WO2015140709A1

WO2015140709A1 - Solid pharmaceutical dosage forms

Info

Publication number: WO2015140709A1
Application number: PCT/IB2015/051944
Authority: WO
Inventors: Unmesh Deodhar; Lei Zhang; Sreehari BABU
Original assignee: Novartis Ag
Priority date: 2014-03-19
Filing date: 2015-03-17
Publication date: 2015-09-24

Abstract

The present invention relates to the use of active pharmaceutical ingredients (API) as lubricant and/or antiadherent in the manufacturing of solid pharmaceutical dosage forms. It further relates to solid pharmaceutical dosage forms the production of which involves a granulation process step followed by a capsule filling or tablet compression step. Said pharmaceutical dosage form is comprised of an intragranular phase and an extragranular phase wherein the latter is comprised of one or more active pharmaceutical ingredients (API) which functions as lubricants and/or antiadherents in the manufacturing of said solid dosage form. Specifically, the API Artemether with its endoperoxide structural element was surprisingly found to exhibit lubricant and/or antiadherent effects when used extragranularly. In further aspects, the present invention relates to the manufacturing process to produce said pharmaceutical dosage forms as well as to a test method to determine whether an API functions as lubricant and/or antiadherent.

Description

SOLID PHARMACEUTICAL DOSAGE FORMS

FIELD OF THE INVENTION

The present invention relates to solid pharmaceutical dosage forms the production of which involves a granulation process step followed by a capsule filling or tablet compression step and is negatively affected by problems of the blend materials sticking to the metal surfaces of filling or compression machines.

BACKGROUND OF THE INVENTION

Many solid pharmaceutical dosage forms, such as capsules or tablets, are produced by three consecutive basic process steps.

In a first step, the active pharmaceutical ingredient (API) is co-processed with inactive pharmaceutical ingredients (IPI) to form granules. This first process step is referred to as granulation and the ingredients involved are referred to as intragranular ingredients. The part of the final drug product originating from this first process step is referred to as intragranular phase.

In a second step, the granules resulting from the first process step are co-processed with further IPI by mixing to form a blend. These further ingredients introduced during the second process step are referred to as extragranular ingredients and form the extragranular phase.

Finally, in a third process step, the blend of the second process step is either filled into capsules or compressed to form tablets.

To ensure smooth and effective pharmaceutical processing, especially during the third process step, lubricants and/or antiadherents are used as extragranular ingredients.

The role of the lubricants is to ensure that tablet formation and ejection can occur with low friction between the tablet ingredients and the die walls of the tableting machine. The role of the antiadherents is to reduce adhesion between the ingredients and the punch faces and thus prevent particles sticking to the punches. Many lubricants, such as magnesium stearate, have also antiadherent function.

Common technical problems associated with the extragranular use of lubricants or antiadherents, such as magnesium stearate, are that the water penetration into the drug product is hindered due to the hydrophobic nature of those IPI and as a consequence the rate of disintegration of the solid dosage form is reduced and the dissolution of the API ingredients is retarded. To avoid the disadvantages of hydrophobic lubricants hydrophilic lubricants, such as certain polyethylene glycols (PEG), e.g. PEG 4000 or PEG 6000, might be suitable as an alternative in some situations. However, the use of those hydrophilic lubricants may also be associated with technical problems as they cause the drug product to become more hygroscopic and/or to become prone to peroxide formation which may cause oxidation reactions with other components of the dosage form. Further, hydrophilic lubricants such as PEG do not posses antiadherent effects and require to be combined with other IPI which can act as antiadherents.

A further problem which is in general associated with IPI but which is especially related to the most widely used lubricant/antiadherent, magnesium stearate, is that its quality has a "notorious history of batch-to-batch and supplier-to-supplier variability" (Graham Buckton, Excipient Design and Characterization, Chapter 9 of Modern Pharmaceutics, 5^th edition, 2009, CRC Press, page 313) which in turn will cause variations of the drug product's quality whenever a new batch of the inactive ingredient is used for drug product manufacturing. It would be therefore advantageous to find alternative means to solve the stickiness problems to avoid all the problems associated with the use of the typical IPI-type lubricants and/or antiadherents as mentioned above.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there is provided the use of one or more active pharmaceutical ingredients (API) as lubricant and/or antiadherent in the manufacturing of a solid pharmaceutical dosage form. In accordance with a second aspect of the invention, there is provided a solid pharmaceutical dosage form comprising:

(i) an intragranular phase comprising one or more inactive pharmaceutical ingredients (IPI) and optionally one or more active pharmaceutical ingredients (API), and

(ii) an extragranular phase comprising one or more API and optionally one or more IPI, characterized in that said extragranular phase comprises at least one API which functions as a lubricant and/or antiadherent in the manufacturing of said solid pharmaceutical dosage form, and wherein the said extragranular API is not Artesunate. In accordance with a third aspect, there is provided, a solid pharmaceutical dosage form as specified in the second aspect for use in the treatment or prevention of parasitic diseases, e.g. Malaria.

In accordance with a fourth aspect, there is provided a method of preparation of a solid pharmaceutical dosage form comprising the following steps:

(1) preparation of an intragranular phase comprising one or more IPI and optionally one or more API by granulation;

(2) preparation of a blend by mixing the intragranular phase of step 1 together with one or more API of which at least one API functions as lubricant and/or antiadherent and optionally with one or more IPI,

and wherein the said extragranular API is not Artesunate;

(3) compression of the blend of step 2 into a tablet or filling of the blend of step 2 into capsules. In accordance with a fifth aspect, there is provided a method of testing APIs for their lubricant and/or antiadherent function comprising the following steps:

(1) preparation on an intragranular phase comprised of one or more IPI and optionally one or more APIs by granulation;

(2) blending of the intragranular phase of step 1 together with one or more API in any amount from 25% up to 35% (w/w) of the extragranular phase and with one or more IPI;

(3) compression of the blend of step 2 to form ca. 1000 tablets in a compression machine which is equipped with concave punches and which is adjusted to achieve tablets with a hardness of around 1 10 N and weights of ca. 240 mg/tablet;

(4) inspecting the lower punch for residual blend material in a semi-quantitative way by optical means or by quantitative mass determination and comparing such determined residual amount with those of a corresponding reference batch without having said API in the extragranular phase;

(5) concluding that an API has lubricant and/or antiadherent function in case the inspection under step 4 reveals that the amount of residual blend material adhered on the lower punch is reduced by more than 75% relative to the reference batch.

The present invention provides a solution to the above mentioned problems associated with extragranular inactive pharmaceutical ingredients (IPI) acting as lubricants and/or antiadherents by the surprising finding that certain active pharmaceutical ingredients (API) can be used as extragranular lubricants and/or antiadherents.

The above mentioned aspects of the present invention provide the following advantages: By using the API of a drug as lubricant and/or antiadherents the use of hydrophobic inactive lubricants and/or antiadherents can be limited or even entirely omitted to avoid reduced rates of dosage form disintegration or drug dissolution. In contrast, the extragranular API may lead to an increased drug release rate as the extragranular API becomes more quickly available after drug product disintegration than any intragranular API.

Further, the quality of API is generally very tightly controlled and the batch-to-batch or supplier-to-supplier variabilities will be much less compared to the much less regulated and less quality-controlled IPI.

As a further advantage, the use of an API as lubricant and/or antiadherent presents an opportunity to further maximize the drug load of the drug product which is important for any drug which needs to be delivered in a high dose.

As another advantage of the application of this invention, the API that is incorporated as extragranular component is not exposed to the high-energy wet granulation and the consecutive drying step. Thus, the invention could increase the chemical and/or physical stability of thermo- and/or moisture sensitive API.

BRIEF DESCRIPTION OF THE FIGURES In the following the present invention is described in detail with reference to accompanying photographs in which:

Figure 1 a shows a photograph of the lower concave punch of the herein exemplarily used compression machine after having prepared ca. 1000 tablets of the reference batch according to Example 1 to demonstrate that without extragranular Artemether as API with lubricant and/or antiadherent function significant amounts of blend material is adhered.

Figure 1 b shows a photograph of the lower concave punch of the herein exemplarily used compression machine after having prepared ca. 1000 tablets of the test batch according to Example 1 to demonstrate that with extragranular Artemether as API with lubricant and/or antiadherent function only very small amounts of blend material is adhered.

Figure 2 shows a photograph of the lower concave punch of the herein exemplarily used compression machine after having prepared ca. 1000 tablets according to Example 2 to demonstrate that with Artemether being present only intragranularly (not extragranularly) again significant amounts of blend material are adhered.

Figure 3 shows a photograph of the lower concave punch of the herein exemplarily used compression machine after having prepared ca. 2000 tablets according to Example 3 to demonstrate that with extragranular Artemether as API with lubricant and/or antiadherent function no blend material is adhered and confirms the positive effect observed in example 1 on larger scale. DETAILED DESCRIPTION OF THE INVENTION

Herein after, the present invention is described in further detail and is exemplified.

In the aspects of the invention, the API may be any API having lubricant and/or antiadherent function such that said API when present in an effective amount is able to significantly reduce the amount of blend material adhered to the manufacturing machine parts after the manufacture of a certain amount of drug product units compared to a corresponding blend without said API as lubricant and/or antiadherent processed under comparative manufacturing conditions. For example, the API may have lubricant and/or antiadherent function such that when present in the extragranular phase in one or more of amounts up to 35% (w/w) the API is able to reduce the amount of blend material adhered to the lower punch of a compression machine after having compressed ca. 1000 tablets by more than 75%, preferably by more than 90%, more preferably by more than 95%, relative to a corresponding blend without said API in the extragranular phase processed under comparative manufacturing conditions.

In an aspect, the API having lubricant and/or antiadherent function may have an endoperoxide structure, such as Artemisinin or any of its derivatives, e.g. like, Dihydroartemisinin, Arteether, Artemether, Artenimol, Artemotil, Artesunate, Artelinic acid or any pharmaceutically acceptable salt thereof, or compounds with a similar trioxolane structure, e.g. Arterolane or any pharmaceutically acceptable salt thereof. Especially suitable for such a use is Artemether. The use of Artemether as lubricant and/or antiadherent is especially suitable for the manufacturing of solid dosage forms also comprising Lumefantrine.

In aspects where the manufacture of the solid dosage form comprises a granulation process step, the API may be provided as an extragranular lubricant and/or antiadherent. In these aspects, the API which functions as a lubricant and/or antiadherent in the manufacturing of said solid pharmaceutical dosage form may be present only in the extragranular phase. Alternatively, the API which functions as a lubricant and/or antiadherent in the manufacturing of said solid pharmaceutical dosage form may be present in both the extragranular phase and the intragranular phase. In an aspect, e.g. according to the second aspect of the invention at least one extragranular API has an endoperoxide structure. More specifically, a solid pharmaceutical dosage form is provided wherein at least one extragranular API is Artemether. Even more specifically, a solid pharmaceutical dosage form is provided wherein at least one extragranular API has an endoperoxide structure and at least one intragranular API is Lumefantrine. Even more specifically, a solid pharmaceutical dosage form according to an aspect of the invention e.g. the second aspect, is provided wherein at least one extragranular API is Artemether and at least one intragranular API is Lumefantrine. The term "in one or more of the amounts up to 35% (w/w)" has herein the meaning of any one amount value from 0% up to 35%. E.g. "one amount" can be 1 %, 10% or 35%. "More amounts" can be e.g. a range such as from 10% to 20% or from 25% to 35%. The term blend material has herein the meaning of a mixture of solid materials which is prepared to be compressed into a tablet or to be filled into a capsule. Typically this blend material comprises granules formed by use of API and IPI and further IPI which are mixed with the granules. In the present invention, the blend material may comprise granules formed by use of IPI and optionally API, and API and optionally IPI which are mixed with the granules.

The term manufacturing machine parts is used herein to describe any type of machine parts which are in contact with the blend material during the capsule filing or tablet compression step.

The term compression machine is used herein to describe any type of machine suitable to compress the blend material into a tablet. Such compression machines can be single station compression machines, e.g. LSP-50 by Noya, also referred to as single-punch tablet press, or a rotary tablet press, preferably a single station compression machine is used for testing lubricant and/or antiadherent function of the API's according to the first aspect of the present invention.

Such compression machines typically possess a lower punch and an upper punch as well as a die to compress the powder into a tablet of a specific form. The amount of the blend material adhered at the lower punch shall be determinative to assess on the lubricant and/or antiadherent function of the API. Preferably, a concave punch is used herein. More preferably, the concave punch is of size number 9. Even more preferably, said punch is without any embossing or score line. The quantitative assessment of the blend material adhered at the lower punch shall be performed after having compressed enough blend material for ca. 1000 tablet. The term "ca. 1000" herein means any number around 1000, e.g. 900 - 1 100. Preferably, the compression is performed with suitable equipment and a weight loading axis and hardness adjustment to yield tablets with a hardness of around 1 10 N and weights of around 240 mg/tablets. This assessment is performed relative to a comparative compression experiment using a corresponding blend without the API in the extragranular phase. In this reference experiment, the extragranular API material is preferably replaced by the comparable amount of a filler or diluent, preferably of that filler/diluent which is anyway used in the blend formula. Alternatively, in the reference blend sample the extragranular API might be simply removed without compensation with additional filler/diluent material.

Typical filler/diluents used in such granules and blends are lactose, mannitol, sorbitol sucrose, dextrose, starch, microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate or derivates thereof.

To allow a reasonable head-to-head comparision between the test blend and the reference blend all the test equipment (e.g. the compression machine, the punches, the die) and the test parameters shall be the same for the comparative tabletting experiments. Preferably, as a set of test equipment and test parameters the LSP-50 single station compression machine with concave punches in size number 9 and without any embossing or score line shall be used to produce ca. 1000 tablets under weight loading axis and tablet hardness adjustments to yield tablets with a hardness of around 1 10 N and weights of around 240 mg/tablet. Preferably, in the reference blend the extranular API is replaced by the comparable amount of the same or similar type of filler/diluent which is anyway being used in the blend formula, e.g. cellulose (e.g. microcrystalline cellulose such as Avicel PH101 or Avicel PH102 by FMC), preferably replaced by a microcrystalline cellulose suitable for direct compression, e.g. Avicel PH102. In the third aspect of the invention, the parasitic diseases may be those caused by protozoan infections, e.g. malaria including all types thereof such as avian malaria, celebral malaria, vivax malaria, falciparum malaria and complication thereof such as blackwater fever.

Said protozoan infections for which the solid pharmaceutical dosage form can be used for might be caused by the genus Plasmodium, e.g. by its species P. falciparum, P. vivax, P. ovale, or P. malariae.

In a preferred embodiment, the parasitic disease is Plasmodium falciparum malaria, more preferably the acute uncomplicated form thereof.

Alternatively, in the third aspect, there is provided a method of treatment or prevention of parasitic diseases comprising the administration of a solid pharmaceutical dosage form as specified in the second aspect to a patient in need thereof. As a further alternative of the third aspect, there is provided a solid pharmaceutical dosage form as specified in the second aspect for the preparation of a medicament for the treatment or preventation of parasitic diseases as defined above. Although the lubricant and/or antiadherent function herein is defined in terms of fulfilling certain conditions of a tablet compression experiment, the concept of the present invention is not limited to the preparation of tablets but also incorporates the preparation of capsules in which also lubricants and/or antiadherents play an important role to ensure smooth pharmaceutical processing (by e.g. prevention adhesion of the blend the metal surfaces of the capsule filling equipment), especially during the dosing or filling step.

Although the concept of the present invention in all its aspects is exemplified herein by a compound having an endoperoxide structure, i.e. Artemether, the concept of the present invention is not restricted to such class or type of API. Other classes or types of API may also exhibit lubricant and/or antiadherent functions sufficient for efficient pharmaceutical processing. The present invention in a fifth aspect provides a test method which allows to determine whether or not a specific API possesses sufficient function as lubricant and/or antiadherent. The inspection step (4) of the fifth aspect may be performed in a semi-quantitative way by optical means, e.g. as an assessment by looking on the residual blend material by naked eye or by taking photographs and make the assessment with the help of an image analysis software program. Alternatively, the inspection step (4) may be performed by quantitative mass determination, e.g. by transferring the residual blend material from the punch to a scale and determining the weight by said scale.

Not being bound to any specific theory, the inventors believe the lubricant and/or antiadherent function of artemisinin and its derivatives or compounds with a similar trioxolane structure originates from its endoperoxide structural element with its unique peroxide bridge which makes this part of the chemical molecule hydrophilic. Said unique hydrophilic part of the molecule together with the more hydrophobic part of the rest of the molecule constitutes to a typical surfactant-like structure, which is also observed for typical lubricants, such a magnesium stearate with its hydrophilic carboxy functional group and its hydrophobic stearyl chain. Further, the inventors observed that API with lubricant function, such as Artemether have a wax-like consistency, similar to that of polyethylene glycols (PEG), which serves as another indicator for an API having potential as lubricant and/or antiadherent.

The present invention is exemplified herein by pharmaceutical compositions comprising Artemether in combination with Lumefantrine. It should be mentioned that Lumenfantrine is a very sticky material with a very low bulk density (ca. 0.15 g/cc) and needs to be present in the composition in high amounts as this API needs to be delivered at high dose. Therefore, the development of any pharmaceutically processable composition comprising Lumefantrine is an example of a particularly challenging technical problem which however can be solved by applying the concept of the present invention.

The inventors of the present invention have further discovered that Arthemether and Lumefantrine form eutectic mixtures with lower melting points (ca. 79°C) compared to the melting point of its components (ca 87°C for Artemether, ca. 130°C for Lumefantrine). These decreased melting points were observed for practically all ratios in which the two API were mixed. When granulated together, the eutectic nature of the two API mixture may cause further issues during pharmaceutical processing and makes the development of a combination drug product of those two API to a particularly challenging technical problem. The present invention, however, provides a solution also to this technical problem by avoiding co-localization of the two API.

In a preferred aspect there is provided a solid pharmaceutical dosage form in the form of either a tablet or a capsule comprising 2 - 50 %, 4 - 30 %, or 5 - 12 %, preferably 5 - 12%, more preferably 7.0 ± 2 % or 8.3 ± 2 % by weight of Artemether based on the total weight of the tablet or the content of the capsule wherein at least part of the Artemether is present extragranularly, preferably, wherein a substantial part of the Artemether is present extragranularly, e.g. wherein at least 10%, 20%, 50%, 70%, or 90%, preferably at least 90% of the Artemether is present extragranularly. In another preferred aspect there is provided a solid pharmaceutical dosage form in the form of either a tablet or a capsule comprising:

(a) 2 - 50 %, 4 - 30 %, or 5 - 12 %, preferably 5 - 12%, more preferably 7.0 ± 2 % or 8.3 ± 2 % by weight of Artemether, and

(b) 20 - 80 %, 30 - 70 %, or 35 - 60%, preferably 35 - 60%, more preferably 42 ± 5 % or 50 ± 5 % by weight of Lumefantrine based on the total weight of the tablet or the content of the capsule, wherein the Lumefantrine is present intragranularly, preferably, wherein a substantial part of the Lumefantrine is present intragranularly, e.g. wherein at least 50%, 70%, or 90%, preferably at least 90% of the Lumefantrine is present intragranularly, and

wherein at least part of the Artemether is present extragranularly, preferably, wherein a substantial part of the Artemether is present extragranularly, e.g. wherein at least 10%, 20%, 50%, 70%, or 90%, preferably at least 90% of the Artemether is present extragranularly

FURTHER DEFINITIONS

The term solid pharmaceutical dosage form is used herein as referring to the solid drug products such as capsules or tablets in all its variations.

The term active pharmaceutical ingredient (API) is used herein as referring to a chemical or biological entity which plays an active pharmacological role in the prevention or treatment of a disease of the human or animal body. The term drug substance is often synonymously used for API.

The term inactive pharmaceutical ingredient (IPI) is used herein synonymously for pharmaceutical excipient.

Should the IPI-typed lubricants and antiadherents such as stearic acid or its metal salts (e.g. magnesium stearate, calcium stearate, potassium stearate, aluminium stearate), sodium stearyl fumarate, sodium lauryl sulfate, gliceryl behenate, polyethylene glycol 4000, polyethylene glycol 6000, liquid paraffin, hard paraffin, talc, starch, cellulose, colloidal silica, boric acid or graphite show beside their function as lubricants and/or antiadherents also show a pharmacological effect, those IPI will nevertheless not being understood as APIs herein. The terms intragranular phase and extragranular phase are synonymous with the terms internal phase and external phase, respectively. The extragranular phase is defined as being anything else of the drug product than the intragranular phase (not taking into account any packaging materials or components). The intragranular phase is defined as that phase that is composed of all the components used for the granulation process and which make up the granules. The term granulation is used herein as defining a process in which primary powder particles are made to adhere to form larger multi-particle entities referred to as granules. Known methods of granulation are dry granulation (utilizing no liquids, e.g. slugging, roller compaction), wet granulation (utilizing liquids such as water or alcohols, e.g. granulation by high-speed mixers, spray-drying, fluidized-bed granulation, extrusion-spheronization- pelletization) and are described in detail by pharmaceutical text books, e.g. Michael E. Aulton, Aulton's Pharmaceutics. The term granules is used herein as synonymous with granulates and understood as products of the granulation process.

The term lubricant is used herein for compounds which have a function to ensure that tablet formation and ejection can occur with low friction between the blend material and the die wall or to ensure that the machine parts involved in the filling of capsules and which are in contact with the blend material can move with low friction. "Low friction" herein is understood as a lower friction than that experienced with a blend without a lubricant in the blend formula. The term antiadherent is used herein for compounds which have a function to reduce adhesion between the blend material and the punch faces and thus prevent particles sticking to the punches. Alternatively, the term antiadherent is used herein for compounds which have a function to reduce adhesion between the blend material and the machine parts involved in the capsule filling process and which are in contact with the blend material. "Reduced adhesion" herein is understood as a lower adhesion than that experienced with a blend without an antiadnerent in the blend formula.

Many lubricants also possess some antiadherent function, and many antiadherents also possess some lubricant function. The term "lubricant and/or antiadherent" is used herein to refer to those compounds which possess either one of the two functions alone or those two functions in combination to a substantial extent, preferably to such an extent that the amount of blend material stuck on critical filling or compression machine parts, e.g. the punches of a tablet compression machine, is reduced by more than 75% relative to a reference which does not comprise said compound extragranularly, more preferably reduced by more than 90%, even more preferably reduced by more than 95%.

The term endoperoxide is used herein for any heterocyclic compound comprising as structural element a peroxide residue in the ring. FURTHER PRIOR ART

The incorporation of API in the extragranular phase has been reported before but the motivation behind the work reported was to design a solid oral dosage form with two incompatible drugs which need to be locally separated to prevent drug degradation. C. Lacaze et al. reported in Malaria Journal 201 1 (10) 142, "The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria", about several co-formulation trials of the two drugs artesunate and amodiaquine. One of their formulation strategies was to incorporate artesunate in the extragranular phase of the tablets. However, this formulation approach failed to provide the sufficient API stability. Lubricant or antiadherent effects were not mentioned in that document at all. Nevertheless, in the light of said disclosure, pharmaceutical dosage forms according to the second aspect of the invention comprising Artesunate and methods of their preparation according to the fourth aspect comprising Artesunate are herein disclaimed.

EXAMPLES

Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

Materials:

The API Artemether and Lumefantrine as well as all IPI used for the exemplified embodiments of this invention are commercially available from various sources, e.g. Avicel PH101 -NF and Avicel PH102-NF (microcrystalline celluloses) as well as Ac-Di-Sol (croscarmellose sodium, cross-linked sodium carboxymethyl cellulose) may be purchased from FMC, Cellulose-HP-M603 (Hydroxypropylmethylcellulose, HPMC) may be purchased from Shin-Etsu or Dow, Aerosil 200 (fumed silica, colloidal silicon dioxide) may be obtained from Evonik, Magnesium stearate may be obtained from Peter Greven. The water may be prepared by a Millipore Water System.

Instrumentation:

Retsch Test Sieves with mesh sizes of 355 μηι and 710 μηι were used. A Retsch Fluid Bed Dryer TG200 was used for drying the granules. For compression of the blend to tablets, the single station compression machine by Noya, LSP-50 were used in conjunction with concave punches of size number 9 and without embossing or score line. The Sotax Hardness tester HT1 was used to determine the hardness of the tablets.

Example 1 : Comparative test of a batch with extragranular Artemether (Test batch) with one without any Artemether (Reference batch)

Formula of intragranular phase:

*Not part of final drug product as this component is removed during process. Formula of blend (intragranular phase and extragranular ingredients):

Preparation of the blend:

To prepare the granules, Lumefantrine, Avicel PH101 , Ac-Di-Sol and Aerosil 200 were weighed into a stainless steel bowl in quantities as indicated above and pre-mixed with a spatula. The resulting blend was screened through a sieve of 710 μηι mesh size and finally thoroughly mixed in an ERWEKA Terbula mixer (AR202/Type PRS) with 100 rpm for at least 15 minutes and transferred to ERWEKA planetory mixer.

In amounts as indicated above, HPMC and Tween 80 were dissolved in 100 ml_ water at room temperature. The resulting binder solution was used to prepare granules. The binder solution (100 ml_) was added to Planetory mixer containing blend while mixing at 140 rpm. The speed was increased to 220 rpm after 2 minutes and mixing continued for another 15 minutes while adding additional 175 ml_ of water to achieve granulation end point.

Those granules were placed into a fluid bed dryer to remove the water. The drying process was performed for 60 minutes at 60 °C.

The resulting granules forming the intragranular phase were then mixed with Artemether, Avicel PH102, Ac-Di-Sol, and Aerosil in amounts as indicated above and screened through a sieve of 710 μηι mesh size in a Mixer for 20 minutes.

Finally, Magnesium stearate in an amount as indicated above was added and mixed for 5 min to obtain a blend ready for tablet compression.

The total amount of the extragranular ingredients (20 g Artemether + 23.5 g Avicel PH102 + 19.6 g Ac-Di-Sol + 1 g Aerosil 200 + 4.5 g Mg stearate) is 68.6 g. Thus in this example the amount of extragranular API is 29% (20 g Artemether / 68.6 g extragranular ingredients). Should the tablet - in a further process step - be coated, e.g. with a polymer film, the coating materials shall not be considered in the calculation of the amount of extragranular API.

Compression Test:

For compression, a single station Noya LSP-50 compression machine with a concave punch of size number 9 (without embossing or score line) was used. The weight loading axis and the hardness axis were adjusted to yield tablets with a hardness of around 1 10 N and weights of around 240 mg/tablet.

After having prepared ca. 1000 tablets the lower punch were investigated for any sticking materials. An optical evaluation of the Reference batch and the Test batch is provided in Figure 1 a and Figure 1 b, respectively:

The reference batch (without extragranular Artemether, the missing quantity of Artemether is replaced by a comparable quantity of a filler, here Avicel PH102) showed significant amounts of residual blend material stuck to the surface of the punch. In contrast, the Test batch (with extra-granular Artemether) showed only very minor levels of adhered residuals of the compressed blend which clearly demonstrated the antiadherent and lubricant effects of Artemether. The reduction of the amount of blend material stuck to the lower punch is optically assessed to be more than 95% relative to the amount stuck in the reference. To provide a theoretical example for the quantitative assessment of the adhered material it shall be assumed that the amount of the adhered material of the reference batch is 10.0 mg and the amount of the test batch 0.5 mg. The reduction of the adhered blend material is then 9.5 mg which is a reduction of 95%.

Example 2: Confirmation test with intragranular Artemether but without extragranular Artemether

In accordance to the method described in example 1 , API and IPI as listed in the table below were processed to a blend. In contrast to example 1 , in this example Artemether is present in the intragranular phase but not in the extragranular phase.

Formula of intragranular phase:

Component Quantity for ca. 3000 tablets

Lumefantrine 359.56 g

Artemether 60.08 g

Avicel PH101 126.63 g

Ac-Di-Sol 25.35 g

Aerosil 200 3.06 g

Water* 150 ml_

Tween 80 1 .41 g

HPMC 12.027 g

Additional water* 210 mi-

*Not part of final drug product as this component is removed during process.

Formula of blend (intragranular phase and extragranular ingredients):

Component Batch of Example 2

Quantity for ca. 1000 tablets

Intragranular phase 184.10 g

Artemether -

Avicel PH102 18.09 g

Ac-Di-Sol 18.42 g Aerosil 200 0.98 g

Magnesium stearate 4.21 g

After preparation of ca. 1000 tablets in accordance to the method as described in Example 1 the lower punch as well as the upper punch was inspected. As a result, a substantial amount of sticking blend material was found on the lower punch. Fig. 2 shows a photograph of the lower punch. This test result confirms the finding of example 1 that when no Artemether is present in the extragranular phase the sample demonstrates severe stickiness issues. The presence of Artemether in the intragranular phase does not overcome said stickiness issues.

Example 3: Confirmation test without intragranular Artemether but with extragranular Artemether

In accordance to the method described in example 1 , the components listed in the tables below were processed to the blend ready for compression but this time in a doubled batch size to allow the manufacturing of 2000 tablets.

Formula of intragranular phase:

Component Quantity for ca. 2000 tablets

Lumefantrine 240 g

Avicel PH101 84 g

Ac-Di-Sol 16.8 g

Aerosil 200 2 g

Water 100 ml_

Tween 80 1 g

HPMC 8 g

Additional water 175 mi-

*Not part of final drug product as this component is removed during process.

Formula for blend (intragranular phase and extragranular ingredients):

Component Batch of Example 3

Quantity for ca. 2000 tablets

Intragranular phase 351 .8 g

Artemether 40 g Avicel PH102 38 g

Ac-Di-Sol 39.2 g

Aerosil 200 2 g

Magnesium stearate 9 g

The total amount of the extragranular ingredients (40 g Artemether + 38 g Avicel PH102 + 39.2 g Ac-Di-Sol + 2 g Aerosil 200 + 9 g Mg stearate) is 128.2 g. Thus, in this example the amount of extragranular API is 31 % (40 g Artemether / 128.2 g extragranular ingredients). Should the tablet - in a further process step - be coated, e.g. with a polymer film, the coating materials shall not be considered in the calculation of the amount of extragranular API.

After preparation of ca. 2000 tablets in accordance to the method described in Example 1 , the lower punch as well as the upper punch was inspected. As a result, no adhered blend material was found which amounts to a reduction of residual blend material by 100% relative to the reference of Example 2. Fig. 3 shows a photograph of the lower punch.

Claims

1 . Use of one or more active pharmaceutical ingredients (API) as a lubricant and/or antiadherent in the manufacture of a solid pharmaceutical dosage form.

2. Use of one or more active pharmaceutical ingredients (API) according to claim 1 wherein the API is used as an extragranular lubricant and/or antiadherent and said manufacture comprises a granulation process step.

3. Use of one or more API according to any of the preceding claims wherein at least one API has an endoperoxide structure.

4. Use of one or more API according to any of the preceding claims wherein at least one API is Artemisinin or any of its derivatives.

5. Use of one or more API according to any of the preceding claims wherein at least one API is Artemether.

6. A solid pharmaceutical dosage form comprising:

(i) an intragranular phase comprising one or more inactive pharmaceutical ingredients

(IPI) and optionally one or more active pharmaceutical ingredients (API), and

(ii) an extragranular phase comprising one or more API and optionally one or more IPI, characterized in that said extragranular phase comprises at least one API which functions as a lubricant and/or antiadherent in the manufacturing of said solid pharmaceutical dosage form,

and wherein the said extragranular API is not Artesunate.

7. The solid pharmaceutical dosage form according to claim 6 wherein at least one extragranular API has an endoperoxide structure.

8. The solid pharmaceutical dosage form according to claim 6 wherein at least one extragranular API is Artemether.

9. The solid pharmaceutical dosage form according to claim 7 or 8 wherein at least one intragranular API is Lumefantrine.

10. A solid pharmaceutical dosage form according to claims 6 - 9 for use in the treatment or prevention of parasitic diseases e.g. Malaria.

1 1 . A method of preparation of a solid pharmaceutical dosage form comprising the following steps:

(1 ) preparation of an intragranular phase comprising one or more inactive pharmaceutical ingredients (IPI) and optionally one or more active pharmaceutical ingredients (API) by granulation;

and wherein the said extragranular API is not Artesunate;

(3) compression of the blend of step 2 into a tablet or filling of the blend of step 2 into capsules.

12. The method of preparation of a solid pharmaceutical dosage form according to claim 1 1 wherein at least one of said extragranular API of step 2 has an endoperoxide structure.

13. The method of preparation of a solid pharmaceutical dosage form according to claim 1 1 wherein at least one of said extragranular API of step 2 is Artemether.

14. The method of preparation of a solid pharmaceutical dosage form according to claims 12 or 13 wherein at least one of said intragranular API of step 1 is Lumefantrine.

15. A method of testing active pharmaceutical ingredients (API) for their lubricant and/or antiadherent function comprising the following steps:

(1 ) preparation on an intragranular phase comprising one or more inactive pharmaceutical ingredients (IPI) and optionally one or more APIs by granulation;