Field of the Invention
The present invention relates to process of preparation of oral formulations of tacrolimus and method of treatment or prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants, using formulations prepared by such process.
Background of the Invention
Tacrolimus; [3S- [3R*[E(1S*, 3S*, 4S*)], 4S*, 5R*, 8S*, 9£, 12R*, 14R*, 15S*,
16R*, 18S*, 19S*, 26aR*]]-5, 6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a-
hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1 -
methylethenyl]-14, 16-dimethoxy-4, 10, 12, 18-tetrarnethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2, 1-c][1, 4]oxaazacyclotricosine-1, 7, 20, 21(41-1, 23H)-tetrone, monohydrate is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It has been demonstrated that tacrolimus inhibits T lymphocyte activation by first binding to an intracellular protein, FKBP-12. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF and TNF-a, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to down regulate the expression of FceRI on Langerhans cells.
Tacrolimus possesses immunosuppressive activity and antimicrobial activity and therefore, is useful for the treatment or prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants. However, when orally administered, the absorption of tacrolimus into blood is insufficient due to its insolubility into water, which leads to poor bioavailability. In this regard, some oral formulations of tacrolimus have been developed and reported for improving its bioavailability after oral administration.
U.S. Patent 6,346,537 discloses a solid dispersion comprising tacrolimus, a surfactant(s) and a pharrnaceutically acceptable solid carrier selected from the group consisting of water-soluble polymers, saccharides, and light anhydrous silicic acid, or a combination thereof. The process of preparation of solid dispersion involves dissolving

tacrolimus, surfactant(s) and solid carrier(s) in the organic solvent(s) followed by conventional means of solvent evaporation, and pulverization.
WO 05/020994 teaches a solid dispersion or solid solution composition comprising tacrolimus and analogues thereof dispersed or dissolved in a hydrophilic or water-miscible vehicle having melting point of at least 20°C. This patent application further teaches that the compositions disclosed therein provide different pharmacokinetic parameters compared to innovator formulations Prograf®, i.e., decreased plasma drug concentration fluctuations and improved area under plasma concentration curve (AUC). Further, the compositions are described as being less sensitive to food effect compared to Prograf®.
WO 05/004848 describes a solid dispersion composition comprising tacrolimus and solid surfactant having a property of hydrophilic lipophilic balance (HLB) value higher than or equal to about 7. This patent application teaches that the surfactant used serves the dual purpose of a carrier for the drug and also as the dissolution enhancer. The process of preparation of the solid dispersion formulations described therein involves dispersing/dissolving the tacrolimus and surfactant in an organic solvent(s) followed by the conventional means of solvent evaporation, and pulverization or alternatively spraying the solution/dispersion of tacrolimus onto the pharmaceutically acceptable excipients and drying.
U.S. Patent 4,916,138 discloses a solid dispersion composition comprising tacrolimus and a water-soluble polymer, which is capable of dispersing the tacrolimus and which is present in the ratio of 0.1:1 to 20:1 by weight of tacrolimus. The process of preparation of solid dispersion composition described in this patent is the conventional method which comprises; dissolving tacrolimus in an organic solvent followed by the addition of a water-soluble polymer to obtain a suspension/solution and then removing the organic solvent by evaporation followed by pulverization.
The prior arts discussed above either teach the use of a surfactant to aid in the solubilization of tacrolimus or teach the process that involves the formation of solid dispersion of tacrolimus before mixing with other pharmaceutically acceptable excipients. This use of surfactant or the additional step of preparing the solid dispersion is described to improve the solubility and hence the absorption and bioavailability

characteristics of poorly soluble tacrolimus by providing it into a more soluble form, which otherwise would result in the improper bioavailability after oral administration.
We have now surprisingly found that, an oral formulation of tacrolimus could be obtained by following a more convenient and different process than that of the prior art. The formulations obtained have favourable dissolution characteristics, improved absorption and/or less variation in the absorption profile. Further, it was observed that these formulations are bioequivalent to Prograf® capsules marketed by Astellas. The process for the preparation of oral formulation of the present invention does not require a separate step of preparing the solid dispersion/solid solution composition of tacrolimus and also does not require any surfactant for the solubilization of tacrolimus. The process of the present invention is simple, less time consuming, cost effective and can easily be adopted on the commercial scale units with minimum conventional facilities.
Summary of the Invention
According to one embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers in an amount of 0.1 to 20 parts per part of tacrolimus and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.

According to still another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers in an amount of 1 part per part of tacrolimus and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to further embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler and a disintegrant, followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler in an amount of 5 to 25 parts per part of tacrolimus and a disintegrant in an amount of 0.1 to 5 parts per part of tacrolimus, followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler in an amount of 7 parts per part of tacrolimus and a disintegrant in an amount of 1 part per part of tacrolimus, followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.

According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler in an amount of 15 parts per part of tacrolimus and a disintegrant in an amount of 1 part per part of tacrolimus, followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to further embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets, wherein the drug solution of step a) is loaded onto the premix in more than one lot.
According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers in an amount of 1 part per part of tacrolimus and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler in an amount of 15 parts per part of tacrolimus and a disintegrant in an amount of 1 part per part of tacrolimus followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
According to another embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers in an amount of 1 part per part of tacrolimus and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising a filler in an amount of 7 parts per part of tacrolimus and a disintegrant in an amount of 1 part per part of

tacrolimus followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets, wherein the drug solution of step a) is loaded onto the premix in more than one lot.
Detailed Description of the Invention
The oral formulations obtained by the process of present invention may be in the form of capsules, tablets, granules or any other formulation suitable for administration by oral route. Preferably, the oral formulation is a capsule.
Tacrolimus includes tacrolimus, single enantiomers, pharmaceutically acceptable salts, solvates, hydrates and mixtures thereof. Preferably, tacrolimus is in the form of tacrolimus monohydrate.
According to one embodiment there is provided a process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
The process for the preparation of the oral formulation of tacrolimus involves the following two steps: a) preparation of drug solution, b) loading of the drug solution onto a premix comprising one or more pharmaceutically acceptable excipients.
The drug solution is prepared by dissolving tacrolimus in one or more organic solvents to obtain a solution. One or more water soluble polymers are sifted through a suitable sieve and then added to the tacrolimus solution obtained above with continuous stirring. Optionally, one or more organic solvents are added to further dissolve the tacrolimus and one or more water soluble polymers.

One or more pharmaceutically acceptable excipients are sifted through a suitable sieve and mixed to obtain a premix. Now, the drug solution comprising tacrolimus and water soluble polymer(s) is loaded onto the premix, followed by the removal of the organic solvent(s)/drying by conventional means such as by applying heat and/or vacuum to obtain granules. All of the drug solution may be loaded onto the premix in one single step followed by drying. Alternatively, the drug solution may be loaded onto the premix in more than one lot ie. about 25-35% of the drug solution may be loaded onto the premix followed by drying. This process being repeated for 3-4 times till all the drug solution is loaded onto the premix.
These granules are then optionally mixed with one or more pharmaceutically acceptable excipients to obtain a final blend. The final blend is then filled into capsules or into other suitable pack or the blend is compressed into tablets of desired size and shape.
The organic solvents used in the present process are selected from one or more of ethanol, methanol, propanol, isopropyl alcohol, dichloromethane, ethyl acetate, diethyl ether and mixtures thereof. Preferably, the organic solvents are selected from one or more of ethanol and dichloromethane. More preferably, the organic solvent is a mixture of ethanol and dichloromethane.
The water soluble polymers used in the present process are selected from one or
• ^
more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof capable of dispersing tacrolimus. Preferably, the water soluble polymers are cellulose derivatives selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. More preferably, the water soluble polymer is hydroxypropyl methylcellulose. The drug solution may contain water soluble polymer in an amount of 0.1 to 20 parts per part of tacrolimus. Preferably, the amount of water-soluble polymer is 0.5 to 2 parts, more preferably 1 part per part of tacrolimus.
The pharmaceutically acceptable excipients include any such materials known in the art or conventional in the art that aid in the development of an oral formulation to be administered in the form of granules, capsule, tablet or in any other suitable form.

The pharmaceutically acceptable excipients may be selected from one or more of fillers, binders, disintegrants, lubricants and mixtures thereof.
The fillers are selected from one or more of lactose, microcrystalline cellulose, starch, dicalcium hydrogen phosphate, calcium carbonate, mannitol, sorbitol, xylitol, maltitol and mixtures thereof. Preferably, the filler is lactose or microcrystalline cellulose. More preferably the filler is lactose. The fillers may be present from about 50% to about 98% w/w of the formulation. Preferably, the fillers are present in an amount from about 70% to about 95% w/w of the formulation. The premix may contain fillers in an amount of 5 to 25 parts per part of tacrolimus.
The binders are selected from one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate. The water soluble polymers present in the solution or dispersion containing tacrolimus may also serve as the binder by aiding in the formation of wet mass.
The disintegrants are selected from one or more of croscarmellose sodium, croscarmellose calcium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose and mixtures thereof. Preferably, the disintegrant is croscarmellose sodium. The disintegrant may be present from about 1% to about 20% w/w of the formulation. Preferably, the disintegrant is present in an amount from about 3% to about 15% w/w of the formulation. The premix may contain disintegrants in an amount of 0.1 to 5 parts per part of tacrolimus.
The lubricants are selected from one or more of talc, magnesium stearate, colloidal silicon dioxide, zinc stearate and mixtures thereof. Among the lubricants, magnesium stearate and talc are preferred. The amount of lubricants may be from about 0.1% to about 5% w/w. Preferably, the amount of lubricant is from about 0.5% to about 3% w/w.
i
The term "loading" as used herein refers to pouring, spraying, sprinkling, incorporating or any other conventional means of adding/mixing. Especially, the loading in the present context refers to conventional means of adding or mixing the drug

solution comprising tacrolimus and water soluble polymer(s) with the premix to obtain a wet mass. The loading step can be carried out in a suitable equipment wherein the addition and removal of solvent can be carried out simultaneously, for example, Roto processor and Fluidized bed granulator.
The "pack" as used herein may include sachets, bottles, unit dose packs, multi dose packs, or any other suitable packs used to provide an effective packing/containment for oral formulations.
The oral formulation of tacrolimus prepared by the process described in the specification may be bioequivalent to the innovator formulation.
The term "innovator formulation" as used herein refers to capsule formulation, commercially available under the trade name Prograf® manufactured by Astellas.
The following non-limiting examples further illustrate the oral formulations of tacrolimus and process of preparing such formulations.
Examples 1 -3
Ingredients j Quantity (mg/capsule)
I Example 1 Example 2 ] Examples
^Intragranujar ! Tacrolimus monohydrate Equivalent to : ! >
Tacrolimus anhydrous 5.1 ; 5.1 ! 5.1
jHydroxypropyl methylcellulose (5 cPs) ; 5.0 \ 5.0 ; 5.0
jCrpscarmellose sodium , 5.0 ! 15.0 j 7.0 __
(Lactose monohydrate ! 34.9 j 104.9 i 52.9
IDehydrated ethanol ; Q.S. | Q.S. j Q.S.
jDichloromethane ( Q.S. j Q.S. | Q.S.
] Basesflranulesj 50.0 j 130 ] 70
lExtragranular i
I aJLj.JiuJ,iJ...uL.. . | . ,_| 4
lactose monohydrate j 88.6 j 8.6 ! 68.6
Croscarmellose sodium ; - j - |
iHydroxypropyl methylcellulose (5 cPs) \-\-i-
iMagnesium stearate ' 1.4 1.4 1.4
14~0.0 140.0 r 140.0
• ! •• 1 <
: - j | -
(Empty hard gelatin shell of size '4^ [ 1 No. 1 No. j 1 No.

Process of preparation:
1. All ingredients were accurately weighed.
2. Tacrolimus was dissolved in ethanol to obtain a solution.
3. Hydroxypropyl methylcellulose was added to solution of step 2 and, dispersed
under stirring.
4. Dichloromethane was added to the dispersion obtained in step 3 under constant
stirring to obtain the drug solution.
5. The drug solution of step 4 was kept aside with intermittent stirring.
6. Croscarmellose sodium and Lactose Monohydrate were sifted through BSS #36
and blended to obtain a premix.
7. The premix of step 6 was transferred in to the bowl of Roto Processor and
mixed for homogeneity.
8. The drug solution of step 5 was loaded onto the premix of step 7 in the Roto
Processor and the premix wet /granular mass was vacuum dried for suitable time
to evaporate most of the organic solvent to obtain granules.
9. The dried granular mass was milled through a suitable screen using Quadro
Comil.
10. The milled granules were dried again under vacuum in the Roto processor till the
desired LOD was achieved and sifted through BSS #60.
11 .The granules were fractionated between BSS #60 and BSS #350.
12. The desired sieve fraction of granules were mixed in a suitable blender to
achieve homogenous granules.
13. Extragranular lactose monohydrate was sifted through BSS #36 and mixed with
the granules of step 12 by geometric mixing in the desired ratio and blended for
a suitable time.
14. Magnesium Stearate was sifted through sieve BSS #60 and added to the blend
of step 14 and mixed.
15. The lubricated blend of step 14 was filled into capsules using suitable capsule
filling machine.
(Table Remove)
Empty hard gelatin shell of size '4' • 1 No. 1 No. j
Process of preparation:
1. All ingredients were accurately weighed.
2. Tacrolimus was dissolved in ethanol to obtain a solution.
3. Hydroxypropyl methylcellulose was added to solution of step 2 and, dispersed
under stirring.
4. Dichloromethane was added to the dispersion obtained in step 3 under constant
stirring to obtain the drug solution.
5. The drug solution of step 4 was kept aside with intermittent stirring.
6. Croscarmellose sodium and Lactose Monohydrate were sifted through BSS #36
and blended to obtain a premix.
7. The premix of step 6 was transferred in to the bowl of Roto Processor and
mixed for homogeneity.
8. The drug solution of step 5 was loaded onto the premix of step 7 in the Roto
Processor and the premix wet /granular mass was vacuum dried for suitable time
to evaporate most of the organic solvent to obtain granules.
9. The dried granular mass was milled through a suitable screen using Quadra
Cornil.
10. The milled granules were dried again under vacuum in the roto processor till the
desired LOD was achieved and sifted through BSS #60.
11 .The granules were fractionated between BSS #60 and BSS #350.

12. The desired sieve fraction of granules were mixed in a suitable blender to
achieve homogenous granules.
13. Extragranular lactose monohydrate, croscarmellose sodium and hydroxypropyl
methylcellulose was sifted through BSS #36 and mixed with the granules of step
12 by geometric mixing in the desired ratio and blended for a suitable time.
14. Magnesium Stearate was sifted through sieve BSS #60 and added to the blend
of step 13 and mixed.
15. The lubricated blend of step 14 was filled into capsules using suitable capsule
filling machine.
Example 5

Ingredients
Intragranularl
Tacrolimus monohydrate Equivalent to Tacrolimus anhydrous iHydroxypropyl methylcellulose (5 cPs) jCroscarmellose sodium [Lactose monphydrate iDehydrated ethanol Dichloromethane
Base granules Extragranulari

Quantity (mg/capsule)
5.1
5.0
5.0 74.9 Q.S.
Q-S. 90.0



lactose monohydrate Magnesium stearate
Totah/yeiflhtl
Empty hard gelatin shell of size '4'

48.6
14
140.0
1 No.

Process of preparation:
1. All ingredients were accurately weighed.
2. Tacrolimus was dissolved in ethanol to obtain a solution.
3. Hydroxypropyl methylcellulose was added to solution of step 2 and, dispersed
under stirring.
4. Dichloromethane was added to the dispersion obtained in step 3 under constant
stirring to obtain the drug solution.
5. The drug solution of step 4 was kept aside with intermittent stirring.
6. Croscarmellose sodium and Lactose Monohydrate were sifted through BSS #36
and blended to obtain a premix.

7. The premix of step 6 was transferred in to the bowl of Roto Processor and
mixed for homogeneity.
8. The drug solution of step 5 was loaded onto the premix of step 7 in the Roto
Processor and the premix wet /granular mass was vacuum dried for suitable time
to evaporate most of the organic solvent to obtain granules.
9. The dried granular mass was milled through a suitable screen using Quadro
Comil.
10. The milled granules were dried again under vacuum in the roto processor till the
desired LOD was achieved and sifted through BSS #60.
11 .The granules were fractionated between BSS #60 and BSS #350.
12. The desired sieve fraction of granules were mixed in a suitable blender to
achieve homogenous granules.
13. Extragranular lactose monohydrate was sifted through BSS #36 and mixed with
the granules of step 12 by geometric mixing in the desired ratio and blended for
a suitable time.
14. Magnesium Stearate was sifted through sieve BSS #60 and added to the blend
of step 13 and mixed.
15. The lubricated blend of step 14 was filled into capsules using suitable capsule
filling machine.
Dissolution data:
The above oral formulations of tacrolimus provide the following in vitro dissolution profile in 900 ml of water containing 0.005% w/v of hydroxypropyl cellulose with pH 4.5, at 50 rpm, using USP type II (Paddle) method and Japanese sinkers and at 37 ± 0.5 °C.
Time in Percentage drug dissolved
• minutes | Example! ~T ~ Example 5
;15 : 45~ ~ :" ~"~ 36
:30 ...;.. 69 j 71
|6o • ' '"" "liei""." [\ "'. T. i 88
190 91 ! 93
120 : 93 \ 96

Pharmacokinetic study design:
Products evaluated
Test (T): Tacrolirnus capsules 5 mg
Manufactured by Ranbaxy Research Lab. Ltd., India Example No.1
Reference (R): Prograf® capsules 5 mg
Manufactured by Astellas Pharma US Inc.
Treatments*: Single oral dose of Test & Reference product (Fed)
Single oral dose of Test & Reference product (Fasting)
16. Single oral dose of Test & Reference (Fed)
(Table Remove)

WE CLAIM:
Claim 1: A process for the preparation of an oral formulation of tacrolimus, the process comprising the steps of: a) preparing a drug solution, the solution comprising tacrolimus, one or more water-soluble polymers and one or more organic solvents; b) loading the drug solution of step a) onto a premix comprising one or more pharmaceutically acceptable excipients followed by drying and optionally blending with one or more pharmaceutically acceptable excipients to obtain a final blend; and c) filling the final blend into capsules or a pack or, compressing the final blend into tablets.
Claim 2: The process according to claim 1, wherein the water-soluble polymers are selected from one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof.
Claim 3: The process according to claim 2, wherein the cellulose derivatives are selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
Claim 4: The process according to claim 1, wherein the drug solution comprises water-soluble polymer in an amount of 0.1 to 20 parts per part of tacrolimus.
Claim 5: The process according to claim 1, wherein the organic solvents are selected from one or more of ethanol, methanol, propanol, isopropyl alcohol, dichloromethane, ethyl acetate, diethyl ether and mixtures thereof.
Claim 6: The process according to claim 1, wherein the pharmaceutically acceptable excipients are selected from one or more of fillers, binders, disintegrants, lubricants and mixtures thereof.
Claim 7: The process according to claim 1, wherein the premix comprises a filler and a disintegrant.

Claim 8: The process according to claim 7, wherein the premix comprises a filler in an amount of 5 to 25 parts per part of tacrolimus and a disintegrant in an amount of 0.1 to 5 parts per part of tacrolimus.
Claim 9: The process according to claim 1, wherein the drug solution of step a) is loaded onto the premix in more than one lot.
Claim 10: A process for the preparation of an oral formulation of tacrolimus substantially described and exemplified herein.