g. a salt of an acid that is partially dissociated in aqueous solution, and include those buffering components which - upon disintegration of the composition in an aqueous medium (e.g. the oral cavity) - are capable of maintaining a pH at which terbinafine . remains substantially insoluble, e.g. a pH in acidic range, e.g. a pH of greater than 4, preferably of from about 5 to about 6, on treatment with excess water, e.g. 5 to 100 ml. Examples of ’ suitable buffers include carbonate, citrate, acetate, phosphate, phthalate, tartrate salts of the alkali and alkaline earth metal cations, such as sodium, potassium, magnesium and calcium.

Preferred buffering agents include e.g. calcium carbonate, trisodium citrate and sodium hydrogen carbonate. The buffering agents may be used singly or in any suitable combination for achieving the desired pH and may be of a buffer strength of from about 0.01 to about 1 mole/litre, preferably from about 0.01 to about 0.1 mole/litre.

The molar ratio of terbinafine (base equivalent) to buffering component may be from about 1 : 0.02 to about 1 : 10, e.g. from about 1 : 0.2 to about 1 : 10, preferably from about 1 : 0.5 to about 1 : 5, more preferably from about 1 : 0.5 to about 1 : 2.

It will be appreciated that the invention encompasses: a) in respect of the disintegrant any of components i) to v) individually or in combination with one or more of the other components i) to v); 'b) in respect of the binder and filler or plasticizing agent any of those specified above individually or in combination; and ¢) in respect of the buffering component any of the buffers specified above individually or in combination.

The compositions may conveniently also include one or more further additives or ingredients in an amount of e.g. from about 0.01 to about 5 % by weight based on the total weight of the uncoated composition, for example: sweetening agents, e.g. sorbitol, saccharin, aspartame, acesulfame or sugars such as glucose, fructose or saccharose; flavouring agents, e.g. chocolate, cocoa, banana, strawberry or vanilla flavour; and so forth. Additives to sugar or shellac coating commonly used in confectioning may be employed where appropriate. ’ Determination of workable proportions in any particular instance will generally be within the capability of the man skilled in the art. All indicated proportions and relative weight ranges described above are accordingly to be understood as being indicative of preferred or individually inventive teachings only and not as limiting the invention in its broadest aspect.

Claims (34)

1. Claims:

   ) 1. Aterbinafine solid dosage form for oral administration which is coated and/or is . multiparticulate.
2. 2. A dosage form of claim 1 which comprises coated tablets.
3. 3. A dosage form of claim 1 which is multiparticulate.
4. 4. A dosage form of claim 1 which comprises optionally coated minitablets or pellets, preferably in capsules.
5. 5. A dosage form of claim 1 which is adapted for release of the active substance terbinafine in the stomach.
6. 6. A dosage form of claim 5 in which terbinafine is released and dissolves within 30 minutes to the extent of at least 50 % in 0.04 M citrate buffer pH 3.0 at 37°C.
7. 7. A dosage form of claim 1 which has taste-masking properties and/or prevents taste disturbance or taste loss and associated adverse effects.
8. 8. A dosage form of claim 1 which comprises coated minitablets or pellets wherein the coating comprises a polyacrylate coating, whereby the polyacrylate coating and the terbinafine-containing core optionally are separated by a readily-dissolving coating, and optionally further coated with a layer preventing sticking.
9. 9. A dosage form of claim 8 wherein the polyacrylate is Eudragit® E.
10. 10. A dosage form of claim 8 wherein the readily-dissolving coating comprises a cellulose derivative.
11. 11. A dosage form of claim 8 wherein the layer preventing sticking comprises colloidal silica.
12. 12. A dosage form of claim 8 which is the minitablets in hard gelatin capsules of Example 8.
13. 13. A process for preparing a dosage form of claim 1 which is coated, comprising appropriately coating a corresponding uncoated precursor form thereof,
14. 14. Use of a dosage form of claim 1 in the manufacture of a medicament for the treatment of fungal infection of the human body, in particular of onychomycosis. : 15. Use of a dosage form of claim 1 in the manufacture of a medicament for inhibiting or reducing taste disturbance or taste loss and associated adverse effects after terbinafine intake.
15. 3 X B6
16. 16. A dosage form of claim 1 for use in inhibiting or reducing taste disturbance or taste loss and associated adverse effects after terbinafine intake.
17. 17. A dosage form of claim 1 for use in the treatment of fungal infection.
18. 18. Terbinafine for use in treating a subject in need of terbinafine treatment by administering to the subject terbinafine in an intermittent cycle wherein the terbinafine is administered for more than one- third of the cycle.
19. 19. The compound of claim 18 wherein terbinafine is administered for about one-half of the cycle.
20. 20. The compound of claim 18 wherein there are 3 or 4 cycles.
21. 21. The compound of claim 18 wherein a cycle is a 28 days or a calendar month.
22. 22. The compound of claim 18 wherein the terbinafine is administered in three 28 days or monthly cycles of once daily oral administration of 350 mg/day (base equivalent) for 14 consecutive days of each cycle.
23. 23. The compound of claim 18 wherein the subject is suffering from onychomycosis.
24. 24. The compound of any one of claims 18 to 23 wherein terbinafine is administered as a dosage form of claim 1.
25. 25. Use of terbinafine as an active agent in the manufacture of a medicament for use as a compound of any one of claims 18 to 23.
26. 26. Use of a dosage form of claim 1 in the manufacture of a medicament for use as a compound of any one of claims 18 to 23.
27. 27. A pack containing a plurality of terbinafine compositions arranged to be dispensed as a compound of any one of claims 18 to 23, where convenient together with instructions for use, such as a calendar pack.
28. 28. A dosage form of claim 1, substantially as herein described and exemplified and/or described with reference to the accompanying figures. AMENDED SHEET h 364A
29. 29. A process of claim 13 substantially as herein described and exemplified and/or described with reference to the accompanying figures.
30. 30. Use of claim 14 or 15, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
31. 31. A dosage form of claim 16 or 17, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
32. 32. A compound of claim 18 substantially as herein described and exemplified and/or described with reference to the accompanying figures.
33. 33. Use of claim 25 or 26, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
34. 34. A pack of claim 27 substantially as herein described and exemplified and/or described with reference to the accompanying figures. AMENDED SHEET