DESC:Field of the invention
The present invention relates to pharmaceutical compositions comprising a tyrosine kinase inhibitor. More particularly, the present invention relates to a composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and process for preparing such compositions.

Background of the invention

Alectinib Hydrochloride is a tyrosine kinase inhibitor that inhibits the anaplastic lymphoma kinase (ALK) and RET, is described chemically as 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride.
Alectinib as a hydrochloride salt is approved in the form of capsules and marketed by Hoffmann La Roche under the brand name ALECENSA®. The Capsules are approved in the strength of Eq 150 mg base.
Alectinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.
US 9126931 discloses Alectinib and its salt or solvate.
US 9440922 and US 2016/0340308 discloses a method of treating or preventing cancer, cancer metastasis, depression or cognitive function disorder in a subject in need thereof comprising administering Alectinib or a salt or solvate thereof.
US 9365514 and US 2016/0317494 discloses a composition comprising Alectinib or a pharmaceutically acceptable salt thereof and a dissolution aid. The references discloses that Alectinib is poorly water-soluble or insoluble in water, and further studies are needed to develop Alectinib in the form of orally administrable formulation. The references further disclose that, by allowing a dissolution aid to co-exist with Alectinib, the solubility of the substance can be significantly improved and the dissolution aid is a surfactant.
US 2017/0035773 discloses a pharmaceutical composition comprising (i) a granule containing Alectinib or a salt thereof and (ii) a disintegrating agent. The reference further discloses that if granules of Alectinib or a salt thereof are formed and used together with a disintegrating agent, a formulation with satisfactory solubility containing a large amount of Alectinib can be obtained.
US 2017/0119781 discloses a pharmaceutical composition comprising a) one or more active ingredients or pharmaceutically acceptable salt thereof, b) a non-ionic surfactant A solid at room temperature, and c) a non-ionic surfactant B liquid at room temperature, wherein the HLB of surfactants A and B are independently equal or greater than 8 and wherein the active ingredients or pharmaceutically acceptable salt thereof are dispersed in the matrix formed by the other ingredients.
US 2017/0217927 discloses a solid dispersion comprising an amorphous form of Alectinib or a salt thereof and an inert carrier which is a solid polymer.
The above prior art references discloses different compositions for increasing the dissolution of Alectinib using sodium lauryl sulfate as a dissolution aid, using combination of surfactants, using specific disintegrants or by preparing a solid dispersion. Still, there exists a need to develop compositions of Alectinib with increased dissolution as well as bioavailability. The inventors of the present inventors have surprisingly found that a capsule composition comprising Alectinib which is free of sodium lauryl sulfate and free of disintegrant showed comparable/better dissolution with respect to the marketed capsule dosage forms of Alectinib which contain sodium lauryl sulfate and a disintegrant.

Objective of the invention
The main objective of the present invention relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof.
The present invention also relates to a capsule composition comprising Alectinib hydrochloride and one or more pharmaceutically acceptable excipients.
The present invention also relates to a process for the preparation of capsule composition comprising Alectinib hydrochloride and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Alectinib capsule dosage form.

Summary of the invention
Accordingly, the present invention provides a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.

Detailed description of the invention
The present invention relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of a disintegrant.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of a disintegrant.
The present invention further relates to a pharmaceutical composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.
The present invention relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of a disintegrant.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of a disintegrant.
The present invention further relates to a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients, wherein the composition is free of sodium lauryl sulfate and wherein the composition is free of a disintegrant.
In an embodiment, “Alectinib” according to the present invention includes but not limited to Alectinib free base and its pharmaceutically acceptable salts, ethers, esters, prodrugs, polymorphs and derivatives thereof.
In another embodiment, the pharmaceutically acceptable salt of Alectinib is a hydrochloride salt.
As used herein, the term “% w/w” refers to the weight of the component based on the total weight of a composition comprising the component.
“Pharmaceutically acceptable excipient/s” are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc.
In another embodiment, the composition according to the present invention further comprises one or more pharmaceutically acceptable excipients which include but not limited to diluents, binders, surfactants, polymers, glidants and lubricants. These excipients may be present intragranularly or extragranularly.
Diluents according to the present invention include but not limited to microcrystalline cellulose, lactose monohydrate, lactose anhydrous, fructose, maltose, trehalose, dextrose, polydextrose, dextrates, dextrins, isomalt, mannitol, maltitol, xylitol, maltodextrin, lactitol, sorbitol, erythritol, inulin, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, sodium chloride, cellulose acetate, ethyl cellulose, cellulose powdered, kaolin and the like or combinations thereof. The diluent can be used in the range of about 5-90% w/w of the composition.
Binders according to the present invention include but not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate, polyvinyl pyrrolidones (povidone), copovidone, microcrystalline cellulose, gelatin, polymethacrylates, polyethylene glycols (PEG), Poly(vinyl caprolactam-co-vinyl acetate-ethylene glycol) graft polymer (SOLUPLUS®), poloxamers, polyethylene oxide, acrylate based copolymers and the like or combinations thereof. The binder can be used in the range of about 0-15% w/w of the composition.
Surfactants according to the present invention may be selected from anionic, cationic or non- ionic surface-active agents or surfactants. Suitable anionic surfactants include but not limited to carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include but not limited to those containing long chain cations, such as benzalkonium chloride, bis-2- hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include but not limited to polyoxyethylene sorbitan fatty acid esters (polysorbates), fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol. The surfactant can be used in the range of about 0-20% w/w of the composition.
Polymers according to the present invention include but not limited to cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, propylene glycol alginate ester, sodium caseinate, a carboxyvinyl polymer, powdered agar, guar gum, copolyvidone, hydroxyethylmethyl cellulose, or polyvinyl alcohol, the gastric-soluble polymer is amino alkylmethacrylate copolymer E, or polyvinylacetal diethylaminoacetate, and the enteric-soluble polymer is methacrylic acid copolymer LD, purified shellac, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid copolymer S, casein, zein and mixtures thereof. The polymer can be used in the range of about 0-60% w/w of the composition.
Glidants according to the present invention include but not limited to silica, colloidal silicon dioxide, talc and magnesium silicate and mixtures thereof. The glidants can be used in the range of 0-10% w/w of the composition.
Lubricants according to the present invention include but not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito stearic ester, hydrogenated castor oil and mixtures thereof. The Lubricants and/or glidants can be used in the range of 0-10% w/w of the composition.
In another embodiment of the present invention, Alectinib may be present in crystalline form or amorphous form.
In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) formulating the blend of step (i) into suitable dosage form.
In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) optionally, lubricating the blended material of step (i) with a lubricant, and
(iii) preparing the lubricated material of step (ii) into a suitable dosage form.
In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) optionally, lubricating the blended material of step (i) with a lubricant, and
(iii) filling the lubricated material of step (ii) into capsules.

In another embodiment, the present invention relates to a process for the preparation of stable pharmaceutical composition, comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i),
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iii) filling the blend of step (i) into capsules.

In another embodiment, the present invention relates to a capsule composition prepared by a process comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i),
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iv) filling the blend of step (iii) into capsules,
wherein the composition is free of sodium lauryl sulfate,
wherein the composition is free of a disintegrant.

In another embodiment, the present invention relates to a capsule composition prepared by a process comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i),
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iv) lubricating the blend of step (iii) and
(v) filling the blend of step (iv) into capsules,
wherein the composition is free of sodium lauryl sulfate,
wherein the composition is free of a disintegrant.

In another embodiment, the present invention relates to a capsule composition prepared by a process comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more diluents, a surfactant and a polymer,
(ii) granulating the blend of step (i) with a binder solution comprising a surfactant,
(iii) blending the granules of step (ii) with one or more diluents,
(iv) lubricating the blend of step (iii) with a lubricant and
(v) filling the blend of step (iv) into capsules,
wherein the composition is free of sodium lauryl sulfate,
wherein the composition is free of a disintegrant.

In another embodiment, the pharmaceutical composition according to the present invention is in the form of tablets, capsules, granules, powder, pellets and sachets.
In another embodiment, the blend is formulated into a suitable dosage form like tablets or capsules using different techniques which are well known in the prior art.
In another embodiment, the compositions of the present invention may be prepared using any method known in the art, but are not limited to wet granulation, melt granulation, dry granulation, roller compaction, solid dispersion, encapsulation and direct compression.
In another embodiment, the granulation can be done using one pharmaceutically acceptable excipient, a binder, which can be added to the drug substance in a dissolved state (e.g. in an aqueous/non-aqueous solution) or in a powder form and then granulated by adding a granulation liquid. A combination of more than one binder can be used.
In another embodiment, the granulation can be done using a solvent alone without any binder.
In another embodiment, the solvents used for granulation process may be selected from water, isopropyl alcohol, methanol, ethanol, methylene chloride or combination thereof.
In another embodiment, the granulation can be done using any method known in the art, but are not limited to fluidized bed granulation, high-shear granulation, low shear granulation, spray granulation, melt granulation and hot melt extrusion.
The pharmaceutical composition may be further film coated with functional or non functional layer. The coating may be selected from amongst one or more of those suitable coating materials known in the art. For example, the coating material can be Opadry or Opadry AMB. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
Coloring agent may be selected from FDA approved colorants such as Iron Oxide, Lake of Tartrazine, Allura Red, Lake of Quinoline Yellow, Lake of Erythrosine, Titanium Dioxide and the like.
In one preferred embodiment, the pharmaceutical composition according to the present invention is in the form of capsules.
In yet another embodiment, the present invention provides a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof in the range of about 1mg to about 1000 mg, preferably 100mg to 500mg and more preferably 150mg.
In another embodiment, the present invention provides a capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC).
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Capsule composition comprising Alectinib hydrochloride
S. No Ingredients Quantity (mg/capsule)
Intra-granular
1 Alectinib hydrochloride 161.33
2 Lactose monohydrate 61.82
3 Microcrystalline cellulose 56.00
4 Poloxamer 8.07
5 Hydroxypropyl cellulose 15.00
6 Polyethylene glycol 16.13
7 Purified water Qs
Extra-granular
8 Microcrystalline cellulose 10.00
9 Magnesium stearate 1.65
Total Capsule fill weight 330.000

The processing steps involved in manufacturing the capsules were given below:
(i) Alectinib hydrochloride, Lactose monohydrate, intragranular portion of microcrystalline cellulose, poloxamer and hydroxypropyl cellulose were sifted separately and blended,
(ii) polyethylene glycol was dissolved in purified water,
(iii) the blend of step (i) was granulated using the solution of step (ii) and dried,
(iv) the granules obtained in step (iii) were blended with extra-granular microcrystalline cellulose,
(v) the blend of step (iv) was lubricated with magnesium stearate,
(vi) the lubricated granules of step (v) were filled into capsules.

Example 2: Capsule composition comprising Alectinib hydrochloride
S. No Ingredients Quantity (mg/capsule)
Intra-granular
1 Alectinib hydrochloride 161.33
2 Lactose monohydrate 127.82
3 Hydroxypropyl cellulose 15.00
4 Poloxamer 8.07
Granulating fluid
5 Polyethylene glycol 16.13
6 Purified water Qs
Extra-granular
7 Magnesium stearate 1.65
Total Capsule fill weight 330.000

The processing steps involved in manufacturing the capsules were given below:
(i) Alectinib hydrochloride, Lactose monohydrate, poloxamer and hydroxypropyl cellulose were sifted separately and blended,
(ii) polyethylene glycol was dissolved in purified water,
(iii) the blend of step (i) was granulated using the solution of step (ii) and dried,
(iv) the granules obtained in step (iii) was lubricated with magnesium stearate,
(v) the lubricated granules of step (iv) were filled into capsules.

Example 3: Capsule composition comprising Alectinib hydrochloride
S. No Ingredients Quantity (mg/capsule)
Intra-granular
1 Alectinib hydrochloride 161.33
2 Lactose monohydrate 84.47
3 Sodium starch glycolate 15.00
4 Hydroxypropyl cellulose 15.00
5 Poloxamer 8.07
Granulating fluid
6 Polyethylene glycol 16.13
7 Purified water Qs
Extra-granular
8 Sodium starch glycolate 28.35
9 Magnesium stearate 1.65
Total Capsule fill weight 330.000

The processing steps involved in manufacturing the capsules were given below:
(i) Alectinib hydrochloride, Lactose monohydrate, poloxamer, sodium starch glycolate and hydroxypropyl cellulose were sifted separately and blended,
(ii) polyethylene glycol was dissolved in purified water,
(iii) the blend of step (i) was granulated using the solution of step (ii) and dried,
(iv) the granules obtained in step (iii) was blended with extra granular Sodium starch glycolate and lubricated with magnesium stearate,
(v) the lubricated granules of step (iv) were filled into capsules.
Dissolution Data: Table-1 given below provides the comparative dissolution profile of Alectinib capsules prepared according to Examples 1-4 and ALECENSA® (Alectinib) capsules, 150 mg using the following dissolution conditions:
Dissolution Conditions:
Media : Simulated gastric fluid without pepsin pH 1.2 with 4.0 % Triton X -100
Volume: 900 mL
Apparatus: Paddle with sinker (31 size)
Speed : 100 RPM

Table 1: Comparative dissolution profile of Alectinib capsules prepared according to Examples 1-4 and ALECENSA® (Alectinib) capsules 150 mg
Time
(Minutes) Cumulative % drug released
ALECENSA®
(Alectinib) capsules Capsules of
Ex-1 Capsules of
Ex-2 Capsules of
Ex-3
0 0.00 0.00 0.00 0.00
10 14.00 28.00 44.00 8.00
30 66.00 70.00 68.00 51.00
60 82.00 82.00 80.00 68.00
90 87.00 88.00 86.00 76.00
120 90.00 92.00 90.00 82.00

Based on the above dissolution date, it was found that the release of Alectinib from the capsules free of a disintegrant were found to be more compared to the release of Alectinib from capsules containing a disintegrant.
,CLAIMS:We Claim:
1. A capsule composition comprising Alectinib or a pharmaceutically acceptable salt thereof, combination of two or more surfactants and one or more pharmaceutically acceptable excipients,
wherein the composition is free of sodium lauryl sulfate,
wherein the composition is free of a disintegrant.

2. The capsule composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, binders, surfactants, polymers, glidants and lubricants.

3. The capsule composition as claimed in claim 2, wherein the diluent is selected from lactose monohydrate, lactose anhydrous, fructose, maltose, trehalose, dextrose, polydextrose, dextrates, dextrins, isomalt, mannitol, maltitol, xylitol, maltodextrin, lactitol, sorbitol, erythritol, inulin, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, sodium chloride, cellulose acetate, ethyl cellulose, cellulose powdered, kaolin and combination thereof.

4. The capsule composition as claimed in Claim 2, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, Polyvinylpyrrolidone (povidone), gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate and combination thereof.

5. The capsule composition as claimed in Claim 2, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate (SLS), sodium laurate, bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate, benzalkonium chloride, bis-2- hydroxyethyl oleyl amine, lauryl alcohol, cetyl alcohol, stearyl alcohol, glyceryl esters, polyglycolized glycerides, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block co-polymer, propylene glycol, polyethylene glycol and combination thereof.
6. The capsule composition as claimed in Claim 2, wherein the polymer is selected from the group consisting of cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, propylene glycol alginate ester, sodium caseinate, a carboxyvinyl polymer, powdered agar, guar gum, copolyvidone, hydroxyethylmethyl cellulose, polyvinyl alcohol, amino alkylmethacrylate copolymer E, polyvinylacetal diethylaminoacetate, methacrylic acid copolymer, purified shellac, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid copolymer S, casein, zein and combination thereof.

7. The capsule composition as claimed in Claim 2, wherein the glidant and lubricant is selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated castor oil and combination thereof.

8. The capsule composition as claimed in Claim 1, wherein the composition is prepared by a process comprising the steps of:
(i) blending Alectinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i),
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iv) lubricating the blend of step (iii) and
(v) filling the blend of step (iv) into capsules,
wherein the composition is free of sodium lauryl sulfate,
wherein the composition is free of a disintegrant.