Preparation of a powdery pharmaceutical composition by means of cryo-milling

Abstract

A method for the preparation of a powdery pharmaceutical composition composed of a pharmaceutical excipient and a pharmaceutical component, among other possible ingredients, wherein the pharmaceutical excipient is a polyalkylene glycol, the method involving grinding a mixture of the pharmaceutical excipient and the pharmaceutical component at a temperature below ambient temperature.

Claims

1. A method for preparing a powdery pharmaceutical composition comprising a pharmaceutical excipient and a pharmaceutical component, wherein the pharmaceutical excipient is polyethylene glycol having a molecular weight of up to 50,000 g/mol; the method comprising the steps of: (a)(i) mixing the pharmaceutical excipient with the pharmaceutical component outside an extruder and then feeding the pharmaceutical excipient and the pharmaceutical component as mixed into the extruder; or (ii) feeding the pharmaceutical excipient and the pharmaceutical component into the extruder at different feeding points, where either (1) the feeding point for the pharmaceutical excipient is located upstream with respect to the feeding point for the pharmaceutical component, or (2) the feeding point for the pharmaceutical component is located upstream with respect to the feeding point for the pharmaceutical excipient; (b) extruding a mixture of the pharmaceutical excipient and the pharmaceutical component in the extruder at a temperature profile allowing a liquid melt of the mixture to congeal in the extruder and to exit the extruder in form of a powder extrudate; and (c) grinding the powder extrudate at a temperature below ambient temperature, wherein the temperature below ambient temperature is at most 10 C.

2. The method according to claim 1, wherein step (c) is performed using a cryo-mill, which is equipped with a cooling system and a milling chamber capable of providing mechanical impact on the material to be milled.

3. The method according to claim 2, wherein the cryo-mill is equipped with a sieve that allows material of the desired particle size to exit the milling chamber but keeps the coarser material within the milling chamber.

4. The method according to claim 2, wherein the cryo-mill is selected from the group consisting of ball mills, colloid mills, conical mills, disintegrators, disk mills, edge mills, gristmills, hammer mills, jet mills, pellet mills, planetary mills, plate mills, stirred mills, and vibratory mills.

5. The method according to claim 1, wherein in step (a) the pharmaceutical component is dissolved in the molten pharmaceutical excipient, or the pharmaceutical excipient is dissolved in the molten pharmaceutical component.

6. The method according to claim 1, which further comprises after step (d): (d) grading the powder.

7. The method according to claim 1, wherein in step (b) the temperature profile comprises a temperature gradient of temperature T.sub.1 to temperature T.sub.2, where T.sub.1>T.sub.2 and where T.sub.1 is above the melting point/range of the pharmaceutical excipient and/or the pharmaceutical component; and/or T.sub.2 is below the melting point/range of the pharmaceutical excipient and/or the pharmaceutical component.

8. The method according to claim 1, wherein the powdery pharmaceutical composition has an average particle size of at most 100 m.

9. The method according to claim 1, wherein the pharmaceutical excipient is hydrophilic and the pharmaceutical component is hydrophobic, or the pharmaceutical component is hydrophilic and the pharmaceutical excipient is hydrophobic.

10. The method according to claim 1, wherein the pharmaceutical component is a second pharmaceutical excipient.

11. The method according to claim 10, wherein the second pharmaceutical excipient is alpha-tocopherol.

12. The method according to claim 11, wherein the relative weight ratio of the polyethylene glycol to the alpha-tocopherol is within the range of from 1000:1 to 5:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 compares the particle size distribution (PSD) of alpha-tocopherol/PEG with other excipients.

(2) FIG. 2 shows the particle size distribution (PSD) of Trials 6, 7 and 8 in comparison to that of a commercial vitamin E/PEG 6000 blend.

(3) FIG. 3 shows a DSC of the commercial vitamin E/PEG 6000 blend.

(4) FIG. 4 shows a DSC of Vitamin E/PEG 4% material after cryo-milling.

(5) FIG. 5 shows a DSC of Vitamin E/PEG 14% material after cryo-milling.

(6) FIG. 6 shows the influence of the temperature on the particle size distribution (PSD).

(7) FIG. 7 shows the influence of the cryo-milling technology on the particle size distribution (PSD).

(8) FIG. 8 shows a comparison of particle size distribution (PSD) after blending.

(9) A first aspect of the invention relates to a method for the preparation of a powdery pharmaceutical composition comprising a pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and a pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol; the method comprising the step of (c) grinding a mixture of the pharmaceutical excipient and the pharmaceutical component at a temperature below ambient temperature.

(10) Preferably, the grinding in step (c) is performed in form of a cryo-milling. For the purpose of the specification, the terms grinding and milling are synonymous.

(11) Preferably, the temperature below ambient temperature is at most 0 C., or at most 5 C., or at most 10 C., or at most 15 C., or at most 20 C., or at most 25 C., or at most 30 C., or at most 35 C., or at most 40 C., or at most 45 C., or at most 50 C., or at most 55 C., or at most 60 C., or at most 65 C., or at most 70 C., or at most 75 C., or at most 80 C., or at most 85 C., or at most 90 C., or at most 95 C., or at most 100 C. Preferably, the temperature is that of liquid nitrogen (i.e. about 196 C.).

(12) Preferably, the cryo-milling in step (c) of the method according to the invention is performed until the desired particle size and particle size distribution of the powdery pharmaceutical composition is achieved. The duration depends upon the equipment and the process parameters and can be determined by routine experimentation.

(13) Cryo-milling in step (c) can be performed continuously or discontinuously.

(14) Preferably, the pharmaceutical composition is subjected to cryo-milling in step (c) for at least about 10 seconds, or at least about 20 seconds, or at least about 30 seconds, or at least about 1 minute.

(15) When cryo-milling in step (c) is performed continuously, the above time intervals refer to the mean residence time of the material within the mill.

(16) In principle, many different mill apparatuses that are known to the skilled person can be used for cryo-milling, although some of them appear to better adapt to cryogenic conditions. Plate mills and hammer mills are preferred.

(17) Typically, the mill is a cryo-mill, i.e. a mill capable of operating at low temperatures and being equipped with a suitable cooling system.

(18) Preferably, the cryo-mill is equipped with a milling chamber comprising means for providing mechanical impact on the material to be milled, sometimes also referred to as grinding jar. Depending upon the type of the cryo-mill, said mechanical impact may be provided in different forms that are known to the skilled person and that all have in common that the particle size of fine material is reduced through attrition and compressive forces at the grain size level. Suitable mills include but are not limited to ball mills, rod mills, autogenous mills, SAG mills, pebble mills, high pressure grinding rolls, Buhrstone mills, vertical shaft impactor mills (VSI mills), tower mills. Preferred mills are ball mills, colloid mills, conical mills, disintegrators, disk mills, edge mills, gristmills, hammer mills, jet mills, pellet mills, planetary mills, plate mills, stirred mills, and vibratory mills.

(19) Further, the cryo-mill is preferably equipped with a sieve that allows material of the desired particle size to exit the milling chamber but keeps the coarser material within the milling chamber so that it is subjected to additional mechanical impact.

(20) Still further, the cryo-mill is preferably equipped with a feeding device supplying the cryo-mill with starting material to be milled. Both the feeding device and the milling chamber are preferably equipped with isolating protections and integrated cooling, e.g. suitable pipeline to allow refrigeration with liquid nitrogen. The grinding jar is preferably continuously cooled with liquid nitrogen from the integrated cooling system before and during the grinding process. The sample is thus embrittled and volatile components are preserved. The liquid nitrogen preferably circulates through the system and is continuously replenished from an autofill system in the exact amount which is required to maintain the temperature at about 196 C.

(21) In a preferred embodiment, cryo-milling is performed by means of a plate mill, e.g. a HosokawaAlpine (Germany). The mill preferably comprises a stainless steel milling chamber equipped with high speed rotating elements (plate beater) that apply a centrifugal force guiding the fed coarse material against a radial sieve of appropriate open sieve net. The milled material is then directly collected into a suitable container. Coarse material is preferably loaded by means of a feeding device directly in the center of the milling chamber.

(22) In another preferred embodiment, cryo-milling is performed by means of a hammer mill, e.g. a Nuova Guseo (Italy). The mill preferably comprises a stainless steel milling chamber equipped with an horizontal rotor shaft which carries grinding elements (hammers) rotating at variable speed depending on the mill size. Coarse material is grinded by impact and attrition and finally forced through a radial sieve of appropriate open sieve net. Preferably, the milled material is then directly collected into a suitable container. The mill is preferably loaded by the top by means of an appropriate feeding device.

(23) Milling may be performed continuously or batch-wise.

(24) For the purpose of the specification, a pharmaceutical composition is any composition that is adapted for administration to an animal, typically oral administration of a human being.

(25) The pharmaceutical composition according to the invention comprises a pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and a pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol.

(26) For the purpose of specification, a polyalkylene glycol has a molecular weight of up to 50,000 g/mol, preferably up to 20,000 g/mol, whereas a polyalkylene oxide has a molecular weight of more than 50,000 g/mol, preferably more than 20,000 g/mol.

(27) For the purpose of the specification the term pharmaceutical component encompasses both, pharmacologically active substances (drugs) as well as pharmaceutical excipients. Thus, preferably, the pharmaceutical component is selected from pharmacologically active substances and pharmaceutical excipients.

(28) Pharmaceutical excipients are known to the skilled person (cf. e.g. R. C. Rowe et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 6th edition 2009; E.-M. Hoepfner et al., FiedlerEncyclopedia of Excipients, Editio Cantor, 6th edition 2008).

(29) For the purpose of the specification, a pharmaceutical excipient is preferably to be regarded as any pharmacologically inactive substance typically used as a carrier for the active ingredients of a medication. The pharmaceutical excipient may have a physiological effect, e.g. like a vitamin, but not a pharmacological effect, like a drug. Typical examples of pharmaceutical excipients include antiadherents, binders, coating materials, disintegrants, fillers, diluents, flavours, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, and the like. Any of the foregoing excipients can be divided into sub-groups. For example, preservatives can be divided into antioxidants, buffers, antimicrobial substances and the like; whereas binders can be divided into solution binders and dry binders. Several excipients simultaneously exhibit different properties so that they can serve different purposes. For example, polyethylene glycol can be used as binder, plasticizer and the like.

(30) Pharmacologically active substances are also known to the skilled person. In this regard, it can be referred to e.g. the Anatomical Therapeutic Chemical (ATC) classification system of the WHO.

(31) In a preferred embodiment, the pharmaceutical component is a pharmacologically active substance (drug). Under these circumstances, the pharmaceutical composition according to the invention comprises the pharmacologically active substance already.

(32) In another preferred embodiment, the pharmaceutical component is a second pharmaceutical excipient. Under these circumstances, the pharmaceutical composition according to the invention comprises at least two pharmaceutical excipients, namely the above pharmaceutical excipient (=first pharmaceutical excipient) and the pharmaceutical component (=second pharmaceutical excipient).

(33) When the pharmaceutical component is a pharmacologically active substance, this is preferably selected from the group consisting of hormones and related compounds, such as estrogens, gestagens, androgens, anti-estrogens, anti-gestagens, anti-androgens; and analgesics, such as opioids, preferably selected from the group consisting of tramadol, tapentadol, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphin; and the physiologically acceptable salts thereof.

(34) When the pharmaceutical component is a second pharmaceutical excipient, the pharmaceutical composition according to the invention does not necessarily have to comprise a pharmacologically active substance (drug). Rather, the pharmaceutical composition may exclusively consist of two or more pharmaceutical excipients. Under these circumstances, the pharmaceutical composition is preferably adapted for being further processed into a pharmaceutical dosage form by addition of a pharmacologically active substance and optionally, further pharmaceutical excipients. Thus, in a preferred embodiment, the pharmaceutical composition can be regarded as an intermediate in the preparation of a pharmaceutical dosage form, which intermediate as such does not yet contain the pharmacologically active substance of the pharmaceutical dosage form.

(35) In a preferred embodiment, the mixture comprises a third constituent, preferably another, i.e. additional pharmaceutical excipient.

(36) When the mixture comprises a third constituent beside the pharmaceutical excipient and the pharmaceutical component, said third constituent is preferably an additional pharmaceutical excipient, more preferably a polymer, still more preferably a polyalkylene oxide, yet more preferably a polyethylene oxide having a weight average molecular weight of at least 1 Mio g/mol, most preferably a polyethylene oxide having a weight average molecular weight of at least 4 Mio g/mol.

(37) In a preferred embodiment, the pharmaceutical composition essentially consists of a pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and a pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, but does not contain any further ingredients, i.e. neither further pharmaceutical excipients nor pharmacologically active substances. In another preferred embodiment, the pharmaceutical composition essentially consists of a pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, a pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and a third constituent, preferably an additional pharmaceutical excipient, more preferably a polymer, still more preferably a polyethylene oxide, but does not contain any further ingredients, i.e. neither further pharmaceutical excipients nor pharmacologically active substances.

(38) The pharmaceutical excipient and the pharmaceutical component are not particularly limited.

(39) Preferably, the pharmaceutical excipient, preferably first pharmaceutical excipient, is hydrophilic and the pharmaceutical component, preferably second pharmaceutical excipient, is hydrophobic, or vice versa. When the pharmaceutical composition comprises a third constituent, this is preferably hydrophilic as well.

(40) A skilled person knows how to distinguish hydrophobic substances from hydrophilic substances. For the purpose of the specification, hydrophilic substances preferably have a solubility in pure water at 20 C. of at least 10 g/l, more preferably at least 50 g/l, still more preferably at least 100 g/l, yet more preferably at least 200 g/l, most preferably at least 300 g/l and in particular at least 400 g/l. For the purpose of the specification, hydrophobic substances preferably have a solubility in pure water at 20 C. of at most 1 g/l, more preferably at most 0.5 g/l, still more preferably at most 1.0 g/l, yet more preferably at most 0.05 g/l, most preferably at most 0.01 g/l and in particular at most 0.005 g/l.

(41) In a preferred embodiment, the pharmaceutical excipient, preferably first pharmaceutical excipient, has a melting point/range within the range of 6030 C., more preferably 6025 C., still more preferably 6020 C., yet more preferably 6015 C., most preferably 6010 C., and in particular 605.0 C.

(42) In a preferred embodiment, the pharmaceutical component, preferably second pharmaceutical excipient, has a melting point/range within the range of 2.030 C., more preferably 2.025 C., still more preferably 2.020 C., yet more preferably 2.015 C., most preferably 2.010 C., and in particular 2.05.0 C.

(43) In a preferred embodiment, the pharmaceutical component, preferably second pharmaceutical excipient, has a density (at 20 C.) within the range of 0.9500.040 g/cm.sup.3, more preferably 0.9500.030 g/cm.sup.3, still more preferably 0.9500.025 g/cm.sup.3, yet more preferably 0.9500.020 g/cm.sup.3, most preferably 0.9500.015 g/cm.sup.3, and in particular 0.9500.010 g/cm.sup.3.

(44) In a preferred embodiment, the pharmaceutical excipient, preferably first pharmaceutical excipient, is a polymer, more preferably a linear polymer, still more preferably a water-soluble polymer, yet more preferably a polyalkylene glycol, most preferably a polyethylene glycol; and/or the pharmaceutical component, preferably second pharmaceutical excipient, is an antioxidant, preferably a tocopherol component, more preferably alpha-tocopherol.

(45) For the purpose of the specification, the term polyalkylene glycol comprises e.g. polyethylene glycol, polypropylene glycol, blends thereof and copolymers thereof.

(46) For the purpose of the specification, tocopherol component refers to alpha-tocopherol (vitamin E) and its derivatives such as tocopherol acetate.

(47) In a preferred embodiment, the pharmaceutical excipient, preferably first pharmaceutical excipient, is a polyalkylene glycol, preferably a polyethylene glycol, having a weight average molecular weight within the range of from 6,0005,000 g/mol, more preferably 6,0004,000 g/mol, still more preferably 6,0003,000 g/mol, yet more preferably 6,0002,000 g/mol, most preferably 6,0001,500 g/mol, and in particular 6,0001,000 g/mol.

(48) Preferably, the pharmaceutical composition does not contain any pharmacologically active substance (besides the tocopherol component).

(49) In a preferred embodiment, the relative weight ratio of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, to the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, is within the range of from 1000:1 to 1:1, more preferably 900:1 to 5:1, still more preferably 800:1 to 10:1, yet more preferably 700:1 to 15:1, most preferably 600:1 to 20:1, and in particular 500:1 to 25:1.

(50) In a preferred embodiment, the relative weight ratio of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, to the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, is at most 1000:1, more preferably at most 900:1, still more preferably at most 800:1, yet more preferably at most 700:1, most preferably at most 600:1 and in particular at most 500:1.

(51) In another preferred embodiment, the relative weight ratio of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, to the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, is at least 1:1, more preferably at least 5:1, still more preferably at least 10:1, yet more preferably at least 20:1, most preferably at least 30:1 and in particular at least 50:1.

(52) When the pharmaceutical composition comprises a third constituent, preferably another pharmaceutical excipient, the relative weight ratio of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, to said third constituent, preferably another pharmaceutical excipient, preferably polyethylene oxide, is within the range of from 99:1 to 1:5, more preferably 50:1 to 1:4, still more preferably 30:1 to 1:3, yet more preferably 20:1 to 1:2, most preferably 15:1 to 1:1 and in particular 10:1 to 2:1.

(53) Preferably, the content of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, in the pharmaceutical composition is at least 50 wt.-% or at least 55 wt.-%, still more preferably at least 60 wt.-% or at least 65 wt.-%, yet more preferably at least 70 wt.-% or at least 75 wt.-%, most preferably at least 80 wt.-%, at least 82.5 wt.-%, at least 85 wt.-% or at least 87.5 wt.-%, and in particular at least 90 wt.-%, at least 91 wt.-%, at least 92 wt.-%, at least 93 wt.-%, at least 94 wt.-%, at least 95 wt.-%, at least 96 wt.-%, at least 97 wt.-%, at least 98 wt.-%, or at least 99 wt.-%, based on the total weight of the pharmaceutical composition.

(54) Preferably, the content of the optionally present third constituent, preferably another pharmaceutical excipient, more preferably polyethylene oxide, in the pharmaceutical composition is at least 0.1 wt.-% or at least 0.2 wt.-%, still more preferably at least 0.5 wt.-% or at least 1.0 wt.-%, yet more preferably at least 2.0 wt.-% or at least 5.0 wt.-%, most preferably at least 7.5 wt.-%, at least 10 wt.-%, at least 12.5 wt.-% or at least 15 wt.-%, and in particular at least 20 wt.-%, at least 25 wt.-%, at least 30 wt.-%, at least 35 wt.-%, at least 40 wt.-%, at least 45 wt.-%, at least 50 wt.-%, at least 55 wt.-%, at least 60 wt.-%, or at least 65 wt.-%, based on the total weight of the pharmaceutical composition.

(55) Preferably, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is at most 50 wt.-% or at most 45 wt.-%, more preferably at most 40 wt.-% or at most 35 wt.-%, still more preferably at most 30 wt.-% or at most 25 wt.-%, yet more preferably at most 20 wt.-%, at most 17.5 wt.-%, at most 15 wt.-% or at most 12.5 wt.-%, most preferably 10 wt.-%, at most 9.0 wt.-%, at most 8.0 wt.-%, at most 7.0 wt.-%, or at most 6.0 wt.-%, and in particular at most at most 5.0 wt.-%, at most 4.0 wt.-%, at most 3.0 wt.-%, at most 2.0 wt.-%, or at most 1.0 wt.-%, based on the total weight of the pharmaceutical composition.

(56) In a preferred embodiment, the content of the pharmaceutical component, preferably pharmacologically active ingredient, is at most 10 wt.-% or at most 9.0 wt.-%, more preferably at most 8.0 wt.-% or at most 7.0 wt.-%, still more preferably at most 6.0 wt.-% or at most 5.0 wt.-%, yet more preferably at most 4.5 wt.-%, at most 4.0 wt.-%, at most 3.5 wt.-% or at most 3.0 wt.-%, most preferably 2.5 wt.-%, at most 2.0 wt.-%, at most 1.5 wt.-%, at most 1.0 wt.-%, or at most 0.75 wt.-%, and in particular at most at most 0.5 wt.-%, at most 0.25 wt.-%, at most 0.1 wt.-%, at most 0.05 wt.-%, at most 0.01 wt.-%, at most 0.005 wt.-% or at most 0.001 wt.-%, based on the total weight of the pharmaceutical composition.

(57) In a preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 14.05.0 wt.-%, more preferably 14.04.0 wt.-%, still more preferably 14.03.0 wt.-%, yet more preferably 14.02.0 wt.-%, most preferably 14.01.0 wt.-%, and in particular 14.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(58) In another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 12.05.0 wt.-%, more preferably 12.04.0 wt.-%, still more preferably 12.03.0 wt.-%, yet more preferably 12.02.0 wt.-%, most preferably 12.01.0 wt.-%, and in particular 12.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(59) In still another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 10.05.0 wt.-%, more preferably 10.04.0 wt.-%, still more preferably 10.03.0 wt.-%, yet more preferably 10.02.0 wt.-%, most preferably 10.01.0 wt.-%, and in particular 10.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(60) In yet another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 9.05.0 wt.-%, more preferably 9.04.0 wt.-%, still more preferably 9.03.0 wt.-%, yet more preferably 9.02.0 wt.-%, most preferably 9.01.0 wt.-%, and in particular 9.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(61) In a preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 8.05.0 wt.-%, more preferably 8.04.0 wt.-%, still more preferably 8.03.0 wt.-%, yet more preferably 8.02.0 wt.-%, most preferably 8.01.0 wt.-%, and in particular 8.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(62) In another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 7.05.0 wt.-%, more preferably 7.04.0 wt.-%, still more preferably 7.03.0 wt.-%, yet more preferably 7.02.0 wt.-%, most preferably 7.01.0 wt.-%, and in particular 7.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(63) In still another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 6.05.0 wt.-%, more preferably 6.04.0 wt.-%, still more preferably 6.03.0 wt.-%, yet more preferably 6.02.0 wt.-%, most preferably 6.01.0 wt.-%, and in particular 6.00.5 wt.-%, based on the total weight of the pharmaceutical composition.

(64) In yet another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 5.02.5 wt.-%, more preferably 5.02.0 wt.-%, still more preferably 5.01.5 wt.-%, yet more preferably 5.01.0 wt.-%, most preferably 5.00.5 wt.-%, and in particular 5.00.25 wt.-%, based on the total weight of the pharmaceutical composition.

(65) In another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 4.02.5 wt.-%, more preferably 4.02.0 wt.-%, still more preferably 4.01.5 wt.-%, yet more preferably 4.01.0 wt.-%, most preferably 4.00.5 wt.-%, and in particular 4.00.25 wt.-%, based on the total weight of the pharmaceutical composition.

(66) In still another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 3.02.5 wt.-%, more preferably 3.02.0 wt.-%, still more preferably 3.01.5 wt.-%, yet more preferably 3.01.0 wt.-%, most preferably 3.00.5 wt.-%, and in particular 3.00.25 wt.-%, based on the total weight of the pharmaceutical composition.

(67) In yet another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 2.01.5 wt.-%, more preferably 2.01.25 wt.-%, still more preferably 2.01.0 wt.-%, yet more preferably 2.00.75 wt.-%, most preferably 2.00.5 wt.-%, and in particular 2.00.25 wt.-%, based on the total weight of the pharmaceutical composition.

(68) In another preferred embodiment, the content of the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in the pharmaceutical composition is within the range of 1.00.8 wt.-%, more preferably 1.00.6 wt.-%, still more preferably 1.00.5 wt.-%, yet more preferably 1.00.4 wt.-%, most preferably 1.00.3 wt.-%, and in particular 1.00.2 wt.-%, based on the total weight of the pharmaceutical composition.

(69) The pharmaceutical composition is powdery. A powder is typically defined as an assembly of dry particles dispersed in air. For the purpose of the specification, powdery preferably means that the pharmaceutical composition is a dry bulk solid consisting of a large number of fine or very fine particles that may flow freely when shaken or tilted, i.e. that are not cemented together. Preferably, the texture is smooth in touch. In a preferred embodiment, the powdery pharmaceutical composition is free-flowing.

(70) In a preferred embodiment, the powdery pharmaceutical composition is a homogeneous mixture of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and the optionally present third constituent. For the purpose of the specification, homogeneous preferably means that the standard deviation (SD) as a measure of blend uniformity (BU) of the powdery pharmaceutical composition is at most 5.0 SD %, more preferably at most 4.5 SD %, still more preferably at most 4.0 SD %, yet more preferably at most 3.5 SD %, most preferably at most 3.0 SD % and in particular at most 2.5 SD %. Methods to determine blend uniformity of powders are known to the skilled person. For example, a suitable method is near infrared spectroscopy (NIR), other methods are described in the Eur. Ph.

(71) Preferably, the particle size (grain size) of the powdery pharmaceutical composition is comparatively fine.

(72) In a preferred embodiment, at least 90 wt.-% of the powdery pharmaceutical composition passes sieve size 4.75 mm, 3.35 mm, 2.81 mm, 2.38 mm, or 2.00 mm; more preferably 1.68 mm, 1.40 mm, 1.20 mm, 1.00 mm, or 0.853 mm; still more preferably 0.710 mm, 0.599 mm, 0.500 mm, 0.422 mm, or 0.354 mm; yet more preferably 0.297 mm, 0.251 mm, 0.211 mm, 0.178 mm, or 0.152 mm; most preferably 0.125 mm, 0.104 mm, 0.089 mm, 0.075 mm, or 0.066 mm; and in particular 0.053 mm, 0.044 mm, or 0.037 mm.

(73) In a particularly preferred embodiment, at least 90 wt.-% of the powdery pharmaceutical composition passes sieve size 1.00 mm, 0.95 mm, 0.90 mm or 0.85 mm.

(74) In a preferred embodiment, the powdery pharmaceutical composition is free flowing and preferably, has an average particle size of at most 100 m, more preferably at most 90 m, still more preferably at most 80 m, yet more preferably at most 70 m, most preferably at most 60 m and in particular at most 50 m. Method to determine the average particle size of powders are known to the skilled person. A suitable method is for example laser light scattering or sieve analysis.

(75) In a preferred embodiment, the powdery pharmaceutical composition is characterized by a d 10 value of 1710 m, more preferably 178 m, still more preferably 176 m, yet more preferably 175 m, even more preferably 174 m, most preferably 173 m and in particular 172 m.

(76) In a preferred embodiment, the powdery pharmaceutical composition is characterized by a d 50 value of 8030 m, more preferably 8025 m, still more preferably 8020 m, yet more preferably 8015 m, even more preferably 8010 m, most preferably 808 m and in particular 806 m.

(77) In a preferred embodiment, the powdery pharmaceutical composition is characterized by a d 90 value of 19070 m, more preferably 19060 m, still more preferably 19050 m, yet more preferably 19040 m, even more preferably 19030 m, most preferably 19020 and in particular 19010 m.

(78) When the method according to the invention involves preceding step (b) (see below), the powder which has exited the extruder is further grinded so that the particle size and particle size distribution of the final powdery pharmaceutical composition obtained in step (c) does not correspond to the particle size and particle size distribution of the powder that has exited the extruder in step (b).

(79) Preferably, the method according to the invention additionally comprises the preceding step of (b) extruding a mixture of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, in an extruder at a temperature profile allowing a liquid melt of the mixture to congeal in the extruder and to exit the extruder in form of a powder.

(80) In optional step (b) of the method according to the invention, a mixture of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, optionally together with a third constituent, preferably another pharmaceutical excipient, is extruded.

(81) Typically, extrusion is regarded as a process used to create objects of a fixed cross-sectional profile. A material is pushed or drawn through a die of the desired cross-section. Two main advantages of this process over other manufacturing processes is its ability to create very complex cross-sections and work materials that are brittle, because the material only encounters compressive and shear stresses. It also forms finished parts with an excellent surface finish.

(82) For the purpose of the invention, however, extrusion is preferably performed in an unusual fashion, namely so that the product, i.e. the extrudate, is a powder. This can be achieved by carefully adapting the extrusion parameters, e.g. screw geometry, extrusion temperature, screw speed, throughput, pressure and the like. Preferably, the extruder is not equipped with an extrusion die so that the pressure exerted to the mixture within the extruder is comparatively low. Preferably, the extruder is equipped neither with extrusion die nor with an adapter (e.g. Y-pipe).

(83) For the purpose of the specification the term extrudate refers to any material exiting the extruder, e.g. an extruded strand or a powder.

(84) Preferably, the pressure just ahead of the exit (outlet orifice) of the extruder does not exceed 25 bar or 20 bar, more preferably 15 bar or 10 bar, still more preferably 8.0 bar or 6.0 bar, yet more preferably 5.0 bar or 4.0 bar, most preferably 3.0 bar or 2.0 bar, and in particular 1.5 bar or 1.0 bar. The pressure just ahead of the exit of the extruder can be measured by conventional means and many commercialized extruders are already equipped with a respective manometer at the proper position. In a preferred embodiment, however, no pressure can be measured at all and the extrusion is performed under conditions imparting as minimal pressure as possible, preferably at most 1.0 bar, more preferably at most 0.8 bar, still more preferably at most 0.6 bar, yet more preferably at most 0.4 bar, most preferably at most 0.2 bar, and in particular at most 0.1 bar.

(85) Preferably, the design of the screw elements and the extrusion conditions are adjusted to ensure that the extruded mass, in particular after its congealing, is not compacted or, if compaction cannot be completely avoided, the degree of compaction is as low as possible. A skilled person knows how to adjust such mild extrusion conditions, e.g. by regulating the screw speed.

(86) Preferably, the extruder has an inner diameter of 10 mm to 100 mm, more preferably 12 mm to 90 mm, still more preferably 14 mm to 80 mm, most preferably 15 mm to 70 mm and in particular 15 mm to 60 mm. In a preferred embodiment, the extruder has an inner diameter of 1810 mm, more preferably 188 mm, still more preferably 186 mm, yet more preferably 184 mm, most preferably 182 mm, and in particular 181 mm. In another preferred embodiment, the extruder has an inner diameter of 2710 mm, more preferably 278 mm, still more preferably 276 mm, yet more preferably 274 mm, most preferably 272 mm, and in particular 271 mm. In yet another preferred embodiment, the extruder has an inner diameter of 5010 mm, more preferably 508 mm, still more preferably 506 mm, yet more preferably 504 mm, most preferably 502 mm, and in particular 501 mm.

(87) Preferably, the extruder has a length of 30 cm to 250 cm, more preferably 40 cm to 240 cm, still more preferably 50 cm to 230 cm, most preferably 60 cm to 220 cm and in particular 70 cm to 210 cm.

(88) In a preferred embodiment, the ratio of extruder length in mm and extruder diameter in mm is within the range of 2515, more preferably 2510, still more preferably 258, yet more preferably 256, most preferably 254, and in particular 252.

(89) In another preferred embodiment, the ratio of extruder length in mm and extruder diameter in mm is within the range of 3015, more preferably 3010, still more preferably 308, yet more preferably 3 06, most preferably 304, and in particular 302.

(90) In still another preferred embodiment, the ratio of extruder length in mm and extruder diameter in mm is within the range of 4015, more preferably 4010, still more preferably 408, yet more preferably 406, most preferably 404, and in particular 402.

(91) Preferably, the screw geometry is adapted so that the congealed material within the extruder is exerted a sufficient impact in order to yield a powdery pharmaceutical composition exiting the extruder. Thus, the extrusion parameters of the method according to the invention are preferably in contrast to the extrusion parameters of conventional methods where it is generally desired to manufacture a non-powdery extrusion strand having a smooth and excellent surface finish.

(92) Typically, the screw geometry may be modified by varying the screw elements from which the screw is assembled. Conventional screw extruders are typically equipped with an extrusion axis adapted to carry a number of screw elements. Depending upon the extruder design and the design of the individual screw elements, the extrusion axis may carry about 10 to about 50 or more identical or different screw elements. In twin screw extruders (counter-rotating or co-rotating) the design of the individual screw elements must be such that contra-rotation or co-rotation about the two parallel extrusion axes is possible.

(93) Preferably, each screw is equipped with (assembled from) at least 5, more preferably at least 10, most preferably 15 and in particular at least 20 identical or different screw elements.

(94) The manufactures of screw extruders usually commercialize quite a number of different extrusion elements that can be employed in their extruders depending upon the individual demands of the extrusion technique. Examples of commercially available screw elements include screw transport elements, kneading elements, blank elements and the like. A skilled person is aware of typical screw elements.

(95) Each screw element serves a particular purpose and a skilled person knows what screw element to choose in order to serve a particular purpose.

(96) For example, a main purpose of screw transport elements is to effect transportation of the extruded material within the extruder from the inlet to the outlet and optionally, to impart the necessary pressure in front of the extrusion die. Screw transport elements can typically be divided in sub-types differing in their number of windings (threads) per standard length. For example, a screw transport element having two windings (threads) along a length of e.g. 100 mm differs from a screw transport element having three windings (threads) along the same length.

(97) In contrast, a main purpose of kneading elements is to effect a vigorous mixing of the constituents of the extruded material without any substantial transportation. Kneading elements can typically also be divided in sub-types differing in their design and relative angle of kneaders. For example, a kneading element having two consecutive kneaders that are off-set 90 about the extrusion axis differs from a kneading element having two consecutive kneaders that are off-set 60 about the extrusion axis.

(98) The design of the extrusion screws in the method according to the invention is not particularly limited. Preferably, however, each extrusion screw is equipped with (assembled from) a plurality of screw elements. Preferably, each extrusion screw comprises at least two different types of screw elements, more preferably at least three different types, still more preferably at least four different types, whereas every type of screw element may be represented by a single or a plurality of screw elements (i.e., of the same type). Screw elements of the same type may be located next to one another or in alternating, regular or irregular order and sequence with screw elements of other type(s), respectively.

(99) In a preferred embodiment, each extrusion screw comprises at least having one screw element with a pitch (axial distance for one revolution of screw flight expressed as ratio to screw diameter (D)) within the range of 1.251.0 D, more preferably 1.250.75 D, still more preferably 0.50.4 D, 1.00.5 D or 1.750.5 D, yet more preferably 0.50.3 D, 1.00.4 D or 1.750.4 D, and most preferably 0.50.25 D, 1.00.25 D or 1.750.25 D.

(100) In a preferred embodiment of the method according to the invention, each extrusion screw is equipped with (assembled from) at least two different types of screw transport elements differing, optionally inter alia, in their number of windings (threads) per standard length, whereas in at least a portion of the extrusion screw the type of screw transport elements having the lower number of windings (threads) is located upstream with respect to the screw transport elements having the higher number of windings (threads).

(101) In another preferred embodiment of the method according to the invention, each extrusion screw is equipped with (assembled from) at least two different types of screw transport elements differing, optionally inter alia, in their chamber volume per standard length, whereas in at least a portion of the extrusion screw the type of screw transport elements having the smaller chamber volume is located upstream with respect to the screw transport elements having the larger chamber volume. For the purpose of the specification, the chamber volume is to be regarded as the space between the screw elements and the extruder wall, i.e. the inner hollow space that guides the extruded mass through the extruder.

(102) Preferably, each extrusion screw is equipped with (assembled from) at least two different types of screw transport elements (a) and (b), whereas each type of screw transport element is represented by one or more individuals. In a preferred embodiment, the number of windings (threads) per standard length of elements (b) exceeds the number of windings (threads) of elements (a). In another preferred embodiment, the chamber volume per standard length of elements (b) exceeds the chamber volume of elements (a). In still another preferred embodiment, the pitch of elements (b) exceeds the pitch of elements (a). In yet another preferred embodiment, the conveying speed of elements (b) exceeds the conveying speed of elements (a). In another preferred embodiment, the volumetric displacement of elements (b) exceeds the volumetric displacement of elements (a). Preferably, a sequence of four consecutive elements that are independently chosen from screw transport elements of type (a) and screw transport elements of type (b) forms a portion of the extrusion screw.

(103) In a preferred embodiment, the length of the extrusion screw corresponds to the length of the extruder so that the entire extrusion screw is mounted by the extruder block. In another preferred embodiment the length of the extrusion screw is such that it protrudes from the extruder block, typically by several cm, e.g. about 2.5, 5 or 7.5 cm.

(104) The method according to the invention comprises the extrusion of a mixture of the pharmaceutical excipient and the pharmaceutical component in an extruder at a temperature profile allowing a liquid melt of the mixture to congeal in the extruder and to exit the extruder in form of a powder. Thus, when the extruder is a screw extruder, its extrusion axis or axes, respectively, comprise an upstream portion that serves the purpose of extruding the not yet congealed mixture and a downstream portion that serves the purpose of extruding the congealed mixture.

(105) In a preferred embodiment of the method according to the invention, the screw elements forming said downstream portion of the extrusion screw comprise screw elements imparting a relatively high mechanical impact on the congealed mixture in order to yield a powdery pharmaceutical composition. Thus, as far as the design of the extrusion elements in this downstream portion is concerned, extrusion conditions are comparatively harsh.

(106) Preferably, parallel to the temperature profile in the extruder that allows the liquid melt of the mixture to congeal in the extruder and to exit the extruder in form of a powder, there is an extrusion screw profile increasing the mechanical impact exerted by the extrusion elements further supporting that the extruded material exits the extruder in form of a powder.

(107) The extruder is preferably equipped with at least two heating elements that can be adjusted to different temperatures independently. Preferably, the extruder comprises at least three, more preferably at least four, still more preferably at least five, yet more preferably at least six, most preferably at least seven and in particular at least eight of such heating elements adjustable to different temperatures independently.

(108) These heating elements allow adjusting the desired temperature profile within the extruder.

(109) Preferably, the extruder is equipped with at least four consecutive heating elements H.sub.1, H.sub.2, H.sub.3 and H.sub.4 which are set at the corresponding temperatures T.sub.1, T.sub.2, T.sub.3 and T.sub.4, respectively. H.sub.1 is located upstream with respect to H.sub.2 to H.sub.4, H.sub.2 is located upstream with respect to H.sub.3 and H.sub.4 and H.sub.3 is located upstream with respect to H.sub.4. Preferred embodiments of the relationship T.sub.1 to T.sub.4 are summarized here below: T.sub.1=T.sub.2=T.sub.3=T.sub.4; T.sub.1>T.sub.2=T.sub.3=T.sub.4; T.sub.1=T.sub.2>T.sub.3=T.sub.4; T.sub.1=T.sub.2=T.sub.3>T.sub.4; T.sub.1<T.sub.2=T.sub.3=T.sub.4; T.sub.1=T.sub.2<T.sub.3=T.sub.4; T.sub.1=T.sub.2=T.sub.3<T.sub.4; T.sub.1>T.sub.2>T.sub.3=T.sub.4; T.sub.1>T.sub.2=T.sub.3>T.sub.4; T.sub.1=T.sub.2>T.sub.3>T.sub.4; T.sub.1<T.sub.2<T.sub.3=T.sub.4; T.sub.1<T.sub.2=T.sub.3<T.sub.4; T.sub.1=T.sub.2<T.sub.3<T.sub.4; T.sub.1>T.sub.2>T.sub.3>T.sub.4; or T.sub.1<T.sub.2<T.sub.3<T.sub.4.

(110) Preferably, in step (b) of the method according to the invention, extrusion is performed by means of a screw extruder, preferably a twin screw extruder having contra-rotating or co-rotating screws. It is also possible to perform extrusion by means of a planetary gear extruder (planetary roller extruder). Suitable extruders are known to the skilled person and commercially available. A suitable twin screw extruder is for example commercialized by Leistritz, type ZSE 18PH 40 D.

(111) A skilled person recognizes, however, that the gist of the method according to the invention can also be realized by equivalent means typically employed in order to process viscous or highly viscous masses, wherein processing typically involves heating, mixing, cooling, shearing, and/or the like. Exemplified means include roll coolers or barrel coolers, cool belts, granulators, coaters, etc.

(112) In the course of the extrusion process, the extruded material is typically transported along the longitudinal axis of the extruder from the inlet (feeding point) to the outlet (exit). Material movement is typically effected by the rotation of the screws and by the new starting material entering the inlet of the extruder. For the purpose of the specification, two locations along the longitudinal axis of the extruder may be qualified as upstream and downstream with respect to the direction of extrusion. The location upstream is closer to the inlet of the extruder than the location downstream and vice versa, the location downstream is closer to the exit of the extruder than the location upstream.

(113) The temperature profile within the extruder is adjusted to ensure that a liquid melt of the mixture is allowed to congeal in the extruder before it exits the extruder. Thus, according to the method of the invention, at least at one upstream location within the extruder the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, optionally together with a third constituent, preferably another pharmaceutical excipient, are present in the molten state. Melting is typically achieved by adjusting the temperature profile so that at said upstream location the temperature of the mixture (extruded material) is sufficiently high.

(114) This does not necessarily mean that the temperature of the mixture (extruded material) in the extruder at said one upstream location must be above the melting points/ranges of both, the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent, preferably another pharmaceutical excipient. Depending upon the nature and the amount of the excipients it may be sufficient that the temperature is above the melting point/range of just one of the two or three ingredients so that it forms a liquid melt in which the other is (are) dissolved.

(115) Preferably, however, the temperature of the mixture (extruded material) in the extruder at said one upstream location is above the melting points/ranges of both, the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent.

(116) The liquid melt may be formed, i.e. generated, within the extruder by initially heating the mixture (extruded material) having a temperature below its melting point/range to a temperature above its melting point/range so that a liquid melt is formed. Alternatively, however, the liquid melt may already be fed into the extruder, i.e. the liquid melt of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, optionally together with a third constituent, preferably another pharmaceutical excipient, may be formed outside the extruder and then be supplied to the inlet of the extruder so that the starting material enters the extruder already in molten liquid state. Preferably, said liquid state is maintained for a while in the course of the extrusion process.

(117) In the course of the extrusion process and as a consequence of the temperature profile, the liquid melt is allowed to congeal in the extruder. The liquid melt congeals, i.e. solidifies to a solid material by cooling. Thus, according to the method of the invention, at least at one downstream location within the extruder the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, optionally together with a third constituent, preferably another pharmaceutical excipient, are present in the congealed, i.e. solidified state. Congealing is typically achieved by adjusting the temperature profile so that at said downstream location the temperature of the mixture (extruded material) is sufficiently low.

(118) This does not necessarily mean that the temperature of the mixture (extruded material) in the extruder at said one downstream location must be below the melting points/ranges of both, the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent. Depending upon the nature and the amount of the excipients it may be sufficient that the temperature is below the melting point/range of just one of the two ingredients so that it solidifies with the other ingredient being dissolved in it.

(119) Preferably, when the congealed mixture exits the extruder, it has a temperature of at least 5 C., preferably at least 10 C., more preferably at least 15 C., still more preferably at least 20 C., yet more preferably at least 25 C., most preferably at least 30 C. and in particular at least 35 C., below the melting point/temperature of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent.

(120) In a preferred embodiment of the method according to the invention, in step (b) the temperature profile comprises a temperature gradient of temperature T.sub.1 to temperature T.sub.2, where T.sub.1>T.sub.2 and where T.sub.1 is above the melting point/range of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent; and/or T.sub.2 is below the melting point/range of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol and/or pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and/or the optionally present third constituent.

(121) T.sub.1 and T.sub.2 are preferably adjusted be means of the heating elements of the extruder. Preferably T.sub.1 and T.sub.2 correspond to the temperatures at which the heating elements are heated.

(122) Preferably, T.sub.1 is within the range of from 25 C. to 115 C., or 30 C. to 110 C., more preferably 35 C. to 105 C., or 40 C. to 100 C., still more preferably 45 C. to 95 C., or 50 C. to 90 C., yet more preferably 55 C. to 85 C., most preferably 60 C. to 80 C., and in particular 65 C. to 75 C.; and/or T.sub.2 is within the range of from 20 C. to 50 C., more preferably 10 C. to 40 C., still more preferably 5 C. to 35 C., yet more preferably 0 C. to 30 C., most preferably 5 C. to 25 C., and in particular 10 C. to 20 C.

(123) In a preferred embodiment, T.sub.1 is at least 0.5 C. or at least 1.0 C., more preferably at least 1.5 C. or at least 2.0 C., still more preferably at least 2.5 C. or at least 3.0 C., yet more preferably at least 3.5 C. or at least 4.0 C., most preferably at least 4.5 C. or at least 5.0 C., and in particular at least 5.5 C. or at least 6.0 C. above the melting point of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent.

(124) In another preferred embodiment, T.sub.1 is at least 5 C. or at least 10 C., more preferably at least 15 C. or at least 20 C., still more preferably at least 25 C. or at least 30 C., yet more preferably at least 35 C. or at least 40 C., most preferably at least 45 C. or at least 50 C., and in particular at least 55 C. or at least 60 C. above the melting point of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent.

(125) In a preferred embodiment, T.sub.2 is at least 1.0 C. or at least 2.0 C., more preferably at least 3.0 C. or at least 4.0 C., still more preferably at least 5.0 C. or at least 6.0 C., yet more preferably at least 7.0 C. or at least 8.0 C., most preferably at least 9.0 C. or at least 10 C., and in particular at least 11 C. or at least 12 C. above the melting point of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent.

(126) In another preferred embodiment, T.sub.2 is at least 2.5 C. or at least 5.0 C., more preferably at least 7.5 C. or at least 10 C., still more preferably at least 12.5 C. or at least 15 C., yet more preferably at least 17.5 C. or at least 20 C., most preferably at least 25 C. or at least 30 C., and in particular at least 35 C. or at least 40 C. below the melting point of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and/or the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol and/or the optionally present third constituent.

(127) In a preferred embodiment, the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent, are fed into the extruder in form of a liquid melt having a sufficiently high temperature, preferably within the range of T.sub.110 C., more preferably T.sub.18.0 C., still more preferably T.sub.16.0 C., yet more preferably T.sub.14.0 C., most preferably T.sub.12.0 C., and in particular T.sub.11.0 C.

(128) The congealed mixture then exits the extruder in form of a powder. This means that in the extruder the liquid melt does not only congeal into a solid material but is further comminuted into a powder, at least to a certain extent.

(129) In a preferred embodiment, the method according to the invention comprising steps (b) and (c) comprises the preceding step of (a) mixing the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, with the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent, outside the extruder and then feeding the resultant mixture into the extruder; or feeding the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent, into the extruder at different feeding points, where the feeding point for the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, is located upstream with respect to the feeding point for the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, or vice versa.

(130) Step (a) precedes step (b), i.e. step (b) is performed after step (a) has been completed.

(131) Preferably, in step (a) the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, is dissolved in the molten pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol and/or the optionally present third constituent, or vice versa.

(132) In another preferred embodiment, the method according to the invention comprises the subsequent step of (d) grading the powder.

(133) Typically, the method according to the invention does not comprise any spray congealing or spray drying step. It has been surprisingly found that by the method according to the invention laborious steps that require sophisticated equipment and process control can be omitted without deteriorating product quality. Thus, in a particularly preferred embodiment, besides extrusion, the method according to the invention does not comprise any separate grinding, spray congealing or spray drying steps.

(134) The method according to the invention can be performed batch-wise or continuously.

(135) Preferably, the method is performed continuously and a mixture of the pharmaceutical excipient, preferably first pharmaceutical excipient, which is a polyalkylene glycol, more preferably polyethylene glycol, and the pharmaceutical component, preferably second pharmaceutical excipient, more preferably alpha-tocopherol, and the optionally present third constituent, is automatically dosed into the extruder, preferably in form of a melt. First preliminary tests revealed that continuous dosing can be realized by standard equipment.

(136) A further aspect of the invention relates to a method for the manufacture of a pharmaceutical dosage form comprising the method according to the invention as described above. Preferably, the pharmaceutical dosage form has a breaking strength of at least 400 N, more preferably at least 500 N, still more preferably at least 600 N, yet more preferably at least 700 N, most preferably at least 800 N and in particular at least 900 N. Dosage forms exhibiting such a high breaking strength are known from the prior art. In this regard it can be referred to e.g. WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, WO 2008/107149 and WO2009/092601.

(137) Preferably, the method for the manufacture of a pharmaceutical dosage form comprises the step of formulating the powdery pharmaceutical composition comprising the first pharmaceutical excipient and the second pharmaceutical excipient and the optionally present third constituent, as described above together with a pharmacologically active substance, preferably an opioid, and/or a high molecular weight polyalkylene oxide, preferably polyethylene oxide, preferably having a weight average molecular weight of a least 200,000 g/mol, more preferably at least 500,000 g/mol, still more preferably at least 750,000 g/mol, yet more preferably at least 1,000,000 g/mol and in particular within the range of from 1,000,000 g/mol to 10,000,000 g/mol; and/or a cellulose ether, preferably hydroxypropylmethyl cellulose or hydroxypropylcellulose.

(138) Thus, in the method for the manufacture of a pharmaceutical dosage form according to the invention, the powdery pharmaceutical composition is preferably employed as intermediate.

(139) Preferably, the powdery pharmaceutical composition does not substantially alter the release of the pharmacologically active substance from the pharmaceutical dosage form, i.e. the in vitro release profile of the pharmaceutical dosage form is not substantially influenced by the presence of the powdery pharmaceutical composition. In this regard, substantially preferably means 2%, more preferably 1%, i.e. the presence of the powdery pharmaceutical composition preferably does not alter the in vitro release profile by more than 2% compared to a dosage form not containing the powdery pharmaceutical composition.

(140) In a preferred embodiment, the total amount of the (first) pharmaceutical excipient contained in the pharmaceutical dosage form originates from the powdery pharmaceutical composition, i.e. preferably no further (first) pharmaceutical excipient is added in the course of manufacturing the pharmaceutical dosage form from the powdery pharmaceutical composition.

(141) In a preferred embodiment, the pharmaceutical dosage form contains the pharmaceutical composition in such an amount that the content of the (first) pharmaceutical excipient is within the range of from 1.0 to 20 wt.-%, more preferably 2.0 to 18 wt.-%, still more preferably 4.0 to 16 wt.-%, yet more preferably 6.0 to 14 wt.-%, most preferably 7.0 to 13 wt.-%, and in particular 8.0 to 12 wt.-%, relative to the total weight of the pharmaceutical dosage form.

(142) The invention is further illustrated by the following examples which, however, are not to be construed as limiting its scope.

EXAMPLE 1EXTRUSIONMANUFACTURE OF PRE-BLEND

(143) alpha-tocopherol-polyethylene glycol 6000 pre-blends were manufactured by means of a twin-screw extruder, type Leistritz ZSE27.

(144) All trials were carried out with a screw configuration without kneading elements.

(145) Only trials of 4% alpha-tocopherol concentration with high screw speed (trial 10 and trial 11) were tested with another screw configuration, because with a lower screw speed the extruder throughput was too low. These trials are identified with bis.

(146) TABLE-US-00001 Factors Level Level 0 Level + alpha-tocopherol content [wt.-%] 4 14 14 Feed rate [kg/h] 2 4 6 Screw speed [rpm] 30 80 130

(147) In a 2.sup.3 full factorial design, the following three parameters were varied: alpha-tocopherol content, feed rate, and screw speed. The experimental design thus consisted of 8 runs plus three center point runs for a total of 11 runs. A total of 4 kg of alpha-tocopherol/PEG blend were manufactured in each run.

(148) The experimental design of trails 1 to 11 is summarized in the table here below:

(149) TABLE-US-00002 alpha-tocopherol trial batch concentration [%] feed rate [kg/h] speed [rpm] 1 1 14% 4 80 2 2 130 3 6 30 4 4 80 5 6 130 6 2 30 7 4 80 8 2 4% 6 30 9 2 30 10 2 130 11 6 130

(150) No significant differences among the trials could be observed. A coarse and waxy material was obtained that was difficult to characterize.

(151) The following particle size distribution (PSD) was determined after 500 m screening:

(152) TABLE-US-00003 Yield after screening alpha-tocopherol/PEG 4% (<500 m % w) Trial 8 65.0 Trial 8 (repeated) 67.6 Trial 9 34.0 Trial 10 30.9 Trial 10bis 34.0 Trial 11 36.0 Trial 11bis 32.7

(153) The particle size distribution (PSD) comparison of alpha-tocopherol/PEG with other excipients is also shown in FIG. 1.

(154) Trials 8 and 9 (alpha-tocopherol/PEG 4%) were repeated. alpha-tocopherol/PEG 4% trials led to fine particle size, especially in Trial 8 and in Trial 8 (repeated). Only a few coarse particles were visible.

(155) Trial 8 showed a finer particle size than the other trials. 65 wt.-% of particle had an average diameter of less than 500 m. Trial 8 was repeated at the end of the design of experiments confirming the results. The yield was too low for industrial application. Under these conditions, it was not possible to achieve acceptable powder state at concentration of 14 wt.-% of alpha-tocopherol.

(156) Subsequently, cryo-milling equipments of two manufacturers were tested: HosokawaAlpine (Germany) (Example 2) Nuova Guseo (Italy) (Example 3)

EXAMPLE 2CRYO-MILLING OF PRE-BLENDHOSOKAWAALPINE

(157) The pre-blends of Example 1 comprising alpha-tocopherol/PEG were subsequently subjected to cry-milling in order to obtain fine powders pharmaceutical compositions.

(158) Pre-Blends:

(159) TABLE-US-00004 alpha-tocopherol/PEG 6000 14% material is coarse and waxy, consisting 14% of aggregates of different size alpha-tocopherol/PEG 6000 4% material consists of fine particle size, 4% with few coarse particles visible

(160) Milling trials were performed on 100-UPZ (Hosokawa Alpine) varying the follows process parameters: rotation speed of the plate beater (rpm), temperature, feed rate (kg/h). Only two trials of 14% concentration (trial 9 and 10) were performed with 100 AFG Jet-Mill Micronizer (Hosokawa Alpine).

(161) The material was charged in a screw feeding device. The material fell in a liquid nitrogen bath, and was cooled down to temperatures around 120 C. A whirling screw system transported the brittle material under liquid nitrogen to the grinding system, equipped with a plate rotating beater and a 0.5 mm sieve.

(162) Milling in Hosokawa Alpine: Trials Performed on Alpha-Tocopherol/PEG 4%:

(163) TABLE-US-00005 alpha- feed tocopherol rate temperature content trial machine apparatus (kg/h) (from-to) (batch) 1 100UPZ - liquid nitrogen; 7.5 60 4% 14000 RPM plate beater; C./70 C. sieve 0.5 mm 2 100UPZ - liquid nitrogen; 5.0 100 4% 18000 RPM plate beater; C./120 C. sieve 0.5 mm 3 100UPZ - liquid nitrogen; 12 57 4% 18000 RPM plate beater; C./62 C. sieve 0.5 mm 4 100UPZ - liquid nitrogen; 20 70 4% 18000 RPM plate beater; C./80 C. sieve 0.5 mm 5 100UPZ - liquid nitrogen; 30 30 4% 18000 RPM plate beater; C./40 C. sieve 0.5 mm

(164) The better trial in terms of feed rate was trial 5, performed on alpha-tocopherol/PEG 4%. This batch, produced in the preliminary design of experiments, had a less fine particle size compared to the batches of trials 1 to 4, but better flow property. There were no significant differences among electric current consumption of the system before and after the addition of materials: this indicates that the system can work without trouble even at high feed rate. The standard screw feeding device allows the loading of material. There was no deposit in the milling tools.

(165) Milling in Hosokawa Alpine: Trials Performed on Alpha-Tocopherol/PEG 14%:

(166) TABLE-US-00006 alpha- Feed tocopherol rate Temperature content Trial Machine Apparatus (Kg/h) (from-to) (batch) 6 100UPZ - liquid nitrogen; 13.6 10 14% 14000 RPM plate beater; C./25 C. sieve 0.5 mm 7 100UPZ - liquid nitrogen; 20 10 14% 14000 RPM plate beater; C./25 C. sieve 0.5 mm 8 100UPZ - liquid nitrogen; 17 10 14% 14000 RPM plate beater; C./25 C. sieve 0.5 mm 9 100AFG nozzles 1.9 mm 1.4 n/a 14% 1000 6 bar 10 100AFG nozzles 1.9 mm 0.4 n/a 14% 2000 6 bar

(167) Severe dosing problems on the screw feeder were observed, due the material dimension and the low melting temperature. Feeding was possible with a vibrating feeding system. There were no significant differences among electric current consumption of the system before and after the addition of materials: this indicates that the system can work without trouble even at high feed rate. There was no deposit in the milling tools.

(168) After milling, a fine white powder was obtained.

(169) Flowablity test failed for nozzles 6 mm and 10 mm with stirrer on or off, as the reference (commercial spray-congealed blend). Bulk density was comparable among the trials and with the reference (commercial spray-congealed blend). Tapped density was not considered a significant parameter, due the clogging that happens for the reference material. DSC profiles of material before and after milling were similar and there were no significant differences with the DSC profile of the reference (commercial spray-congealed blend).

(170) The bulk densities are displayed in the table here below:

(171) TABLE-US-00007 alpha-tocopherol/ content of alpha- Density PEG 4% tocopherol Bulk g/ml Trial 1 4 wt.-% 0.502 Trial 2 0.511 Trial 3 0.494 Trial 4 0.475 Trial 5 0.486 Trial 6 14 wt.-% 0.440 Trial 7 0.439 Trial 8 0.433 Trial 9 0.505 Trial 10 0.404 alpha-tocopherol/PEG 0.438 14% commercial blend

(172) The particle size distribution (PSD) of Trials 6, 7 and 8 in comparison to that of the commercial alpha-tocopherol/PEG 6000 blend is shown in FIG. 2.

(173) TABLE-US-00008 alpha-tocopherol/PEG 14% d 10 (m) d 50 (m) d 90 (m) Trial 6 15.1 72.8 167.0 Trial 7 13.0 70.2 162.7 Trial 8 16.41 89.7 209.2 alpha-tocopherol/PEG 14% 18.86 80.49 220.2 commercial blend

(174) A DSC of the commercial alpha-tocopherol/PEG 6000 blend is shown in FIG. 3.

(175) DSC of alpha-tocopherol/PEG 4% material after cryo-milling is shown in FIG. 4.

(176) DSC of alpha-tocopherol/PEG 14% material after cryo-milling is shown in FIG. 5.

EXAMPLE 3CRYO-MILLING OF PRE-BLENDNUOVA GUSEO

(177) The pre-blended material of Example 1 was charged in a throttle feeding device. The material was embrittled in contact with liquid nitrogen. The cooled material fell into the grinding system, equipped with a rotating plate beater and a 0.5 and 0.8 mm sieve.

(178) Milling trials were performed varying the follows process parameters: rotation speed (rpm), net size, and temperature. The first trial (trial 1) was performed with a screw feeding device, with severe dosing problems, due the material dimension and the low melting temperature. The parameters used in the other trials are summarized in the table:

(179) TABLE-US-00009 Trial Rpm Net size (mm) Temperature ( C.) 2 5000 0.8 60 3 6000 0.8 60 4 7000 0.8 58 5 5000 0.5 60 6 6000 0.5 54 7 7000 0.5 50 8 7000 0.5 30 9 7000 0.5 15

(180) After milling, a fine white-yellow powder was obtained. Flowablity test failed for nozzles 6 mm and 10 mm with stirrer on or off, as for the reference (commercial spray-congealed blend). Bulk densities were similar among the trials and compared to the reference (commercial spray-congealed blend). Tapped density was not considered a significant parameter, due the clogging of the material, as well as for the reference (commercial spray-congealed blend):

(181) TABLE-US-00010 Density alpha-tocopherol/PEG 14% Bulk g/ml Trial 1 0.500 Trial 2 0.518 Trial 3 0.501 Trial 4 0.491 Trial 5 0.498 Trial 6 0.485 Trial 7 0.466 Trial 8 0.466 Trial 9 0.478 alpha-tocopherol/PEG 14% 0.438 commercial blend

(182) The influence of the temperature on the particle size distribution (PSD) is shown in FIG. 6.

(183) TABLE-US-00011 d 10 d 50 d 90 (m) (m) (m) alpha-tocopherol/PEG 14% Trial 7 15.2 86.1 174.4 alpha-tocopherol/PEG 14% Trial 8 19.6 96.5 195.0 alpha-tocopherol/PEG 14% Trial 9 21.1 109.0 251.2

(184) The influence of the cryo-milling technology on the particle size distribution (PSD) is shown in FIG. 7.

(185) TABLE-US-00012 d 10 d 50 d 90 (m) (m) (m) alpha-tocopherol/PEG 14% commercial blend 18.9 80.5 220.2 alpha-tocopherol/PEG 14% Trial 7 Hosokawa 19.6 96.5 195.0 alpha-tocopherol/PEG 14% Trial 7 Nuova Guseo 15.2 86.1 174.4
Relative Alpha-Tocopherol Content within Blend Before and after Cryo-Milling:

(186) TABLE-US-00013 alpha- Relative alpha- Relative alpha- Mill tocopherol tocopherol content tocopherol content manufacturer content Before milling After milling Hosokawa 4% 93.7% 93.5-95.5% 14% 111.1% 111.2-111.3% Nuova Guseo 14% 98.5% 95.3-97.4%

(187) As can be concluded from the above data, with cryo-milling process the alpha-tocopherol did not degrade.

EXAMPLE 4ALPHA-TOCOPHEROL/PEG BLENDING TRIALS

(188) 4.1 The cryo-milled blends obtained in Examples 2 and 3, respectively, were blended with other ingredients of a drug product formulation. Content uniformity of distribution of alpha-tocopherol within the blend as well as physical characteristics (i.e. flowability, density, particle size distribution (PSD)) were investigated.

(189) Experimental Design

(190) 3 blending trials (same qualitative and quantitative composition) with:

(191) Reference 14% alpha-tocopherol/PEG commercial blend

(192) 14% alpha-tocopherol/PEG material (cryo-milled by means of Hosokawa, Example 2)

(193) 14% alpha-tocopherol/PEG material (cryo-milled by means of Nuova Guseo, Example 3)

(194) The total batch size was 48 kg.

(195) The following blends were prepared:

(196) TABLE-US-00014 25 mg 50 mg 100 mg 100 mg BIS 150 mg 200 mg 250 mg API 29.12 58.24 116.48 116.48 174.72 232.96 291.20 [mg/tbl] 7.28% 14.56% 29.12% 29.12% 38.83% 35.84% 41.60% PEG 225.16 225.16 187.12 179.32 166.83 260.39 245.00 [mg/tbl] 56.29% 56.29% 46.78% 44.83% 37.07% 40.06% 35.00% HPMC 85.12 56.00 56.00 56.00 63.00 91.00 98.00 [mg/tbl] 21.28% 14.00% 14.00% 14.00% 14.00% 14.00% 14.00% PEG 6000 56.31 56.31 37.54 45.34 42.24 61.01 60.80 [mg/tbl] 14.08% 14.08% 9.39% 11.34% 9.39% 9.39% 8.69% alpha-toc/PEG 4.29 4.29 2.86 2.86 3.21 4.64 5.00 [mg/tbl] 1.07% 1.07% 0.72% 0.72% 0.71% 0.71% 0.71%

(197) A comparison of particle size distribution (PSD) after blending is shown in FIG. 8.

(198) TABLE-US-00015 d 10 d 50 d 90 (m) (m) (m) alpha-tocopherol/PEG 14% commercial blend 24.73 130.10 407.10 alpha-tocopherol/PEG 14% Hosokawa material 22.97 122.00 391.30 alpha-tocopherol/PEG 14% Nuova Guseo 25.15 129.70 404.10 aterial

(199) Densities and flowabilities are summarized in the table here below:

(200) TABLE-US-00016 Density Flowability Bulk Tapped g/ml Carr Stirrer g/ml (2500 taps) Index % 1 s/100 g alpha-tocopherol/PEG 14% 0.455 0.583 21.82 153.5 commercial blend alpha-tocopherol/PEG 14% 0.447 0.582 23.21 156.3 Hosokawa material alpha-tocopherol/PEG 14% 0.450 0.581 22.52 161.1 Nuova Guseo material

(201) alpha-tocopherol content uniformities are summarized in the table here below:

(202) TABLE-US-00017 tamper resistant tamper resistant tamper resistant formulation containing formulation containing formulation containing 100 mg Tapentadol and 100 mg Tramadol and 100 mg Tramadol and alpha-tocopherol/PEG alpha-tocopherol/PEG alpha-tocopherol/PEG 14% commercial blend 14% commercial blend 14% inventive blend alpha-Tocopherol alpha-Tocopherol (%) alpha-Tocopherol (%) Top 1 97.5 94.5 98.6 Middle 1 96.9 102.2 99.3 Bottom 1 95.8 95.0 98.2 Top 2 101.0 93.7 101.0 Middle 2 97.9 98.9 97.3 Bottom 2 95.7 96.1 99.3 Top 3 101.7 94.7 99.8 Middle 3 96.9 95.2 97.8 Bottom 3 95.8 96.8 99.5 Middle 4 96.0 94.7 96.4 Average 97.4 96.2 98.7 RSD % 2.2 2.7 1.4

(203) Weight uniformities in cut rods are summarized in the table here below:

(204) TABLE-US-00018 alpha-tocopherol/PEG 14% alpha-tocopherol/PEG 14% commercial blend (mg/cut rods) inventive blend (mg/cut rods) Time Average Weight Average Weight (min) weight RSD weight RSD Start 669.3 0.55% 668.9 0.43% 20 666.5 0.45% 669.7 0.37% 40 666.4 0.50% 670.6 0.60% 60 669.2 0.45% 669.3 0.39% 80 667.4 0.45% 669.0 0.45% 100 667.7 0.37% 666.0 0.50% 120 667.1 0.37% 669.8 0.30% 140 667.0 0.40% 668.0 0.49% Extrusion speed for both batches: 16.8 kg/h

(205) alpha-tocopherol content uniformities in cut rods are summarized in the table here below:

(206) TABLE-US-00019 Estimated cut- alpha-tocopherol/ alpha-tocopherol/ Time rods manu- PEG 14% commercial PEG 14% inventive (min) factured (#) blend (%) blend (%) Start 0 90.4 92.7 8 3350 90.4 93.7 16 6700 90.7 93.7 32 13400 91.2 93.1 48 20100 90.6 93.4 64 26800 89.4 92.2 80 33500 91.0 94.2 96 40200 90.7 93.0 112 46900 90.6 93.1 128 53600 90.9 93.4 Average 90.6 93.3 St. Dev. 0.48865 0.56421 CV % 0.5 0.6 Extrusion speed for both batches: 16.8 kg/h

(207) The above experimental data demonstrate that the properties of the blends according to the invention are at least as good as the properties of a commercially available product that has been manufactured by a procedure which is significantly more laborious and expensive than the method according to the invention.