WO2018028841A1

WO2018028841A1 - Solid pharmaceutical composition of abacavir, lamivudine, and efavirenz

Info

Publication number: WO2018028841A1
Application number: PCT/EP2017/053326
Authority: WO
Inventors: Biljana JANKOVIC; Aleksandar ALEKSOVSKI; Katja BERGINC; Tatjana JOKSIMOVIC
Original assignee: Sandoz Ag
Priority date: 2016-08-12
Filing date: 2017-02-14
Publication date: 2018-02-15

Abstract

The present invention describes a fixed dose oral formulation of a triple HIV antiviral combination of abacavir (notably abacavir sulphate), lamivudine and efavirenz, useful in the treatment of HIV infections in the form of a multi-layer tablet, preferably a bi-layer tablet. The described formulations combine a number of valuable use attributes, including reduction of mouth burning effect caused by efavirenz as well as for providing of palatable formulations for high drug loaded system that is important for a triple fixed dose combination, without however to the detriment of dissolution properties for each active ingredient.

Description

Solid pharmaceutical composition of Abacavir, Lamivudine, and Efavirenz

Field of the invention The present invention belongs to the field of pharmaceutical industry and relates to anti-viral and particularly anti-HIV medication, in particular involving administration of nucleoside inhibitors of HIV-1 reverse transcriptase abacavir (in particular abacavir sulphate) and lamivudine, and of non-nucleoside inhibitor of HIV-1 reverse transcriptase efavirenz. Description of the background art

A high number of anti-HIV therapeutic compounds and a high number of possible

combination proposals have become known and described. In the development of the present invention, the active compounds abacavir, lamivudine and efavirenz respectively represent particularly selected active compounds to be combined.

The chemical name for abacavir is [4R-(2-Amino-6-(cyclopropylamino)-9H-purin-9-yl)-2- cyclopentene-1 -methanol. It typically is present in the form of its sulphate salt, notably at a ratio of abacavir to sulphate of 2:1 , in the following also denoted as compound of formula 1. It is nucleoside inhibitor of reverse transcriptase. The main mechanism of action for abacavir represents the inhibition of the HIV reverse transcriptase enzyme, an event which results in chain termination and interruption of the viral replication cycle. Intracellular^, the drug is metabolized to the active moiety, carbovir 5'-triphosphate. Recommended daily intake of abacavir is 600 mg.

The empirical formula of the compound of formula 1 is

and the molecular weight is 670.76. Abacavir sulphate is a tan to yellow crystalline powder, soluble in water throughout the pH range from 1 .2 to 8.0, and very slightly soluble in methanol and ethanol. The chemical structure of abacavir sul hate is depicted below.

Chemical structure of abacavir sulphate Lamivudine is effective as chain termination agent of viral reverse transcription. Lamivudine is metabolized intracellular^ to the active moiety, lamivudine 5'-triphosphate. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro. Recommended daily intake of lamivudine is 300 mg.

The chemical name of lamivudine is 2(1 H)-pyrimidinone-4-amino-1 -[(2R,5S)-2- (hydroxymethyl)-1 ,3-oxathiolan-5-yl] , in the following also denoted as compound of formula 2. Its empirical formula is CsHnNsOsS and the molecular weight is 229.3. Lamivudine is white to off-white crystalline powder, soluble in water throughout the pH range from 1.2 to 6.8, sparingly soluble in methanol and ethanol and slightly soluble in acetone.

The chemical structure of lamivu

Chemical structure of lamivudine

Efavirenz (chemical name: (4S)-6-chloro-4-(-2-cyclopropylethynyl)-4-(trifluromethyl)-2,4- dihydro-1 H-3, 1 benzoxazin-2-one), in the following also denoted as compound of formula 3, is a benzoxazinone of the non-nucleoside reverse transcriptase (RT) inhibitors group (NNRTIs), which interrupts the reverse transcription of viral RNA to DNA, a crucial step for HIV replication. Efavirenz is specific for HIV-1 reverse transcriptase and is a mixed type, mainly non-competitive inhibitor. Its empirical formula is C₁₄H₉CIF₃N02 and the molecular weight is 315.68. Efavirenz is white to off-white crystalline powder, practically insoluble in water. It is very slightly to slightly soluble in water and buffers with addition of wetting agent (sodium dodecyl sulphate). The chemical structure of efavirenz is depicted below.

Chemical structure of efavirenz

Current solid formulation of efavirenz at the market is related to compressed tablets (Stocrin^®), which is 50 % by weight drug loaded and film coated with hydroxypropylmethylcellulose/hydroxypropylcellulose (HPMC/HPC), described in EP 1 332 757 A1. According to the summary of product characteristics, efavirenz tablets should be swallowed intact with liquid. The dose strength is 600 mg. W09951239 A1 is directed to formulation of efavirenz capsules (Sustiva^®), that dissolves rapidly thereby enhancing the therapeutic characteristics of the formulation. The registered dose strength of Efavirenz capsules is 200 mg. In case of capsule opening, the content should be taken with grape jelly or yogurt. Nevertheless, such way of administration may result in hot "jalapeno" sensation in oral mucosa (Kaul et al. AHJP 2010; 67: 217-22). According to W09951239 A1 , a high level of disintegrant must be included to achieve sufficient release of efaviranz.

Few documents from the literature reported about oral mucosa irritation caused by efavirenz (Borras-Blasco J Ann Pharmacother. 2006 Jul-Aug; 40(7-8): 1471 -2). Mechanism of this effect has not been explained yet. Besides solid dosage form of efavirenz, liquid formulation is also present at the market, which is intended for HIV therapy of adults, adolescents and children 3 years of age and older, who are unable to swallow hard capsules or film-coated tablets. The formulation contains medium-chain triglycerides as solvent, sucralose and strawberry/mint flavour. The presence of the drug as an oily solution, with a low thermodynamic tendency to partition into the aqueous environment of the throat and mouth, minimizes the intrinsic burning properties of the efavirenz, making it palatable (Bahal et al, Pharm. Dev Technol., 2003).

Efavirenz can be provided as micronized, crystalline and anhydrous powder. It belongs to Class 2 (poor solubility/high permeability) drug according to Biopharmaceutical Classification system. Solubility of efavirenz in water is 0.01 mg/mL. pH of this solution is 5.7.

In the current therapy of HIV, the recommended dose is 600 mg of Abacavir, 300 mg Lamivudine, and 600 mg of Efavirenz given once daily, which represents four (Stocrin^®, 2x Ziagen^®, Epivir^®) or two (Stocrin^® and Kivexa^®) tablets of different reference products. The patient has to swallow multiple tablets of considerable size from different packaging units.

Two fixed dose triple combination dosage forms are currently available, Trizivir^® and Atripla^®. Trizivir^® is in the form of a single film-coated tablet comprising 150 mg of lamivudine 300 mg of zidovudine, and 300 mg of abacavir base (351 mg of abacavir sulphate). Atripla® is in the form of a single film-coated tablet comprising 600 mg of efavirenz, 200 mg of emtricitabine, and 245 mg of tenofovir disoproxil fumarate (expressed as tenofovir disoproxil).

WO201 1/061302A (=US2012283177A) and WO201 1/061303A (=US20120270828A) respectively provide overviews about the current date multi-active anti-HIV therapies and itself teaches a treatment scheme against HIV in humans, including three or four active principles. While a multitude of various triple and quadruple anti-HIV combinations are listed in the description, the respectively claimed combinations are defined as triple or quadruple combinations: in WO201 1/061302A the claimed selected anti-HIV actives are: a nucleoside reverse transcriptase inhibitor (NRTI) selected from lamivudine and emtricitabine; another nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) selected from didanosine, abacavir and tenofovir; and the combination of ritonavir with a protease inhibitor (PI) selected from lopinavir, fosamprenavir, atazanavir and darunavir, or an non-nucleoside reverse transcriptase inhibitor (NNIRT) selected from efavirenz and etravirine, for daily administration to said human being one to four days per week. In WO201 1/061303A the claimed selected anti-HIV actives are: a non-nucleoside reverse transcriptase inhibitor (NNRTI) selected from selected from nevirapine, efavirenz and etravirine, a nucleoside reverse transcriptase inhibitor (NRTI) selected from lamivudine and emtricitabine; and two different nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) selected from didanosine, abacavir and tenofovir. Specific descriptions or examples of formulating triple or quadruple unit dose combinations, let alone specific formulations containing, in one common dosage form, all of abacavir, lamivudine and efavirenz, are not given in WO201 1/061302A and WO201 1/061303A.

Further WO201 1/094150 discloses combinations of dolutegravir (GSK1349572) with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir and possibly lamivudine in addition. Again, specific descriptions or examples of formulating triple or quadruple unit dose combinations, let alone specific formulations containing, in one common dosage form, all of abacavir, lamivudine and efavirenz, are not given in WO201 1/094150 either.

Behind the above background, there was a need to provide an effective while concurrently patient compliant anti-HIV therapy.

Summary of the invention

Despite the challenge facing formulation scientist to provide an effective multi-active component formulation suitable for anti-HIV treatment, the present invention provides a useful fixed dose combination in a common combinational product (dosage form) comprising all of abacavir, lamivudine and efavirenz, which allows high drug load effective to meet the daily dose of each active compound, without compromising bioequivalence with comparative approved drug formulations (notably relevant drug formulations mentioned above), while at the same time being a swallowable dosage and minimizing the generation of mouth burning taste sensation inherent to the active compound efavirenz. Accordingly, the present invention provides, as set forth in the following items, various aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, contribute to solving the object of the present invention as well as further objects:

1. A solid pharmaceutical composition in the form of a single unit tablet, wherein the single unit tablet comprises a fixed combination of active ingredients (a) to (c):

(a) a compound of the followin formula (abacavir)

(b) a compound of formula 2 (lamivudine)

formula 2

(c) a compound of formula 3 (efavirenz)

formula 3 and, as pharmaceutically acceptable excipient, at least a surfactant and a disintegrant, optionally further at least one selected from the group consisting of binders, fillers, lubricants and film-forming agents, wherein

the tablet is structured by multiple layers, wherein lamivudine is present in one layer (i.e. lamivudine-containing layer), and abacavir and efavirenz are present in a layer (i.e. efavirenz and abacavir-containing layer) contiguous with the lamivudine-containing layer, optionally with an intermediate layer in between; preferably the multiple layers constitute a bilayer structure.

2. The solid pharmaceutical composition according to item 1 , wherein the solid pharmaceutical composition is a triple combination of active ingredients (a) to (c); in particular said solid pharmaceutical composition is free of ritonavir and free of didanosine and tenofovir specifically, and preferably contains no any further anti-HIV active substance.

3. The solid pharmaceutical composition according to anyone of the preceding items, wherein the whole composition which defines the multi-unit particulate dosage form contains at least 1500 mg of active ingredients (a) to (c) in total, preferably 1500 mg (calculated on the basis of the free base active compound).

In a preferred embodiment, the triple combination of active ingredients (a) to (c) in the common solid pharmaceutical composition contains 600 mg abacavir (calculated as free base) respectively 702 mg abacavir sulphate, 300 mg lamivudine and 600 mg efavirenz. 4. The solid pharmaceutical composition according to anyone of the preceding items, wherein the amount of active ingredients in total represents at least 60% by weight, preferably at least 70% by weight composition, more preferably up to 90% by weight, most preferably 70% to 90% by weight of the whole composition.

5. The solid pharmaceutical composition according to anyone of the preceding items, wherein the amount of active ingredients (a) and (c) represents at least 70% by weight, preferably at least 80% by weight, more preferably up to 90% by weight, most preferably 80% to 90% by weight of the efavirenz and abacavir-containing layer.

6. The solid pharmaceutical composition according to anyone of the preceding items, wherein the amount of active ingredient (b) represents at least 40% by weight, preferably at least 45% by weight, more preferably up to 70% by weight, most preferably 45% to 60% by weight of the lamivudine-containing layer.

7. The solid pharmaceutical composition according to anyone of the preceding items, wherein the compound (a) is contained in the form of an abacavir salt, preferably the sulphate of formula 1 :

formula 1 8. The solid pharmaceutical composition according to anyone of the preceding items, wherein the initial DO.5 primary particle size of efavirenz, whether agglomerated in the composition or not, is in a range of 2-8 μηη, and DO.9 in a range of 9-26 μηη, preferably efavirenz is incorporated into the composition in micronized form.

9. The solid pharmaceutical composition according to anyone of the preceding items, wherein the single unit tablet comprise a surfactant, a disintegrant, preferably a superdisintegrant, a binder, a lubricant and optionally a filler and/or a coating of a film- forming agent.

10. The solid pharmaceutical composition according to item 9, further comprising a glidant, a sweetener and/or a flavouring agent.

1 1. The solid pharmaceutical composition according to anyone of the preceding items, comprising in association with efavirenz a surfactant, a disintegrant, a binder and a filler; and/or comprising in association with lamivudine a disintegrant and one or more selected from a binder, a filler and a glidant, preferably a disintegrant and a filler and/or a glidant, optionally also a binder in case of the lamivudine-containing layer being obtained by involving granulation;

preferably said disintegrant is a superdisintegrant.

12. The solid pharmaceutical composition according to anyone of the preceding items, wherein efavirenz and abacavir-containing layer is obtainable by dry granulation or by wet granulation, preferably by wet granulation using an aqueous solution of polymer binder and a surfactant.

13. The solid pharmaceutical composition according to the preceding item, wherein the polymer binder is a cellulose derivative, preferably hydroxypropylcellulose, and/or the surfactant is sodium lauryl sulphate.

14. The solid pharmaceutical composition according to anyone of items 1 to 13, wherein the efavirenz and abacavir-containing layer comprises an intra-granular phase and an extragranular phase, wherein the intra-granular phase contain the total of both active ingredients (a) and (c).

15. The solid pharmaceutical composition according to anyone of items 1 to 13, wherein the efavirenz and abacavir-containing layer comprises an intra-granular phase and an extragranular phase, wherein the active ingredients (a) and (c) are present in separate distinct granules (i.e. efavirenz in first granule, and abacavir in second granule), or wherein efavirenz and abacavir are present in same granules;

it is preferred that efavirenz and abacavir are present in same granules.

16. The solid pharmaceutical composition according to anyone of items 1 -13, wherein the efavirenz and abacavir-containing layer comprises an intra-granular phase and an extragranular phase, wherein the total of efavirenz is present in corresponding intra-granular phase (granule) and the total of abacavir is present in the extragranular phase.

17. The solid pharmaceutical composition according to anyone of items 1 -13, wherein the efavirenz and abacavir-containing layer comprises an intra-granular phase and an extragranular phase, wherein the total of efavirenz is present in the intra-granular phase and abacavir is partitioned between the intragranular and the extragranular phase.

18. The solid pharmaceutical composition according to anyone of the preceding items, wherein the lamivudine-containing layer comprises an intra-granular phase and an extragranular phase, wherein the total of lamivudine is present in the intra-granular phase or lamivudine is partitioned between the intragranular and the extragranular phase, preferably the total of lamivudine is present in the intra-granular phase.

19. The solid pharmaceutical composition according to anyone of items 1-17, wherein the lamivudine-containing layer comprises the total of lamivudine in a non-granulated form as a powder mixed with excipients (e.g. lamivudine-containing layer is prepared by a direct compression of mixture comprising lamuvidine and excipients).

20. The solid pharmaceutical composition according to anyone of items 1 -13, wherein efavirenz and abacavir are comprised intragranularly in same granules in efavirenz and abacavir-containing layer and lamivudine is comprised as a powder mixed with excipients in lamivudine-containing layer.

21. The solid pharmaceutical composition according to anyone of the preceding items, wherein the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose and non-cellulose filler of polyol type filler such as mannitol or polymer type filler such as starch or lactose, preferably is microcrystalline cellulose, silicified microcrystalline cellulose and/or the polyol type filler mannitol.

22. The solid pharmaceutical composition according to anyone of the preceding items, wherein the filler is present in an amount of from 2% to 30% by weight, preferably of from 3% to 25% by weight, and most preferably of from 4 % to 20% by weight of the total weight of the pharmaceutical composition without coating.

23. The solid pharmaceutical composition according to anyone of the preceding items, wherein the filler is present in the efavirenz and abacavir-containing layer in an amount of from 2% to 30% by weight, preferably of from 3% to 20% by weight, and most preferably of from 4% to 10% by weight of the total weight of the efavirenz and abacavir-containing layer.

24. The solid pharmaceutical composition according to anyone of the preceding items, wherein the filler is present in the lamivudine-containing layer in an amount of from 20% to 60% by weight, preferably of from 30% to 50% by weight, and most preferably of from 38% to 48% by weight of the total weight of the lamivudine-containing layer. 25. The solid pharmaceutical composition according to anyone of the preceding items, wherein the binder is selected from povidone, tragacanth, sodium alginate, gum arabic, starch pregelatinized, gelatin, and cellulosic derivatives, povidone, and starch pregelatinized, preferably is a cellulosic derivative, more preferably hydroxypropylcellulose.

26. The solid pharmaceutical composition according to anyone of the preceding items, wherein the binder is present in the pharmaceutical composition in an amount of from 1 to 40% by weight, preferably of from 1 % to 20% by weight, more preferably of from 2% to 20% by weight, even more preferably of from 1 % to 10% by weight, even more preferably of from 2% to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 2% to 8% by weight, even more preferably of from 3% to 8% by weight, even more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 6% by weight of the total weight of the pharmaceutical composition without coating.

27. The solid pharmaceutical composition according to anyone of the preceding items, wherein the binder is present in the efavirenz and abacavir-containing layer in an amount of from 1 to 20% by weight, preferably 1 % to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 2% to 8% by weight, even more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 6% by weight of the total weight of the efavirenz and abacavir-containing layer.

28. The solid pharmaceutical composition according to anyone of the preceding items, wherein the binder is present in the lamivudine-containing layer in an amount of from 1 to

10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 1 % to 4% by weight of the total weight of the lamivudine- containing layer.

29. The solid pharmaceutical composition according to anyone of the preceding items, wherein the disintegrant is selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, cross-linked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), and low- substituted hydroxypropylcellulose; particularly preferably the disintegrants are superdisintegrants selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, in particular is croscarmellose sodium.

30. The solid pharmaceutical composition according to anyone of the preceding items, wherein the disintegrant, preferably the superdisintegrant, is present in the pharmaceutical composition in an amount of from 1 to 20% by weight, preferably of from 1 % to 10% by weight, more preferably of from 2% to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 2% to 8% by weight, even more preferably of from 3% to 8% by weight, even more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 6% by weight of the total weight of the pharmaceutical composition without coating.

31. The solid pharmaceutical composition according to anyone of the preceding items, wherein the disintegrant, preferably the superdisintegrant, is present in the efavirenz and abacavir-containing layer in an amount of from 1 to 10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 1 % to 4% by weight of the total weight of the efavirenz and abacavir-containing layer.

32. The solid pharmaceutical composition according to anyone of the preceding items, wherein the disintegrant, preferably the superdisintegrant, is present in the lamivudine- containing layer in an amount of from 1 to 10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 4% by weight of the total weight of the lamivudine-containing layer.

33. The solid pharmaceutical composition according to anyone of the preceding items, wherein the surfactant is selected from the group consisting of sodium lauryl sulphate, docusate sodium, benzalkonium chloride, benzethonium chloride, and cetrimide, and polyoxyethylene-polyoxypropylene copolymers, preferably is sodium lauryl sulphate.

34. The solid pharmaceutical composition according to anyone of the preceding items, wherein the surfactant is present in the pharmaceutical composition in an amount of from above 0 to 7% by weight, preferably of from 0.1 % to 4% by weight, more preferably of from 0.5 % to 4% by weight, even more preferably of from 0.2 % to 3% by weight, even more preferably of from 0.5 % to 3% by weight, and most preferably of from 0.3 % to 2% by weight of the total weight of the pharmaceutical composition without coating.

35. The solid pharmaceutical composition according to anyone of the preceding items, wherein the surfactant is present in the efavirenz and abacavir-containing layer in an amount of from above 0 to 10% by weight, preferably of from 0.1 % to 5% by weight, more preferably of from 0.5 % to 5% by weight, even more preferably of from 0.3 % to 4% by weight, even more preferably of from 0.5 % to 3% by weight, and most preferably of from 0.3 % to 2% by weight efavirenz and abacavir-containing layer.

36. The solid pharmaceutical composition according to anyone of the preceding items, wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and silicon dioxide, preferably the lubricant is magnesium stearate.

37. The solid pharmaceutical composition according to anyone of the preceding items, further comprising a glidant, preferably selected from talc and colloidal silicon dioxide.

38. The solid pharmaceutical composition according to anyone of the preceding items, wherein the lubricant and/or the glidant is present in the pharmaceutical composition in an amount of from above 0 to 10% by weight, preferably of from 0.1 % to 8% by weight, more preferably of from 0.5% to 5% by weight, even more preferably of from 1 % to 5% by weight, even more preferably of from 0.5% to 3% by weight, and most preferably of from 1 % to 3% by weight of the total weight of the pharmaceutical composition without coating.

39. The solid pharmaceutical composition according to anyone of the preceding items, wherein the lubricant and/or the glidant is present in the efavirenz and abacavir-containing layer in an amount of from above 0 to 10% by weight, preferably of from 0.2% to 8% by weight, more preferably of from 0.2% to 5% by weight, and most preferably of from 0.5% to 3% by weight of the total weight of the efavirenz and abacavir-containing layer.

40. The solid pharmaceutical composition according to anyone of the preceding items, wherein the lubricant and/or the glidant is present in the lamivudine-containing layer in an amount of from above 0 to 10% by weight, preferably of from 0.2% to 8% by weight, more preferably of from 0.2% to 5% by weight, and most preferably of from 0.5% to 3% by weight of the total weight of the lamivudine-containing layer.

41. The solid pharmaceutical composition according to anyone of the preceding items, having an outer coating layer of a film-forming polymer.

42. The solid pharmaceutical composition according to the preceding item, wherein the dosage form has an outer coating layer of a film-forming polymer which is uniform and coherent at the body and the edges of the dosage form.

43. The solid pharmaceutical composition according to anyone of the preceding items, wherein the film forming polymer is a hydrophilic polymer, preferably selected from the group consisting of cellulose derivatives, vinyl derivatives, graft copolymer PVA-polyethylene glycol, copolymers of acrylic and/or methacrylic acid esters with trimethylammonium-methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester, preferably hydroxypropylmethyl cellulose (HPMC) and polyvinyl alcohol (PVA, most preferably polyvinyl alcohol (PVA).

44. The solid pharmaceutical composition according to anyone of the preceding items, wherein the film forming polymer is present in the pharmaceutical composition in an amount of from 0.1 to 15% by weight, preferably of from 1 % to 15% by weight, more preferably of from 0.3% to 10% by weight, even more preferably of from 1 % to 10% by weight, and most preferably of from 0.5 % to 5% by weight of the total weight of the pharmaceutical composition.

45. The solid pharmaceutical composition according to anyone of items 38 to 40, wherein the coating layer provides for a lag time sufficient to swallow tablet halves without and mouth- burning sensations, which has been confirmed by the volunteers. 46. The solid pharmaceutical composition according to any one of the preceding items, comprising, respectively based on the total weight of the single unit tablet:

(a) at least 60% by weight, preferably at least 70% by weight, more preferably from 70 to 90% by weight of abacavir, lamivudine and efavirenz;

(b) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 6% by weight of a disintegrant, preferably a superdisintegrant;

(c) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 6% by weight of a binder;

(d) from 0.1 to 7% by weight, preferably from 0.1 to 4% by weight, more preferably from 0.3 to 2% by weight of a surfactant;

(e) from 0 to 30% by weight, preferably from 3 to 35% by weight, more preferably from 4 to 20% by weight of a filler;

(f) optionally up to 10% by weight, preferably from 0.1 to 4% by weight, more preferably from 0.5 to 3% by weight of a lubricant and/or a glidant, and

(g) optionally an outer coating comprising 1 to 15 % by weight of a film-forming polymer.

47. The solid pharmaceutical composition according to any one of the preceding items, comprising, respectively based on the total weight of the single unit tablet:

(a) from 60 to 90% by weight, preferably from 70 to 90% by weight of abacavir, lamivudine and efavirenz;

(b) from 1 to 10% by weight, preferably from 1 to 6% by weight of a superdisintegrant selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, preferably croscarmellose sodium;

(c) from 1 to 10% by weight, preferably from 1 to 6% by weight of a binder selected from cellulosic derivatives, preferably hydroxypropylcellulose;

(d) from 0.5 to 3% by weight, preferably from 0.3 to 2% by weight of sodium lauryl sulphate;

(e) from 2 to 25% by weight, preferably from 4 to 20% by weight of a filler selected from the group consisting of microcrystalline cellulose and mannitol;

(f) optionally 0.1 to 8% by weight, preferably from 0.5 to 3% by weight of magnesium stearate and/or colloidal silicon dioxide; and

(g) optionally an outer coating comprising 1 to 10 % by weight of a film-forming polymer.

48. The solid pharmaceutical composition according to anyone of preceding items, wherein the total of efavirenz and abacavir is present in the efavirenz and abacavir-containing layer together with a part of filler, a part of a disintegrant, the total of a binder and the total of a surfactant, and wherein the other active layer or the extragranular phase, comprises the remaining part of a filler and a disintegrant.

Herein, the type and the amount of the filler in the efavirenz and abacavir-containing layer can be the same or different as the filler in the other active layer, and the type and the amount of the disintegrant in the efavirenz and abacavir-containing layer can be the same or different as the disintegrant in the other active layer; preferably the types of the filler and the disintegrant are the same and the respective amounts of the filler and the disintegrant can be appropriately apportioned. Typically the weight ratio of the filler and the disintegrant of the efavirenz and abacavir-containing layer to other layer is for example half-half or higher than 50%, preferably higher than 60%

49. The solid pharmaceutical composition according to any one of the preceding items, wherein the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

(a) at least 70% by weight, preferably at least 80% by weight, more preferably from 80 to 90% by weight of abacavir and efavirenz;

(b) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 4% by weight of a disintegrant, preferably a superdisintegrant;

(d) from 0.1 to 10% by weight, preferably from 0.1 to 5% by weight, more preferably from 0.3 to 2% by weight of a surfactant;

(e) from 2 to 30% by weight, preferably from 3 to 20% by weight, more preferably from 4 to 10% by weight of a filler;

(f) optionally up to 10% by weight, preferably from 0.2 to 5% by weight, more preferably from 0.5 to 3% by weight of a lubricant and/or a glidant.

50. The solid pharmaceutical composition according to any one of the preceding items, wherein the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

(a) from 80 to 90% by weight of abacavir and efavirenz;

(b) from 1 to 10% by weight, preferably from 1 to 4% by weight of a superdisintegrant selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, preferably croscarmellose sodium;

(d) from 0.5 to 3% by weight, preferably from 0.3 to 2% of sodium lauryl sulphate;

(e) from 2 to 25% by weight, preferably from 4 to 10% by weight of a filler selected from the group consisting of microcrystalline cellulose and mannitol;

(f) optionally 0.1 to 8% by weight, preferably from 0.5 to 3% by weight of magnesium stearate and/or colloidal silicon dioxide. 51. The solid pharmaceutical composition according to any one of the preceding items, wherein the lamivudine-containing layer comprises, respectively based on the weight of the lamuvidine-containing layer:

(a) at least 40% by weight, preferably at least 45% by weight, more preferably from 45 to 60% by weight of lamivudine;

(b) from 1 to 10% by weight, preferably from 1 to 6% by weight, more preferably from 2 to 4% by weight of a disintegrant, preferably a superdisintegrant;

(c) optionally from 1 to 10% by weight, preferably from 1 to 6% by weight, more preferably from 1 to 4% by weight of a binder;

(e) from 20 to 60% by weight, preferably from 30 to 50% by weight, more preferably from 38 to 48% by weight of a filler;

52. The solid pharmaceutical composition according to any one of the preceding items, wherein the lamivudine-containing layer comprises, respectively based on the weight of the lamivudine-containing layer:

(a) from 45 to 60% by weight of lamivudine;

(b) from 2 to 10% by weight, preferably from 2 to 4% by weight of a superdisintegrant selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, preferably sodium starch glycolate;

(c) from 20 to 60% by weight, preferably from 38 to 48% by weight of a filler selected from the group consisting of microcrystalline cellulose and mannitol;

(d) optionally 2 to 10% by weight, preferably from 1 to 4% by weight of a binder selected from cellulosic derivatives, preferably hydroxypropylcellulose;

(e) optionally 0.1 to 8% by weight, preferably from 0.5 to 3% by weight of magnesium stearate and/or colloidal silicon dioxide.

A binder is present in the lamivudine-containing layer only if lamivudine is granulated.

53. The solid pharmaceutical composition according to any one of the preceding items, wherein the abacavir and efavirenz-containing layer comprises efavirenz, abacavir, a filler, a disintegrant, a surfactant and a binder intragranularly and a lubricant extragranularly.

54. The solid pharmaceutical composition according to any one of the preceding items, wherein the abacavir and efavirenz-containing layer comprises efavirenz, abacavir, a filler, a surfactant, a binder and a part of a disintegrant intragranularly and a lubricant and a part of a disintegrant extragranularly.

55. The solid pharmaceutical composition according to the preceding item, wherein a ratio between intragranular and extragranular disintegrant is from 10:1 to 1 :2, preferably from 5:1 to 1 :1 , more preferably 4:1 to 1 :1 , most preferably about 3:1. 56. The solid pharmaceutical composition according to any one of the preceding items, wherein the lamivudine-containing layer comprises lamivudine, a filler, a disintegrant and optionally a binder and a lubricant or a glidant.

57. The solid pharmaceutical composition according to any one of the items 53-56, wherein a disintegrant is a superdisintegrant.

58. The solid pharmaceutical composition according to the items 1-2 and 4-57 comprising the triple combination of active ingredients (a) to (c) in the common solid pharmaceutical composition contains 150 mg abacavir (calculated as free base) respectively 175,5 mg abacavir sulphate, 75 mg lamivudine and 150 mg efavirenz. Preferably, such composition is appropriate for paediatric patients.

59. The solid pharmaceutical composition according to any one of the preceding items for use in the treatment of HIV infection, in particular immunodefiency virus type 1 (HIV-1 ) infection.

60. A process for preparing an solid pharmaceutical composition comprising a fixed combination of active ingredients (a) to (c) according to anyone of preceding items, wherein the active ingredients (a) to (c) are combined in a single unit tablet together with, as pharmaceutically acceptable excipient, at least a surfactant and a disintegrant, optionally further at least one selected from the group consisting of binders, fillers, lubricants, and film- forming agents.

61. The process according to item 60, wherein the efavirenz and abacavir-containing layer is prepared using a wet-granulation process or a dry-granulation process, preferably a wet-granulation process.

62. The process according to item 60 or item 61 , wherein the lamivudine-containing layer is prepared using a wet-granulation process, a dry-granulation process or a direct compression process, preferably a direct compression process.

63. The process according to item 61 or item 62, wherein the wet granulation uses an aqueous solution of polymer binder and surfactant.

64. The process according to the preceding item, wherein the polymer binder is a cellulose derivative, preferably hydroxypropylcellulose, and/or the surfactant is sodium lauryl sulphate. 65. The process according to anyone of items 60 to 64, wherein the wet-granulation process further involves drying, sieving, optionally preparation of granules or compressing into tablets, and coating.

66. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-i) mixing the active ingredients abacavir and efavirenz with appropriate pharmaceutical excipients including a surfactant, a binder, a filler and/or a disintegrant, preferably each of the aforementioned excipient type; (1-ii) optionally sieving of the obtained mixture of step (i) through appropriate mesh size, preferably through a 1 .0-2.0 mm mesh sieve;

(1-iii) optionally adding a binder and/or a surfactant into granulation fluid, for example water;

(1-iv) wet granulation of mixture from step (1-i) or (1-ii) with the granulation fluid (1 -iii) in a fluid bed dryer or a high shear mixer;

(1-v) drying of the wet granules to appropriate water content;

(1-vi) sieving of the obtained granules (1 -v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve and more preferably through a 0.71 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size;

(1-vii) mixing of the obtained granules (1-vi) with any remaining excipients, including at least a lubricant, optionally further including a disintegrant, a diluent and/or a binder;

(1-viii) compression of the final blend (1-vii) to the efavirenz and abacavir-containing layer, for instance using standard rotary tablet press;

(2-i) mixing the active ingredient lamivudine with appropriate pharmaceutical excipients including a filler, a disintegrant, a lubricant and optionally with a binder;

(2-ii) optionally sieving of the obtained mixture of step (i) through appropriate mesh size, preferably through a 1 .0-2.0 mm mesh sieve;

(2-iii) compression of the final blend (2-ii) to the lamivudine-containing layer upper to the efavirenz and abacavir-containing layer, for instance using standard rotary tablet press;

(3) optionally and preferably coating of the tablets in fluid bed system, preferably using a

Wurster insert, with a coating material comprising film-forming polymer.

67. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-i) mixing the active ingredients abacavir and efavirenz with appropriate pharmaceutical excipients including a surfactant, a binder, a filler and/or a disintegrant , preferably each of the aforementioned excipient type;

(1-ii) optionally sieving of the obtained mixture of step (i) through appropriate mesh size, preferably through a 1 .0-2.0 mm mesh sieve;

(1-v) drying of the wet granules to appropriate water content;

(1-vi) sieving of the obtained granules (1 -v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve and more preferably through a 0.71 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size; (1-vii) mixing of the obtained granules (1-vi) with any remaining excipients, including at least a lubricant, optionally further including a disintegrant, a diluent and/or a binder;

(2-i) mixing the active ingredient lamivudine with appropriate pharmaceutical excipients including a filler and/or a disintegrant, and optionally with a binder;

(2-iii) optionally adding a binder into granulation fluid, for example water;

(2-iv) wet granulation of mixture from step (2-i) or (2-ii) with the granulation fluid (2-iii) in fluid bed dryer or a high shear mixer;

(2-v) drying of the wet granules to appropriate water content;

(2-vi) sieving of the obtained granules (2-v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve and more preferably through a 0.71 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size;

(2-vii) mixing of the obtained granules (2-vi) with any remaining excipients, including at least a lubricant and/or glidant, optionally further including a disintegrant, a diluent and/or a binder; (2-vi ii) compression of the final blend (2-vii) to the lamivudine-containing layer upper to the efavirenz and abacavir-containing layer, for instance using standard rotary tablet press;

(3) optionally and preferably coating of the tablets in fluid bed system, preferably using a Wurster insert, with a coating material comprising film-forming polymer.

68. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-iii) optionally adding a binder and/or surfactant into granulation fluid, for example water; (1-iv) wet granulation of mixture from step (1-i) or (1-ii) with the granulation fluid (1 -iii) in a fluid bed dryer or a high shear mixer;

(1-v) drying of the wet granules to appropriate water content;

(1-vii) mixing of the obtained granules (1-vi) with any remaining excipients, including at least a lubricant, optionally further including a disintegrant, a diluent and/or a binder; (1-viii) compression of the final blend (1-vii) to the efavirenz and abacavir-containing layer, for instance using standard rotary tablet press;

(2-i) mixing the active ingredient lamivudine with appropriate pharmaceutical excipients including a filler and/or a disintegrant, and optionally with a lubricant;

(2-iii) dry granulation of mixture from step (2-ii), preferably by roller compaction;

(2-v) milling;

(2-vi) optionally sieving of the obtained granules (2-v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve and more preferably through a 0.71 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size; (2-vii) mixing of the obtained granules (2-vi) with any remaining excipients, including at least a lubricant and/or a glidant, optionally further including a disintegrant, a diluent and/or a binder;

(2-vi ii) compression of the final blend (2-vii) to the lamivudine-containing layer upper to the efavirenz and abacavir-containing layer, for instance using standard rotary tablet press;

69. A process of manufacturing a single unit tablet according to any one of items 59-67, wherein a disintegrant is a superdisintegrant.

Detailed description of the invention The present invention is in further described in more details by preferred embodiments and examples, which are however presented for illustrative purpose only and shall not be understood as limiting the scope of the present invention.

The present invention overcomes shortcomings of the prior art related to single dose administration of listed compounds abacavir, lamivudine, and efavirenz (Ziagen^®, Epivir^®, Stocrin^®, and combinational product Kivexa^®) as well as liquid formulation of efavirenz. The present invention made feasible a fixed combination of all three compounds abacavir, lamivudine and efavirenz within one and the same, i.e. a common solid pharmaceutical composition, despite the remarkably different properties and use constraints of the specifically combined distinct active compounds. Accordingly, the solid pharmaceutical composition according to the present invention has demonstrated to combine, in a common solid dosage form, specifically selected active ingredients being associated with properties which seemingly are in conflict when brought together for formulation purposes, notably highly water-soluble abacavir (water solubility 77 mg/ml as sulphate salt) and lamivudine (water solubility 70 mg/ml) with poorly water-soluble efavirenz (water solubility 0.00855 mg/ml), while allowing to reduce mouth-burning effect of efavirenz in a still maintained high variability of solid dosage form designs to an acceptable level. Unexpectedly, bioequivalent common fixed dose triple combination abacavir, lamivudine and efavirenz was feasible at a high total drug load of at least 60% by weight based on the total weight of the whole single unit tablet composition, which correspondingly means low content of functional excipients which normally is considered responsible for processing, stability and dissolution performance of an entire pharmaceutical composition.

Further, a high freedom of fixed dose solid dosage form design has been found even by combination of abacavir, lamivudine and efavirenz in a common solid composition, without detriment to a fast disintegration and rapid onset of action.

Further, the fixed-dose combination formulation of abacavir, lamivudine and efavirenz according to the present invention has been found to satisfy a hitherto unmet need to a simplification of anti-HIV therapy by decreasing the number of individual dosage forms to be taken by the patient, notably to fixed dose to be taken only once per day, thereby significantly improving patient compliance compared with prior art reference products. The improvement of patient compliance is considered especially important in situations where it may contribute reducing the incidence of resistance. Thereby, the triple fixed-dose combination of the present invention is associated with advantages for the individual patient as well as for the whole society with regards to the burden of disease and fighting the emergence of resistance.

Accordingly and in more detail, particular advantages achieved by the present invention are:

Decrease of pill burden (administration from single dossier):

With the once daily, single dose in-take of the fixed combination, a decrease in the number of administrations can be achieved compared to the single agent preparations or fixed dose combinations currently available on the market.

- Increased compliance:

Simplification of therapy improves patient compliance. This was demonstrated not only in the case of HIV but also in other aspects of anti-infective treatments where way of drug administration or dose frequency had an impact on patient compliance especially in paediatric patients. Depending on a patient's choice and convenience, the solid pharmaceutical composition can be provided in easy swallowing form and flexible for intake.

Fighting emergence of resistance: Poor adherence can result in sub-therapeutic plasma antiretroviral drug concentrations, facilitating development of drug resistance to one or more drugs in a given regimen, and possibly cross-resistance to other drugs in the same class. Multiple factors (including regimen potency, pharmacokinetics, drug interactions, viral fitness, and the genetic barrier to antiretroviral resistance) influence the adherence-resistance relationship.

Acceptable swallowable dosage form:

The present invention provides dosage forms in still acceptable in physical volume even at high drug loading (1500 mg of active compounds).

Prevent mouth burning effect:

Despite the different use attributes of the distinct active ingredients to be combined, the solid fixed-dose combination formulation according to the present invention still allows by suitable physical separation and/or by physical barrier to protect oral mucosa from direct contact with efavirenz, which is primarily involved in mouth burning effect. Ameliorated palatability of proposed dosage form can improve compliance in comparison to efavirenz liquid formulation or for the patients with difficulties with the swallowing. Adequate taste, aftertaste and texture could be demonstrated by representative common oral dosage forms described in more detail below by reference to illustrative embodiments.

Accordingly, the formulations disclosed herein combine a number of valuable use attributes which are difficult to unify in a fixed triple combination of abacavir, lamivudine and efavirenz, including bioequivalence, reduction of mouth burning effect caused by efavirenz as well as for providing of palatable formulations even for high drug loaded system that is important for a triple fixed dose combination but which inherently cannot make use of a high amount of functional excipients. In the drawings:

Figure 1 shows the dissolution profile of abacavir, respectively from a single unit tablet according to the present invention and from conventional reference abacavir mono-product (Ziagen^®), in 900 ml. of 0.01 M HCI with salts, Apparatus 2, 50 rpms using peak vessels; Figure 2 shows the dissolution profile of lamivudin, respectively from a single unit tablet according to the present invention and from conventional reference lamivudine mono-product (Epivir^®) in 900 ml. of 0.001 M HCI with salts, Apparatus 1 , 75 rpms; and

Figure 3 shows the dissolution profile of efavirenz, respectively from a single unit tablet according to the present invention and from conventional reference efavirenz mono-product (Stocrin^®) under non-sink conditions in 900 ml. of 0.01 M HCI with salt and SIF powder, Apparatus 2, 50 rpms using peak vessels. Particularly, the solid pharmaceutical composition of the present invention is a special fixed dose combination comprising:

(a) a compound of formula I

formula 1

(b) a compound of formu

formula 2

(c) a compound of formula 3

formula 3

Preferably, the solid pharmaceutical composition of the present invention is in the form of a single unit tablet wherein, the tablet is structured by multiple layers, wherein lamivudine is present in one layer (i.e. lamivudine-containing layer), and abacavir and efavirenz are present in a layer (i.e. efavirenz and abacavir-containing layer) contiguous with the lamivudine-containing layer, optionally with an intermediate layer in between. Preferably the multiple layers constitute a bilayer structure.

Accordingly, the present invention provides a triple combinational product containing abacavir, lamivudine, and efavirenz which is beneficially suitable for once daily administration. The preferred quantity of the total of the three active substances in triple combination product is at least 1500 mg, notably 1500 mg exact - noting that in case a salt or other modified form is used, such as abacavir sulphate, the amount of the modified form is recalculated into the active substance - e.g. abacavir - itself. The invention makes use of appropriately dosage form of single unit tablets. Easier handling of single unit tablets still meets acceptable patient compliance

All % indications used herein denote % by weight unless stated otherwise. The abacavir compound in the triple combination product is suitably in salt form, preferably sulphate salt and notably at a ratio of abacavir to sulphate of 2:1 . The amount of abacavir is calculated as the free base abacavir compound; hence for instance 600 mg of abacavir is equivalent to 702 mg of abacavir sulphate which can be used for formulation design. The lamivudine compound in the triple combination is suitably present in stable form, for example the known anhydrous polymorphic form (form II). The amount of lamivudine in the formulation is equivalent to once daily dose and it represents 300 mg.

The solid pharmaceutical composition comprising the triple combination of active ingredients (a) to (c) in the common solid pharmaceutical composition suitable for paediatric patients contains 150 mg abacavir (calculated as free base) respectively 175,5 mg abacavir sulphate, 75 mg lamivudine and 150 mg efavirenz.

The efavirenz compound in the triple combination product is beneficially enhanced in its otherwise poor solubility by micronization and increment of specific surface area. The efavirenz form preferably included into the pharmaceutical composition according to present invention has a primary particle size of D(0.5) of 2-8 μηη, for example about ~ 5 μηη, and of D(0.9) in the range of 9-26 μηη, for example in the range of D(0.9) of 10-14 μηη. The primary efavirenz particles of indicated size can be in the form of agglomerated particles, without inacceptable detriment to solubility increase. Specific surface area of efavirenz is mostly influenced by extent of particle agglomeration, and is preferably ranged from 2.5 to 7.0 m²/g. Particle size distribution can be measured for instance using a laser diffraction analyzer, such as with a Malvern Mastersizer 3000. Formulating efavirenz together with a surfactant has been found to further significantly enhance the poor solubility thereof.

In a preferred embodiment the solid pharmaceutical composition of the present invention has an outer coating. In particular when the coating comprises a water swellable, or preferably a water soluble hydrophilic polymer as a film forming polymer, effective physical barrier function against mouth burning effect due to presence of efavirenz is combined with a rapid onset of action due to appropriate swelling or solubility of the coating after swallowing. The coating is provided as outer tablet layer of the single unit tablet. The water soluble or water swellable hydrophilic polymer is preferably selected from the group consisting of cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose sodium, hydroxyethylcellulose; vinyl derivatives such as polyvinyl alcohol (PVA), graft copolymer PVA-polyethylene glycol such as Kolicoat^®; copolymers of acrylic and/or methacrylic acid esters with trimethylammonium-methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters; polymers of methacrylic acid or methacrylic acid esters; copolymers of acrylic acid ethylester and methacrylic acid methyl ester; and copolymers of acrylic acid and acrylic acid methylester. In view of the intended function, most preferred film-forming polymer in the coating is HPMC or polyvinyl alcohol (PVA), in particular PVA. Besides the film-forming polymer the coating may contain further ingredients, such as a plasticizer, a pigment, etc.

Accordingly, the coating layer beneficially provides for a lag time not less than 3 minutes. That is, the coating ensures lag time not less than 3 minutes in mouth before swallowing of the dosage form with an appropriate amount of water. Further, the coating contributes to obtaining smoother surfaces, thereby assisting in swallowing and reducing the retention time of the dosage form in the mouth to thereby further reducing the chance of generating mouth burning effect, what has been confirmed by the volunteers. More preferred are dosage units comprising the triple combination which have a constant specific surface, a smooth outer surface, and robust mechanical properties. The film forming polymer is suitably present in the pharmaceutical composition in an amount of from 1 to 20% by weight, preferably of from 1 % to 15% by weight, more preferably of from 1 % to 10% by weight, even more preferably of from 3% to 15% by weight, and most preferably of from 4 % to 10% by weight of the total weight of the pharmaceutical composition.

The filler, when preferably contained in the solid pharmaceutical composition according to the present invention, is preferably selected from cellulose fillers such as microcrystalline cellulose, e.g. Avicel^® such as Avicel PH 102, and silicified microcrystalline cellulose (e.g. Prosolv^®), and non-cellulose fillers such as polyols, for instance isomalt (e.g. GalenlQ^®), mannitol (e.g. Pearlitol^®) or xylitol, or polymer filler such as starch (e.g. starch 1500). The selected filler preferably has plastic deformation properties under compression. Microcrystalline cellulose or silicified microcrystalline cellulose are particularly preferred, as these do have beneficial plastic deformation properties and additionally have diluent as well as disintegrant function (in the specified content ranges, these cellulose types are however counted as filler materials, not as diluents or disintegrants). Depending on the type of formulation, notably in case of granules, mannitol has the benefit of not only mainly acting as filler (which hence, when present, will be counted as such), but also as taste modifier.

The filler when preferably present is contained in the solid pharmaceutical composition in an amount of from 2% to 30% by weight, preferably of from 3% to 25% by weight, and most preferably of from 4% to 20% by weight of the total weight of the pharmaceutical composition without coating.

The filler is preferably present in the efavirenz and abacavir-containing layer in an amount of from 2% to 30% by weight, preferably of from 3% to 20% by weight, and most preferably of from 4% to 10% by weight of the efavirenz and abacavir-containing layer.

The filler is preferably present in the lamivudine-containing layer in an amount of from 20% to 60% by weight, preferably of from 30% to 50% by weight, and most preferably of from 38% to 48% by weight of the lamivudine-containing layer.

The binder, when preferably contained in the solid pharmaceutical composition according to the present invention, is preferably selected from matrix type polymer binder and/or a granulation polymer binder, specifically cellulose derivative-type polymer binder such as hydroxypropyl cellulose (e.g. Klucel^®), hydroxypropylmethylcellulose (e.g. Methocel^®), povidone, tragacanth, sodium alginate, gum arabic, gelatin, and starch pregelatinized. Preferably the binder is cellulosic derivatives, more preferably hydroxypropylcellulose. Binding agents is generally used to improve adhesion of powder particles during wet granulation. The selected binder preferably has plastic deformation properties under compression. For that purpose, excipients from the group of cellulose derivatives can favourably be utilized and are preferred.

In this context, it is noted that it lies in the nature of pharmaceutical excipients that they sometimes can perform more than one function in a pharmaceutical formulation. In the context of the present invention, in order to provide an unambiguous definitions, the fiction will therefore preferably apply that a substance which is used as a particular excipient, is not simultaneously also used as a further pharmaceutical excipient. For example, a filler such as microcrystalline cellulose used as a filler, is not also used for example as a disintegrant and not also used for example as a binder (even though a microcrystalline cellulose filler might also exhibit a certain disintegrating effect and a certain binding effect) while the term "binder" is meant within the context of the present invention as defined above and which, in particular in the form of a polymer binder and more specifically as a cellulose derivative polymer binder, and should be counted as such.

The binder when preferably present is contained in the solid pharmaceutical composition in an amount of from 1 to 40% by weight, preferably of from 1 % to 20% by weight, more preferably of from 1 % to 20% by weight, even more preferably of from 1 % to 10% by weight, even more preferably of from 2% to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 2% to 8% by weight, even more preferably of from 3% to 8% by weight, even more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 6% by weight of the total weight of the pharmaceutical composition without coating.

The binder is preferably present in the efavirenz and abacavir-containing layer in an amount of from 1 to 20% by weight, preferably of from 1 % to 20% by weight, more preferably of from 1 % to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 1 % to 6% by weight and most preferably of from 2% to 6% by weight of the total weight of the efavirenz and abacavir-containing layer.

The binder is preferably present in the lamivudine-containing layer in an amount of from 1 to 10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 1 % to 4% by weight of the total weight of the lamivudine- containing layer.

The disintegrant, when preferably contained in the solid pharmaceutical composition according to the present invention, is preferably selected from the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, cross-linked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose. Particularly preferable disintegrants are superdisintegrants and are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, in particular is croscarmellose sodium. When preferably present, the disintegrant and preferably the superdisintegrant is added to be in contact with the efavirenz compound, for instance by adding it into the same compartment or granulate of the dosage form as efavirenz, significantly contributing to its better wettability dissolution from the dosage form. When an efavirenz containing granulate (containing the disintegrant, preferably the superdisintegrant, and further preferred containing surfactant) - no matter whether further active ingredients are also contained in the efavirenz containing granulate - is formulated, it is further preferred that the extragranular phase - no matter whether further active ingredients are also contained in the extragranular phase - also contains the disintegrant, preferably the superdisintegrant.

The disintegrant when preferably present is contained in the solid pharmaceutical composition in an amount of from 1 to 20% by weight, preferably of from 1 % to 10% by weight, more preferably of from 2% to 10% by weight, even more preferably of from 1 % to 8% by weight, even more preferably of from 2% to 8% by weight, even more preferably of from 3% to 8% by weight, even more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 6% by weight of the total weight of the pharmaceutical composition without coating, if present.

The disintegrant is preferably present in the efavirenz and abacavir-containing layer in an amount of from 1 to 10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 1 % to 4% by weight of the total weight of the efavirenz and abacavir-containing layer, if present.

The disintegrant is preferably present in the lamivudine-containing layer in an amount of from 1 to 10% by weight, preferably of from 1 % to 8% by weight, more preferably of from 1 % to 6% by weight, and most preferably of from 2% to 4% by weight of the total weight of the lamivudine-containing layer, if present. The lubricant, when contained in the solid pharmaceutical composition and especially in the tablets according to the present invention, is preferably selected from the group consisting of colloidal silicon dioxide such as Aerosil^®, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and colloidal silicon dioxide; more preferably the lubricant is magnesium stearate or colloidal silicon dioxide.

The glidants, when contained in the solid pharmaceutical composition according to the present invention, can improve the flow characteristics of granulation material or a powder mixture, and is preferably selected from talc and colloidal silicon dioxide.

The lubricant and/or the glidant when preferably present is contained in the solid pharmaceutical composition in an amount of from 0 to 10% by weight, preferably of from 0.1 % to 8% by weight, more preferably of from 0.5% to 5% by weight, even more preferably of from 1 % to 5% by weight, even more preferably of from 0.5% to 3% by weight, and most preferably of from 1 % to 3% by weight of the total weight of the pharmaceutical composition without coating.

The lubricant and/or the glidant is preferably present in the efavirenz and abacavir-containing layer in an amount of from above 0 to 10% by weight, preferably of from 0.2% to 8% by weight, more preferably of from 0.2% to 5% by weight, and most preferably of from 0.5% to 3% by weight of the total weight of the efavirenz and abacavir-containing layer.

The lubricant and/or the glidant is preferably present in the lamivudine-containing layer in an amount of from above 0 to 10% by weight, preferably of from 0.2% to 8% by weight, more preferably of from 0.2% to 5% by weight, and most preferably of from 0.5% to 3% by weight of the total weight of the lamivudine-containing layer.

The solid pharmaceutical composition may optionally further comprise the glidant, preferably selected from the group consisting of colloidal silica, silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof.

The surfactant, when preferably contained in the solid pharmaceutical composition according to the present invention, is preferably selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulphate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predominantly d₄ alkyl, and polyoxyethylene- polyoxypropylene copolymers; preferably the surfactant is sodium lauryl sulphate. It improves wettability and rate of dissolution of efavirenz, in particular if present in micronized form. The surfactant when preferably present is contained in the solid pharmaceutical composition in an amount of from 0 to 5% by weight, preferably of from 0.1 % to 4% by weight, more preferably of from 0.5 % to 4% by weight, even more preferably of from 0.2 % to 3% by weight, even more preferably of from 0.5 % to 3% by weight, and most preferably of from 0.3 % to 2% by weight of the total weight of the pharmaceutical composition without coating. The surfactant is preferably present, more preferably only in the efavirenz and abacavir- containing layer, in an amount of from above 0 to 10% by weight, preferably of from 0.1 % to 5% by weight, more preferably of from 0.5 % to 5% by weight, even more preferably of from 0.3 % to 4% by weight, even more preferably of from 0.5 % to 3% by weight, and most preferably of from 0.3 % to 2% by weight efavirenz and abacavir-containing layer. Sweeteners and/or flavours/aromas, when contained in the solid pharmaceutical composition according to the present invention and notably in the embodiment of granules, is preferably selected from aspartame, saccharine sodium, sucralose, glycyrrhiza, and one or more flavors such as mint, orange, lemon, strawberry, vanilla, raspberry and cola flavour. The solid pharmaceutical composition according to the present invention may beneficially further include substances having pleasant cooling effect, for instance menthol and polyols such as mannitol, xylitol, isomalt, eritriol). Alternative to and preferably in addition to the physical barrier obtained by the above described outer coating layer, the addition of sweeteners and/or flavours/aromas and optionally cooling-effect substances further contributes to a beneficial taste masking effect.

The excipient selected from the group of sweeteners, flavours/aromas and cooling effect substances when preferably present is contained in the solid pharmaceutical composition in an amount of from 0 to 5% by weight, preferably of from 0.1 % to 4% by weight, more preferably of from 0.5 % to 3% by weight, and most preferably of from 0.5 % to 2% by weight of the total weight of the pharmaceutical composition without coating (calculated without polyol, if present, due to their main function as filler). Plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol.

The particular advantage of the solid pharmaceutical composition according to the present invention resides in that dosage forms with a respective high drug load covering all of active ingredients (a) to (c) could be formulated while correspondingly minimizing, without however abstaining from relevant excipients that compromise the different use attributes of the three distinct active compounds. Accordingly, despite high drug load of all active ingredients (a) to (c) while managing for low amounts of excipients, the solid pharmaceutical composition can beneficially comprise each (at least one of each group) of a disintegrant, a binder, a lubricant, a surfactant and a film-forming agent, optionally further comprising a glidant, a sweetener and/or a flavouring agent.

It has been found that the triple combination in the single unit tablet of the present invention allows to make use of a separation and/or partition of the three active ingredients into discrete compartments. In the described embodiments, specific requirements of each active ingredient alone or in combination with one another can be well harmonized, especially in terms of overall performance of: dissolution and bioequivalence at high drug load and correspondingly inherent relative low proportion of functional excipients, combined with prevention of mouth burning effect.

Such separation or partitioning concepts is particularly described below. This separation concept can be beneficially accomplished by applying a separation structure of:

The single unit tablet is structured by multiple layers and preferably as bilayer, wherein lamivudine is present in one layer (i.e. lamivudine-containing layer), and abacavir and efavirenz are present in a layer (i.e. efavirenz and abacavir-containing layer) contiguous with the lamivudine-containing layer. An intermediate layer may optionally be provided in between. The compositions of the layers are specifically adjusted to the respective active ingredient. In the abacavir and efavirenz-containing layer, efavirenz and abacavir in the selected dose (specifically 600mg efavirenz; specifically 600 mg abacavir base or 702 mg abacavir sulphate;) are preferably combined with a surfactant such as sodium lauryl sulphate, a disintegrant, preferably a superdisintegrant such as croscarmellose sodium or sodium starch glycolate, a binder such as hydroxypropyl cellulose and/or hydroxypropylmethylcellulose and preferably hydroxypropyl cellulose, a filler such as microcrystalline cellulose and/or mannitol and preferably microcrystalline cellulose, and a lubricant such as magnesium stearate. Efavirenz and abacavir are comprised in same granules or separated granules or efavirenz is comprised intragranularly and abacavir extragranularly or efavirenz is comprised intragranularly and abacavir is comprised partially intragranularly and partially extragranularly. Preferably, efavirenz and abacavir are comprised in same granules. In the other active layer, lamivudine in the respectively selected dose (specifically 300mg lamivudine) is preferably combined with a superdisintegrant such as sodium starch glycolate or croscarmellose sodium, a filler such as microcrystalline cellulose, and a lubricant or a glidant such as magnesium stearate and colloidal silicon dioxide. Lamivudine is comprised intragranularly or lamivudine is comprised as a powder mixed with excipients. Preferably lamivudine is comprised as a powder mixed with excipients.

According to the preferred embodiment of the invention efavirenz and abacavir are comprised intragranularly in same granules in the efavirenz and abacavir-containing layer and lamivudine is comprised as a powder mixed with excipients in the lamivudine-containing layer.

Preferably, the abacavir and efavirenz-containing layer comprises efavirenz, abacavir, a filler, a disintegrant, a surfactant and a binder intragranularly and a lubricant and/or a glidant extragranularly. A disintegrant is preferably a superdisintegrant.

Even more preferably, the abacavir and efavirenz-containing layer comprises efavirenz, abacavir, a filler, a surfactant, a binder and part of disintegrant intragranularly and a lubricant and/or a glidant and part of a disintegrant extragranularly. A disintegrant is preferably a superdisintegrant.

A ratio between intragranular and intragranular disintegrant is from 10:1 to 1 :2, preferably from 5:1 to 1 :1 , more preferably 4:1 to 1 :1 , most preferably about 3:1 . A disintegrant is preferably a superdisintegrant. Preferably, the lamivudine-containing layer comprises lamivudine, a filler, a disintegrant and a lubricant and/or a glidant as a powder mixture or the lamivudine-containing layer comprises lamivudine, a filler, a disintegrant and optionally a binder intragranularly and a lubricant and/or a glidant extragranularly. A disintegrant is preferably a superdisintegrant.

In another preferred embodiment the solid pharmaceutical composition according to any one of the preceding items, comprising, respectively based on the total weight of the single unit tablet:

(g) optionally an outer coating comprising 1 to 10 % by weight of a film-forming polymer. In another preferred embodiment the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

In another preferred embodiment the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

(a) from 80 to 90% by weight of abacavir and efavirenz;

(b) from 2 to 10% by weight, preferably from 2 to 4% by weight of a superdisintegrant selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, preferably croscarmellose sodium;

(f) optionally 0.1 to 8% by weight, preferably from 0.5 to 3% by weight of magnesium stearate and/or colloidal silicon dioxide. In another preferred embodiment the lamivudine-containing layer comprises, respectively based on the weight of the lamivudine-containing layer:

(b) from 1 to 10% by weight, preferably from 1 to 6% by weight, more preferably from 2 to 4% by weight of a disintegrant;

(c) optionally from 1 to 10% by weight, preferably from 1 to 6% by weight, more preferably from 1 to 4% by weight of a binder; (e) from 20 to 60% by weight, preferably from 30 to 50% by weight, more preferably from 38 to 48% by weight of a filler;

In another preferred embodiment the lamivudine-containing layer comprises, respectively based on the weight of the lamivudine-containing layer:

(a) from 45 to 60% by weight of lamivudine;

According to the preferred embodiments of the present invention a binder is present in lamivudine containing layer only when lamivudine is granulated.

The single unit tablet of this embodiment is preferably prepared in that the efavirenz and abacavir-containing layer was obtained including wet granulation of efavirenz and abacavir with surfactant and polymer binder and other mentioned excipients and then compressed into the corresponding layer, and that the lamivudine-containing layer was obtained including dry granulation or wet granulation of lamivudine and other mentioned excipients or direct compression of lamivudine and other mentioned excipients, preferably by a direct compression, and then compressed into the corresponding layer, using standard bilayer tablet compression machine.

In any of the above embodiments, the resulting single unit tablet is preferably coated, as described elsewhere herein.

Applying the concept of layering of the present invention provides superior balance between otherwise conflicting API-specific properties. In particular, a dual mode action of favourable disintegration for the first layer effectively co-acts with disintegration and/or dissolution for the second layer, combined with effective taste masking and mouth-burning prevention. In the following further exemplified embodiments to formulate the fixed solid pharmaceutical combination composition in the form of single unit tablets will be described.

Unexpectedly and despite of relevantly different properties concerning the respective active ingredients (a), (b) and (c) specifically, it was possible to formulate the fixed triple combination into a single unit tablet even at a high drug load of all active ingredients (a) to (c) of approximately 70% by weight or higher of the total formulation, the remainder being composed of functional excipients including coating as described above.

A suitable process of manufacturing the single unit tablets may include wet granulation. For example, abacavir sulphate, lamivudine and efavirenz are granulated, together or separately, with excipients, for instance a binder, a filler and/or a disintegrant (preferably a superdisintegrant), using water solution including the binder and the surfactant. Granulation may be performed in a fluid-bed dryer or a high shear mixer. Drying of the wet granules is conducted until adequate water content is achieved (for instance LOD 2.0% or lower, suitably at LOD of 1.0%). Obtained mixture is sieved through appropriate mesh size, for instance through a 0.71 mm mesh sieve. Sieved granulated powder is mixed with the extragranular excipients, such as further filler, further disintegrant (preferably superdisintegrant), and a lubricant and/ or a glidant and optionally a diluent. Lubricated final blend is compressed into tablets, for example using standard rotary press. Tablet cores are preferably coated, e.g. in pan-coater, with outer coating, using film-forming polymer such as HPMC or PVA. Compositions for the respective layers can be prepared in a manner better suited for the respectively included active compound. Preferably, the composition of the efavirenz and abacavir-containing layer is prepared by a process including wet granulation and further formulated as described above. Lamivudine active-containing layer is prepared by a process including wet granulation, dry granulation or direct compression. In case of granulation process granulated powder is mixed with the extragranular excipients, such as further disintegrant (preferably superdisintegrant), a filler and a lubricant and/or a glidant and optionally diluent. The respective layer-specific lubricated blends are then compressed into a bilayer tablet using standard bilayer tablet compression machine.

The term "single unit tablet" means that the respectively defined active and inactive ingredients are formulated together to become constitutional part of a physically commonly formulated tablet dosage form.

The possibility of combining, despite the presence of a high drug load, the three active ingredients abacavir, lamivudine and efavirenz (a correspondingly advantageous high percentage by weight of the triple combination for the total composition is represented in every single tablet) in a single unit tablet with adequate mechanical strength makes this dosage form suitable for the purpose of a triple fixed solid pharmaceutical composition, while at the same time further reducing the risk of mouth burning effect. Advantageously, the amount of the active ingredients abacavir, lamivudine and efavirenz in total can be even increased to at least 70% by weight of the whole tablet composition.

In view of a preferred provision of an outer protective coating, the embodiment of the triple fixed combination of abacavir, lamivudine and efavirenz utilizing single unit tablets have revealed several advantages. It was found that they can be coated reproducibly with relatively low amount of coating material, and due to their constant specific surface area, smooth outer surface and robust mechanical properties were obtained. Surprisingly, although most of reported cases relate to single API to incorporate into tablets with the intention of immediate or delayed drug release, it was found that a high drug load inherent to the fixed triple combination of APIs could be compressed into the tablets. Further, the preparation of tablets has been found to be particularly suitable for the fixed triple combination of efavirenz, lamivudine and abacavir according to the present invention, as this was able to provide a good compromise between opposing use attributes of efavirenz, which typically in its crystalline and micronized form has poor flowability and compressibility properties, and lamivudine and abacavir, which conventionally in their conventional single formulation forms required relatively high amounts of compressible filler.

Moreover, it was found that the embodiment of single unit tablets according to the present invention is particularly amenable to applying the layering concept as described above, wherein by the targeted distribution of the three active ingredients into discrete layers allows to even better harmonize otherwise hardly consistent API-specific attributes despite of the high drug load and thus inherent low functional excipient content, notably poor water- solubility, poor flowability and compressibility of efavirenz, combined with good water solubility, yet stickiness and limited compressibility of either or both of lamivudine and abacavir, while still simultaneously preventing mouth burning effect associated with efavirenz.

A suitable process of manufacturing an oral dosage form in the form of a single unit tablet is described. In one embodiment, the single unit tablet form is prepared using a wet-granulation process, drying, sieving, compressing into tablets for preparing efavirenz and abacavir- containing layer, and using a direct compression process for preparing lamivudine-containing layer, and optionally and finally using a coating preferably.

More specifically, the process may comprise the steps of:

(1-i) mixing the active ingredients abacavir and efavirenz with appropriate pharmaceutical excipients including a surfactant, a binder, a filler and/or a disintegrant, preferably each of the aforementioned excipient type;

(1-v) drying of the wet granules to appropriate water content;

(2-i) mixing the active ingredient lamivudine with appropriate pharmaceutical excipients including a filler, a disintegrant, a lubricant and/or a glidant and optionally with a binder;

In another embodiment, the single unit tablet form is prepared using a wet-granulation process, drying, sieving, compressing into tablets, and optionally and finally using a coating preferably.

More specifically, the process may comprise the steps of:

(1-iii) optionally adding a binder and/or a surfactant into granulation fluid, for example water; (1-iv) wet granulation of mixture from step (1-i) or (1-ii) with the granulation fluid (1 -iii) in a fluid bed dryer or a high shear mixer;

(1-v) drying of the wet granules to appropriate water content;

(2-iii) optionally adding a binder into granulation fluid, for example water;

(2-v) drying of the wet granules to appropriate water content;

(2-vii) mixing of the obtained granules (2-vi) with any remaining excipients, including at least a lubricant and/or a glidant, optionally further including disintegrant, diluent and/or binder;

Wurster insert, with a coating material comprising film-forming polymer.

In another embodiment, the single unit tablet form is prepared using a wet-granulation process, drying, sieving, compressing into tablets for preparing efavirenz and abacavir- containing layer, and using a dry-granulation process, milling, sieving, compressing into tablets for preparing lamivudine-containing layer, and optionally and finally using a coating preferably.

More specifically, the process may comprise the steps of:

(1-i) mixing the active ingredients abacavir and efavirenz with appropriate pharmaceutical excipients including a surfactant, a binder, a filler and/or a disintegrant , preferably each of the aforementioned excipient type; (1-ii) optionally sieving of the obtained mixture of step (i) through appropriate mesh size, preferably through a 1 .0-2.0 mm mesh sieve;

(1-v) drying of the wet granules to appropriate water content;

(2-v) milling;

Examples

The present invention is described below in more detail by reference to non-limiting, illustrative Examples. Example 1

^* 702 mg of abacavir sulphate is equivalent to 600 mg of abacavir as base.

*^* Extragranular

*^**PVA is applied on tablet cores.

Abacavir sulphate and efavirenz were granulated with the listed excipients (microcrystalline cellulose, croscarmellose sodium) by using water solution of hydroxypropylcellulose and sodium lauryl sulphate. Granulation was performed in fluid-bed dryer. Drying of the wet granules was conducted until adequate water content was achieved (LOD 1 .0%). Obtained mixture was sieved through appropriate mesh size, preferably through a 0.71 mm mesh sieve. Sieved granulated powder was mixed with the remaining component - lubricant (material for lower layer 1 ).

Lamivudine was granulated with the listed excipients (microcrystalline cellulose, sodium starch glycolate) by using water solution of hydroxypropylcellulose. Granulation was performed in fluid-bed dryer. Drying of the wet granules was conducted until adequate water content was achieved (LOD 1 .0%). Obtained mixture was sieved through appropriate mesh size, preferably through a 0.71 mm mesh sieve. Sieved granulated powder was mixed with the remaining component - lubricant (material for upper layer 2).

Lubricated final blend 1 was compressed as a lower layer of bi-layer tablet. Lubricated final blend 2 was added and compressed as upper layer of bi-layer tablets using bi-layer tablet press. Tablet cores were coated in perforated pan coating system by using HPMC or PVA coating solution.

Example 2

^* 702 mg of abacavir sulphate is equivalent to 600 mg of abacavir as base.

*^* Extragranular

^***PVA is applied on tablet cores. Abacavir sulphate and efavirenz were granulated with the listed excipients (microcrystalline cellulose, croscaramellose sodium, and hydroxypropylcellulose and sodium lauryl sulphate) by using water. Granulation was performed in high shear mixer-granulator. Drying of the wet granules was conducted until adequate water content was achieved (LOD 1 .0%). Obtained mixture was sieved through appropriate mesh size, preferably through a 1 mm mesh sieve. Sieved granulated powder was mixed with the remaining components (croscarmellose sodium and magnesium stearate).

Lamivudine was mixed with the listed excipients (microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate) (material for upper layer 2).

Lubricated final blend 1 was compressed as a lower layer of bi-layer tablet. Lubricated final blend 2 was added and compressed as upper layer of bi-layer tablets using bi-layer tablet press. Tablet cores were coated in perforated pan coating system by using HPMC or PVA coating solution. Example 3

Composition Content [mg] % Function

Abacavir sulphate 702.0 33.4 API

Efavirenz 600.0 28.6 API

87.0 4.1 Filler (also acts as binder in

Microcrystalline cellulose

the wet granulation phase)

Hydroxypropylcellulose 24.0 2.1 Binder

Croscarmellose sodium 45.0 2.1 Superdisintegrant

Sodium lauryl sulphate 12.0 0.6 Surface active agent

Water q.s. q.s. Granulation liquid

Croscarmellose sodium^** 15.0 0,7 Superdisintegrant

Magnesium stearate^** 15.0 0.7 Lubricant

Layer 1 Sum 1500.0 / /

Lamivudine 300.0 14.3 API

270.0 12.5 Filler (also acts as binder in

Microcrystalline cellulose

the wet granulation phase)

Sodium starch glycolate 18.0 0.8 Superdisintegrant

Colloidal silicon dioxide 6.0 0,3 Glidant

Magnesium stearate (1/2^**) 6.0 0.3 Lubricant

Layer 2 Sum 600.0 / /

Tablet core Sum 2100.0 / /

PVA coating^*** 21.0 / Coating Sum 2121.0 /

702 mg of abacavir sulphate is equivalent to 600 mg of abacavir as base.

* Extragranular

^**PVA is applied on tablet cores.

Abacavir sulphate and efavirenz were granulated with the listed excipients (microcrystalline cellulose, croscaramellose sodium, and hydroxypropylcellulose and sodium lauryl sulphate) by using water. Granulation was performed in high shear mixer-granulator. Drying of the wet granules was conducted until adequate water content was achieved (LOD 1 .0%). Obtained mixture was sieved through appropriate mesh size, preferably through a 1 mm mesh sieve. Sieved granulated powder was mixed with the remaining components (croscarmelose sodium and magnesium stearate). Lamivudine, microcrystalline cellulose, sodium starch glycolate and 1/2 of the magnesium stearate were mixed in appropriate mixing device and granulated using roller compaction coupled with milling and screening. Obtained granules were further lubricated with the remaining ½ of magnesium stearate. Bi-layer tablet cores were compressed at standard rotary press with mixture containing abacavir and efavirenz being lower layer and lamivudine containing mixture being higher layer. Tablet cores were coated in pan-coater with HPMC or PVA coating.

Example 4 - Dissolution tests

For the assessment of in vitro behavior of the bilayer tablets, in vitro dissolution was assessed. Physiological fluids in the gastrointestinal tract exert different properties pertinent to the anatomical position and function.

Abacavir and lamivudine are highly soluble BCS 1 and BCS 3 class drugs, respectively, therefore their dissolution was monitored under acidic conditions without surface acting compounds in the dissolution media. Because their dissolution and absorption from the gastrointestinal tract are very fast, the target was set to achieve > 85% of drugs released at 15 min for both compounds from the bilayer tablet according to the present invention, as representatively illustrated here by way of Example 2. Efavirenz on the other hand is poorly soluble and highly permeable (i.e. it is classified as BCS 2 compound). The rate limiting step in achieving bioequivalence with reference Stocrin is thus by assuring the same dissolution of efavirenz from the abacavir-efavirenz layer under non-sink conditions. Dissolution was performed as follows:

• Lamivudine: 900 ml. of 0.001 M HCI with salts using Apparatusl , 75 rpm,

• Abacavir: 900 ml. 0.01 M HCI with salts using Apparatus 2, 50 rpms and peak vessels,

· Efavirenz: 900 ml. 0.01 M HCI with salts and SIF powder (i.e. under non-sink conditions) using Apparatus 2, 50 rpm and peak vessels.

A dissolution profile of all three APIs was compared to reference formulations (i.e. Epivir 300 mg film-coated tablets for lamivudine - cf. Figure 2, two 300 mg Ziagen film-coated tablets for abacavir - Figure 1 , and 600 mg Stocrin film-coated tablets for efavirenz - Figure 3).

It was surprisingly found that the multi-layer tablet according to the present invention, represented by a bilayer composition as illustrated in Example 2, makes possible a very fast release of both highly soluble drugs - abacavir and lamivudine (i.e. > 85% released @ 15 min) and similar efavirenz dissolution as that from Stocrin under non-sink conditions in biorelevant media. Because the dissolution for all APIs from multi- (bi-) layer tablet is the same as that from the reference tablets, the multi- (bi-) layer tablet according to the present invention, such as that presented in Example 2, enables similar or even the same in vivo plasma profiles as Ziagen, Epivir and Stocrin but with the advantage of decreasing pill- burden and improving patient compliance.

Example 5 - In vitro prediction for prevention of mouth burning effect

Mouth burning sensation in oral mucosa depends from efavirenz solubility in the saliva and surface/textural properties of dosage forms used to deliver it. Namely, if the surface of the administered dosage form is not smooth, the probability of physically entrapment of the applied formulation on the mucosal membrane increases, thus increasing the residence time of formulation on the oral mucosa and consequently the probability of more pronounced mouth burning effect.

To simulate efavirenz solubility in saliva and surface properties of different dosage forms presented herein, in vitro efavirenz micro-dissolution in artificial saliva (Marques MRC et al, "Simulated biological fluids with possible application in dissolution testing", Dissolution Technologies, August 201 1 , pp.15-28) is monitored.

Adhesive properties of different dosage forms are assessed with the aid of standard laboratory labware (rough filter paper); after a short period of time (approximately 20 sec) that formulation is allowed to stand on wetted filter paper, the filter was thoroughly rinsed in 100 ml of artificial saliva and the entrapped quantity of efavirenz is extracted.

Effects

Single unit tablets according to the Examples of the present invention containing all three APIs do provide the best protection of oral mucosa from efavirenz, and despite being fixed together in a common dosage form they surprisingly do yield comparable dissolution profile as already commercially available, comparable mono reference products such as Ziagen^®, Epivir^® and Stocrin^® tablets, while showing patient compliance benefits.

Claims

1. A solid pharmaceutical composition in the form of a single unit tablet,

wherein the single unit tablet comprises a fixed combination of active ingredients (a) to (c) (a) a compound of the following formula (abacavir)

(b) a compound of formula 2 (lamivudine)

formula 2

(c) a compound of formula 3 (efavirenz)

formula 3 and, as pharmaceutically acceptable excipient, a surfactant and a disintegrant, optionally further at least one selected from the group consisting of binders, fillers, lubricants, and film- forming agents, wherein

the tablet is structured by multiple layers, wherein lamivudine is present in one layer (i.e. lamivudine-containing layer), and abacavir and efavirenz are present in a layer (i.e. efavirenz and abacavir-containing layer) contiguous with the lamivudine-containing layer, optionally with an intermediate layer in between.

2. The solid pharmaceutical composition according to claim 1 , wherein the multiple layers constitute a bilayer structure.

3. The solid pharmaceutical composition according to claim 1 or 2, wherein the solid pharmaceutical composition is a triple combination of active ingredients (a) to (c) and contains no further anti-HIV active substance.

4. The solid pharmaceutical composition according to anyone of claims 1 to 3, wherein the compound (a) is contained in the form of an abacavir salt, preferably the sulphate of formula 1 :

formula 1

and/or wherein the initial DO.5 primary particle size of efavirenz, whether agglomerated in the composition or not, is in a range of 2-8 μηη and DO.9 in a range of 9-26 μηη; preferably efavirenz is incorporated into the composition in micronized form.

5. The solid pharmaceutical composition according to anyone of claims 1 to 4, wherein the whole single unit tablet contains at least 1500 mg of active ingredients (a) to (c) in total, preferably 1500 mg, respectively calculated on the basis of the free active compound; preferably wherein the whole composition contains 600 mg abacavir (calculated as free base) respectively 702 mg abacavir sulphate, 300 mg lamivudine and 600 mg efavirenz.

6. The solid pharmaceutical composition according to anyone of claims 1 to 4 comprising 150 mg abacavir (calculated as free base) respectively 175,5 mg abacavir sulphate, 75 mg lamivudine and 150 mg efavirenz.

7. The solid pharmaceutical composition according to anyone of the preceding claims, wherein the amount of active ingredients in total represent at least 60% by weight, preferably at least 70% by weight, more preferably up to 90% by weight, most preferably 70% to 90% by weight of the whole single unit tablet.

8. The solid pharmaceutical composition according to anyone of the preceding claims, wherein the single unit tablet has an outer coating layer of a film-forming polymer, preferably wherein the coating layer provides for a lag time not less than 3 minutes.

9. The solid pharmaceutical composition according to anyone of the preceding claims, wherein the tablet comprises a disintegrant, a surfactant, a binder, a filler and a lubricant and a coating of a film-forming agent, optionally further comprising a glidant, a sweetener and/or a flavouring agent, preferably wherein tablet excipients are partitioned as follows between the multiple layers, respectively independent from each other:

the efavirenz and abacavir-containing layer comprises a surfactant, a disintegrant, a binder and a filler;

and the lamivudine-containing layer comprises a disintegrant and one or more selected from a binder, a filler and a glidant, preferably a disintegrant and a filler and/or a glidant, optionally a binder in case of the lamivudine-containing layer being obtained by involving granulation; wherein the disintegrant in the efavirenz and abacavir-containing layer and in the lamivudine- containing layer is preferably a superdisintegrant.

10. The solid pharmaceutical composition according to anyone of the preceding claims, wherein

the efavirenz and abacavir-containing layer comprises an intra-granular phase and an extragranular phase, wherein

either the active ingredients (a) and (c) (i.e. efavirenz and abacavir) are present in same granules; or wherein the active ingredients (a) and (c) are present in separate distinct granules (i.e. efavirenz in first granule, and abacavir in second granule);

wherein preferably the active ingredients (a) and (c) (efavirenz and abacavir) are present in same granules.

1 1. The solid pharmaceutical composition according to any one of the preceding claims, comprising, respectively based on the total weight of the single unit tablet:

(b) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 6% by weight of a disintegrant, preferably a superdisintegrant; (c) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 6% by weight of a binder;

12. The solid pharmaceutical composition according to any one of the preceding claims, comprising, respectively based on the total weight of the single unit tablet:

(d) from 0.5 to 3% by weight, preferably from 0.3 to 2% by weight of sodium lauryl sulphate; (e) from 2 to 25% by weight, preferably from 4 to 20% by weight of a filler selected from the group consisting of microcrystalline cellulose and mannitol;

13. The solid pharmaceutical composition according to any one of the preceding claims, wherein the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

(b) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 4% by weight of a disintegrant; (c) from 1 to 20% by weight, preferably from 1 to 10% by weight, more preferably from 1 to 6% by weight of a binder;

14. The solid pharmaceutical composition according to any one of the preceding claims, wherein the efavirenz and abacavir-containing layer comprises, respectively based on the weight of the efavirenz and abacavir-containing layer:

(a) from 80 to 90% by weight of abacavir and efavirenz;

(f) optionally 0.1 to 8% by weight, preferably from 0.5 to 3% by weight of magnesium stearate and/or colloidal silicon dioxide.

15. The solid pharmaceutical composition according to any one of the preceding claims, wherein the lamivudine-containing layer comprises, respectively based on the weight of the lamuvidine-containing layer:

16 The solid pharmaceutical composition according to any one of the preceding claims, wherein the lamivudine-containing layer comprises, respectively based on the weight of the lamivudine-containing layer:

(a) from 45 to 60% by weight of lamivudine;

17. The solid pharmaceutical composition according to any one of the preceding claims, wherein efavirenz and abacavir are comprised intragranularly in same granules in efavirenz and abacavir-containing layer and lamivudine is comprised as a powder mixed with excipients in lamivudine-containing layer.

18. Solid pharmaceutical composition according to any one of the preceding claims for use in the treatment of HIV infection, in particular immunodefiency virus type 1 (HIV-1 ) infection.

19. A process for preparing a solid pharmaceutical composition comprising a fixed combination of active ingredients (a) to (c) according to anyone of claims 1 to 18, wherein the active ingredients (a) to (c) are combined within a common oral solid dosage form in the form of a single unit tablet together with, as pharmaceutically acceptable excipient, at least a surfactant and a disintegrant, optionally further at least one selected from the group consisting of binders, fillers, lubricants, and film-forming agents.

20. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-v) drying of the wet granules to appropriate water content;

(1-vi) sieving of the obtained granules (1 -v) through appropriate mesh size, preferably through a 0.25 mm to 1 .0 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size;

(1-viii) compression of the final blend (1-vii) to the efavirenz and abacavir-containing layer; (2-i) mixing the active ingredient lamivudine with appropriate pharmaceutical excipients including a filler, a disintegrant, a lubricant and/or a glidant and optionally with a binder;

(2-iii) compression of the final blend (2-ii) to the lamivudine-containing layer upper to the efavirenz and abacavir-containing layer;

21. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-iv) wet granulation of mixture from step (1-i) or (1-ii) with the granulation fluid (1 -iii) in a fluid bed dryer or a high shear mixer; (1-v) drying of the wet granules to appropriate water content;

(1-viii) compression of the final blend (1-vii) to the efavirenz and abacavir-containing layer;

(2-iii) optionally adding a binder into granulation fluid, for example water;

(2-v) drying of the wet granules to appropriate water content;

(2-vi) sieving of the obtained granules (2-v) through appropriate mesh size, preferably through a 0.25 mm to 1 .0 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size;

(2-vii) mixing of the obtained granules (2-vi) with any remaining excipients, including at least a lubricant and/or a glidant, optionally further including a disintegrant, a diluent and/or a binder;

(2-vi ii) compression of the final blend (2-vii) to the lamivudine-containing layer upper to the efavirenz and abacavir-containing layer;

22. A process of manufacturing a single unit tablet comprising efavirenz, abacavir and lamivudine, comprising the steps of:

(1-ii) optionally sieving of the obtained mixture of step (i) through appropriate mesh size, preferably through a 1 .0-2.0 mm mesh sieve; (1-iii) optionally adding a binder and/or a surfactant into granulation fluid, for example water;

(1-v) drying of the wet granules to appropriate water content;

(1-vi) sieving of the obtained granules (1 -v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve preferably the dried granules are sieved to achieve an appropriate particle size;

(1-vii) mixing of the obtained granules (1-vi) with any remaining excipients, including at least a lubricant, preferably further including a disintegrant, a diluent and/or a binder;

(2-v) milling;

(2-vi) optionally sieving of the obtained granules (2-v) through appropriate mesh size, preferably through a 0.25 mm to 1.0 mm mesh sieve; preferably the dried granules are sieved to achieve an appropriate particle size;

(2-vii) mixing of the obtained granules (2-vi) with any remaining excipients, including at least a lubricant and/or glidant, optionally further including a disintegrant, a diluent and/or a binder;