Solid dispersions comprising tacrolimus

DESCRIPTION

SOLID DISPERSIONS UNDERSTANDING TACROLIMUS

The present invention relates to a solid solution comprising tacrolimus having increased bioavailability, more specifically a solid solution of tacrolimus in a hydrophilic vehicle; a pharmaceutical composition comprising the solid solution, and dosage forms comprising the solid solution.

BACKGROUND OF THE INVENTION Tacrolimus, also known as FK-506 or FR-900506, has the chemical tricyclic structure shown below:

HjOi

<img file="PT1663217E_D0001.tif" />

which corresponds to C44H₆₉NOi2 · Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol and very soluble in methanol and chloroform.

The preparation of tacrolimus is described in European Patent Application EP-A-0 184 162 and the tacrolimus analogs are for

1/58 examples described in European Patent Application EP-A-0 444 659 and US Patent Application 6,387,918.

tacrolimus is a macrolide compound with immunosuppressive activity, antimicrobial activity and other useful pharmacological activities and is an asset for the treatment or prevention of organ or tissue transplant rejection reactions, graft versus host disease, autoimmune and infectious diseases. 0 tacrolimus prolongs host and transplanted graft survival in animal models of liver, kidney, heart, bone marrow and small intestine and pancreas, lung and trachea, skin, cornea and limb transplantation.

In animals tacrolimus has been shown to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis and graft versus host.

tacrolimus inhibits T lymphocyte activation, although the exact mechanism of its action is unknown. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. An FKBP12-tacrolimus, calcium, calmodulin, and calcineurin complex is then formed and calcineurin phosphatase activity inhibited. This effect may prevent dephosphorylation and nuclear factor translocation of activated T cells, we believe that a nuclear component initiates genetic transcription for lymphokine formation. The net result is inhibition of T lymphocyte activation, i.e. immunosuppression.

Tacrolimus is largely metabolised by the isoenzyme CYP3A4 in the intestinal and liver wall. Therefore, medicinal products affecting this isoenzyme may influence the absorption and subsequent elimination of systemically absorbed tacrolimus. CYP3A4 inhibitors may increase tacrolimus levels, while CYP3A4 inducers may increase tacrolimus metabolism and decrease tacrolimus levels. Consequently, tacrolimus may be administered together with one or more CYP3A4 inhibitors to improve overall bioavailability.

Tacrolimus is usually administered orally and is therefore absorbed into the gastrointestinal tract. Absorption has been observed to be negatively influenced by simultaneous food intake. Thus, the speed and extent of tacrolimus absorption were higher under fasting conditions.

It is generally known that the absorption and bioavailability of a therapeutically active substance may be affected by a number of factors when it is administered orally. These factors include the presence of food in the gastrointestinal tract and, in general, the gastric residence time of a drug substance is significantly longer in the presence of food than in the fasting state. If the bioavailability of a pharmacological substance is affected beyond a certain point due to the presence of food in the gastrointestinal tract, the pharmacological substance is said to exhibit a food effect. Food effects are important because absorption, and therefore plasma levels, become highly variable depending on food intake. Absorption into the bloodstream may be adversely affected to the extent that the patient risks insufficient absorption to remedy the condition for which the medicine was administered. On the other hand, very high peak concentrations seen under fasting conditions may occasionally very well induce significant side effects of nephrotoxic or neurotoxic origin as well as side effects in Gl and others.

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Absorption of tacrolimus into the gastrointestinal tract following oral administration is rapid with a mean peak concentration (t_max) approximately 1-2 hours after administration to healthy subjects or renal or hepatic transplant patients, but incomplete and variable. Bioavailability is generally as low as at most approximately 20% after oral administration.

In most cases the side effects observed were vomiting and nausea but side effects such as tremor, headache, hypertension, renal dysfunction, hyperkalaemia, hypomagnesemia, hyperglycaemia, insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity and neurotoxicity were also observed. .

For oral administration tacrolimus is currently formulated and marketed as soft gelatin capsules comprising the equivalent of 0.5, 1 or 5 mg anhydrous tacrolimus and marketed under the tradename Prograf® and Protropic®. The recommended initial oral dose to patients is approximately 0.1 to 0.2 mg / kg / day. The dose is for a certain minimum plasma concentration of approximately 5 to approximately 20 ng / ml. Prograf® is indicated for prophylaxis of organ rejection in patients who have received allogeneic liver or kidney transplants.

D1 describes a formulation obtainable by spraying a solution of tacrolimus, PEG-24 cholesterol ester, monoglycerides and deoxycholic acid in non-pareil organic solvent and also refers to increased oral bioavailability.

D2 describes sustained release formulations obtainable by dissolving tacrolimus in fused glycerol monostearate or tetraglycerine triglyceride ester and mixing them with

HPM or lactose.

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D3 describes capsules comprising a 20% solid dispersion of tacrolimus in HPMC prepared with a solvent method.

D4 describes a controlled agglomeration method for improving the bioavailability of poorly soluble compounds in solid solutions or dispersions.

The need remains for new pharmaceutical compositions and / or dosage forms comprising tacrolimus that exhibit increased bioavailability. Increased bioavailability may allow a reduction in dose units taken by a patient by lowering them to a single daily dose, and may also reduce or nullify the need to take food at the same time as the dosage form, thereby giving patients more freedom. patients when they want to take the medicine. In addition, it is contemplated that fluctuations in plasma concentration versus time profile may be significantly reduced. In addition, increased bioavailability may also result in a more reproducible release profile (ie less variable compared to Prograf®).

BRIEF SUMMARY OF THE INVENTION

The inventors have now found that the bioavailability of tacrolimus can be significantly increased by dissolving tacrolimus in a hydrophilic or water miscible carrier in an amount that is effective for use in preparing a useful drug dosage form. Tacrolimus is known to have very low solubility in water, but this invention provides compositions and pharmaceutical formulations that exhibit very rapid in vitro release profiles, i.e. immediate release compositions which are contemplated to have significantly increased in vivo bioavailability in patients. that need them.

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Accordingly, in a first aspect the present invention relates to a solid solution comprising tacrolimus dissolved in a mixture of polyethylene glycol and poloxamer and tacrolimus present therein with a concentration of from about 0.01% w / w to as much as about 15%. w / w to form a solid solution at room temperature. We believe that this solution is capable of at least releasing 50% w / w of the amount of tacrolimus within approximately 30 minutes when tested in any USP dissolution test using an aqueous dissolution medium.

In another aspect, the invention relates to a pharmaceutical composition comprising the tacrolimus solid solution and one or more pharmaceutically acceptable excipients, which may be fillers, disintegrants, binders or lubricants. In yet another aspect, the invention relates to dosage forms such as oral solid dosage forms comprising tacrolimus solid solution, pharmaceutically acceptable excipients and optionally pharmaceutically acceptable additives such as flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, moisture adjusting agents, surfactants, suspending agents, absorption enhancing agents and release modifying agents. Especially, the present invention relates to a dosage comprising tacrolimus and release modifying agents, especially delayed release dosage forms such as solid oral dosage forms including the enteric coating. By delaying the release of tacrolimus into the distal part of the duodenum we can reduce the drug-related gastrointestinal side effects and the relatively high degree of metabolism in the proximal part of the gastrointestinal tract (CYP3A4-mediated metabolism). Due to the novel solid solution according to the present invention, it is made without losing systemic bioavailability.

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DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term active ingredient or active pharmaceutical ingredient means any component that is intended to provide pharmacological activity or other direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect structure or any other function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the pharmaceutical product and are present in the pharmaceutical product in a modified form to provide the specified activity or effect.

In the present context, the term hydrophilic describes that something that wants water, that is a hydrophilic molecule or part of a molecule, is one that is typically electrically polarized and capable of forming hydrogen bonds with water molecules, allowing them to dissolve. more easily in water than in oil or other non-polar solvents.

In the context of the present invention, the term amphiphilic describes a molecule (as a surfactant) that has a water-soluble polar group attached to a water-insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other end is hydrophobic (nonpolar).

As used herein, the term carrier means any solvent or carrier fluid in a pharmaceutical product that does not have a pharmacological role. For example, water is the vehicle for xylocaine and propylene glycol is the vehicle for many antibiotics.

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In the context of the present invention the term solid dispersion denotes a medicament or active ingredient or substance dispersed at a particulate level in an inert carrier, carrier, diluent or matrix in the solid state, i.e. generally a fine particulate dispersion.

In the context of the present invention, the term solid solution denotes a medicament or active ingredient or substance dissolved at a molecular level in an inert carrier, carrier, diluent or matrix in the solid state.

As used herein, the term analog means a chemical compound that is structurally identical to another.

"medicament" means a compound intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.

In this context, the term dosage form means the manner in which the medicament is administered to the patient. This may be parenteral, topical, tablet, oral (liquid or dissolved powder), suppository, inhalation, transdermal, etc.

As used herein, the term bioavailability indicates the degree to which a drug or other substance is available in the target tissue upon administration.

As used in the present invention, the term bioequivalence indicates a scientific basis on which generic and branded drugs are compared with each other. For example, medicines are bioequivalent when they enter circulation at the same speed when given at the same doses and under the same conditions. The parameters almost always used in bioequivalence studies are t_max, Ç_max, AUCo-infinity / · AUCo-t ·

Other relevant parameters may be W₅₀, W₇₅ and / or MRT.

Consequently, at least one of these parameters can be applied to determine if there is bioequivalence. Furthermore, in the present context, two compositions are considered bioequivalent if the value of the parameter used is within 80125% of Prograf® or a similar commercially available tacrolimus-containing product used in the test.

In the present context t_max indicates the time to reach the maximum plasma concentration (C_max) after administration; AUCo-infinity indicates the area under the plasma concentration versus time curve from time 0 to infinity; AUCo-t indicates the area under the plasma concentration versus time curve from time 0 to time t; W₅₀ indicates the time when the plasma concentration is 50% or more of C_max; W₇₅ indicates the time when the plasma concentration is 75% or more of C_max; and MRT indicates the average residence time for tacrolimus (and / or an analog thereof).

In this context, the term medicine means a compound used to treat a disease, injury or pain. Medicine is properly distributed in prophylactic, that is the technique of preserving health, and therapy, that is the technique of restoring health.

delayed drug release of one in relation to C_max unchanged, but since the time of the drug, tj / is usually

As used herein, the term means a release profile of a pharmaceutical composition or formulation that has an immediate release profile, it simply has an administration until release time._max is retarded, and unchanged.

In this context, the term erosion or eroding means a gradual rupture of the surface of a material or structure, for example of a tablet or the coating of a length.

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Solid dispersion and / or tacrolimus solid solution

The solid solution of the invention comprises tacrolimus dissolved in a mixture of polyethylene glycol with poloxamer at a concentration of from about 0.01% w / w to about 15% w / w, and which solution forms a solid solution at room temperature (room temperature).

The active ingredient is tacrolimus (FK-506 or FR-900506). However, within the scope of the present invention, it is tacrolimus in any physical form (crystals, amorphous powder, any possible polymorph, any possible solvate including hydrate, anhydrate, complexes thereof etc.). Also included are any active tacrolimus derivative or metabolite, salts, solvates, complexes and prodrugs thereof acceptable to the Pharmaceutical Industry.

The concentration of the active ingredient in the carrier is at most 15% w / w, preferably when much 10% w / w, preferably when much 8% w / w, more preferably when much 6% w / w, even higher. preferably when a lot of 5% w / w, when a lot of 4% w / w, especially when a lot of 3% w / w, particularly when a lot of 2% w / w; and / or at least about 0.05% w / w, preferably at least about 0.1% w / w, more preferably at least about 0.5% w / w, especially at least about

<td>about</td><td>0.7% w / w,</td><td>in</td><td>particularly by</td><td>less than</td>

<td>about</td><td>1% w / w</td><td></td><td></td><td></td>

<td>Physically, the</td><td>combination of</td><td colspan="2">active ingredient with</td><td>the vehicle</td>

<td colspan="2">forms a solid solution,</td><td>this</td><td>is the ingredient</td><td>active is</td>

dissolved in the vehicle at a molecular level. The active ingredient and carrier may also form a solid dispersion having in it a portion of the active ingredient dissolved at a molecular level. The physical state of the dispersion and / or solution may be

10/58 determined using various techniques such as Hot Stage Microscopy (HSM), Differential Scanning Calorimetry DSC, Scanning Electron Microscopy (MEB) optionally in combination with dispersive energy Energy Dispersive X-ray (EDX), and X-ray diffraction under a powder. In a preferred embodiment of the invention, the active ingredient is completely dissolved in the carrier to form a solid solution at room temperature.

By increasing bioavailability, the Area Under the Curve (AUC) will generally reduce intra- and inter-variability related to the absorption of a pharmacological substance. This is particularly true; whenever low and damaged bioavailability is a consequence of poor water solubility. It is contemplated that the compositions according to the invention will provide a CV (Coefficient of Variation) on AUC data that is significantly lower than that of Prograf® and related products.

As mentioned above, one of the basic features of the present invention is that an improvement in bioavailability can be achieved by oral administration of a composition of the present invention. Normally, low bioavailability of a drug substance after oral administration is a barrier to the design of a controlled or modified release drug composition because effective drug levels are almost impossible to achieve over a prolonged period of time. However, with the technology of the present invention it is possible to achieve significantly increased bioavailability and thus for example it is possible to design delayed release compositions.

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The solid solution of the invention exhibits very rapid immediate release of tacrolimus when a composition comprising the solution is tested in a dissolution test according to USP using an aqueous dissolution medium, and at least 50% w / w of the active pharmaceutical ingredient. is released within approximately 30 minutes, preferably within 20 minutes, more preferably within 15 minutes; as for example at least 75% w / w of the active pharmaceutical ingredient is released within approximately 40 minutes, or even better at least 90% w / w of the active pharmaceutical ingredient is released within approximately 60 minutes, preferably within 45 minutes. For example, the test may be performed according to any method and any of the specifications cited in USP. Thus, the dissolution test may be performed in an aqueous dissolution medium at neutral or near neutral pH, for example at pH 6.8, or at any acidic pH that simulates pH conditions in the gastrointestinal tract. However, variations with respect to the specific method employed and the ingredients contained in the dissolution medium etc. are within the scope of the present invention. A skilled technician will know how to perform a suitable dissolution test for example under the guidance of USP, Ph. Eur. And others. Suitable conditions for the in vitro dissolution test employ the USP dissolution test (palette method) and a pH 7.5 buffer containing 2.5% SDS and 1 µg / ml pancreatin as the dissolution medium.

In other embodiments, the following conditions are met for in vitro dissolution tests:

(i) at least about 50% w / w of the total amount of tacrolimus is released within approximately 10 hours, such as for example within approximately 8 hours, within approximately 6 hours, within approximately 4 hours, within approximately 3 hours. hours, within approximately 2 hours, within approximately 1 hour, within 12/58 approximately 45 minutes, within approximately 30 minutes, or within approximately 15 minutes, when tested in an in vitro dissolution test employing a dissolution medium comprising a buffer having a pH of 7.5 ii) at least approximately 50% w / w of the total amount of tacrolimus is released within approximately 1.5 hours as for example, within approximately 1 hour, within approximately 0.75 hours, within approximately 0.5 hours, or within approximately 20 minutes, when tested in an in vitro dissolution test employing a dissolution medium comprising a buffer having a pH of 7.5.

iii) at least approximately 55% w / w such as for example approximately 60% w / w or more, approximately 65% ​​w / w or more, approximately 70% w / w or more, approximately 75% w / w or more or approximately 80% w / w or more of the total amount of tacrolimus is released within approximately 15 hours such as for example within approximately 12 hours, within approximately 10 hours, within 8 hours or within approximately 6 hours, when tested in an in vitro dissolution test employing a dissolution medium comprising a buffer having a pH of 7.5 iv) at least about 55% w / w such as for example about 60% w / w or more, about 65 % w / w or more, approximately 70% w / w or more, approximately 75% w / w or more or approximately 80% w / w or more of the total amount of tacrolimus is released within approximately 5 hours such as, for example, within about 4 hours, within approximately 3 hours, within approximately 2 hours, within approximately 1 hour or within approximately 30 minutes, when tested in an in vitro dissolution test employing a dissolution medium comprising a buffer having a pH of 7.5, and /or

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v) at least about 20% w / w such as for example at least about 25% w / w, at least about 30% w / w, at least about 35% w / w or at least about 40% w / w p of the total amount of tacrolimus is released within the first 3 hours as for example within the first 2 hours or within the first hour when tested in an in vitro dissolution test employing a dissolution medium comprising a buffer having a pH of 7.5.

In other embodiments, the following conditions are met with respect to in vitro dissolution tests performed under acidic conditions:

(i) when much from approximately 30% w / w such as for example when much from approximately 25% w / w, when much from approximately 20% w / w, when much from approximately 15% w / w or when much from approximately 14%. % w / w tacrolimus is released within 2 hours in an in vitro dissolution test employing a dissolution medium with a pH of at least about 5 such as for example when at about 4.5, when at most about 4%. when much from about 3.5, when much from about 3, when much from about 2 or when much from about 1.5 ii) when much from about 10% w / w such as for example when from about 7.5% w / w, when much of approximately 5% w / w or when much of approximately 2.5% w / w of tacrolimus is released within 2 hours in an in vitro dissolution test employing a dissolution medium with a pH of at least about 5 such as for example when a lot of about 4.5, a lot of about 4, a lot of about 3.5, a lot of about 3, a lot of about 2 or a lot of about 1.5

Iii) when much of approximately 60% w / w such as for example when much of approximately 50% w / w, when much of approximately 40% w / w or when much of approximately 30% w / w of tacrolimus is released within 15 hours such as for example within approximately 12 hours when it is tested in an in vitro dissolution test employing a dissolution medium having a pH of at least about 4.5 such as for example when much of about 4.0, when much from about 3.5, when much from about 3, when much from about 2 or when much from about 1.5 iv) when much from about 40% w / w such as for example when from about 30% w / w, when much of about 25% w / w or when much of about 20% w / w of tacrolimus is released within 6 hours when tested in an in vitro dissolution test employing a dissolution medium with a pH of at least about 4.5 such. as for example when much, from about 4.0, when much from about 3.5, when much from about 3, when much from about 2 or when much from about 1.5, and / or

(v) when much of approximately 30% w / w such as for example when much of approximately 25% w / w, when much of approximately 20% w / w or when much of approximately 15% w / w of tacrolimus is released within 4 hours when it is tested in an in vitro dissolution test employing a dissolution medium with a pH of at least about 4.5 such as for example when at about 4.0, when at about 3.5, when at about 3, when much of about 2 or when much of about 1.5.

The vehicles to be used according to the present invention are selected from mixtures of polyethylene glycol with poloxamer.

The carrier is a polyethylene glycol (PEG), in particular a PEG having an average molecular weight of at least 1500, preferably at least 3000, more preferably at least 4000, especially at least 6000, mixed with a poloxamer in a proportion ( weight / weight) from 1: 3

5: 1, plus 10: 1, preferably preferably between 3: 2 and 4: 1, especially between 2: 1 and 3: 1, in particular approximately 7: 3. A specific example of a useful mixture is a mixture of PEG 6000 and poloxamer 188 in a 7: 3 ratio.

For polyethylene glycols (PEG), the melting point (solidification point or freezing point) increases as the average molecular weight increases. For example, PEG 400 is in the range 4-8 ° C, PEG 600 is in the range 20-25 ° C, PEG 1500 is in the range 44-48 ° C, PEG 2000 is approximately 52 ° C, PEG 4000 is approximately 59 ° C, PEG 6000 is approximately 65 ° C and PEG 8000 is approximately 61 ° C.

Useful poloxamers (also called polyoxypropylene polyoxyethylene block copolymers) are for example the poloxamer

188, poloxamer 237, poloxamer 338 or poloxamer 407 or other ethylene oxide and propylene oxide block copolymers such as the Pluronic® and / or Tetronic® series. Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of about 3,000 or more, such as, for example, from about 4,000 to about 20,000 and / or a viscosity (Brookfield) of from about 200 to about 4. 000 cps such as for example from about 250 to about 3,000 cps.

Suitable examples include Pluronic® F38, P65, P68LF, P75, F77,

P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123,

F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable block copolymers of the Tetronic® series include polymers with a molecular weight of approximately 8,000 or more such as for example from

Approximately 9,000 to approximately 35,000 and / or a (Brookfield) viscosity of from about 500 to approximately 45,000 cps such as for example from approximately 600 to approximately 40,000. The above viscosities were determined at 60 ° C for substances which are slurries at room temperature and at 77 ° C for substances which are solid at room temperature.

In a preferred embodiment of the present invention, the poloxamer is poloxamer 188, which has an average molecular weight of approximately 8,400 and a melting point of approximately 50-54 ° C.

Pharmaceutical Compositions

The pharmaceutical composition of the invention comprises the solid solution of the invention and one or more pharmaceutically acceptable excipients, for example one or more excipients useful as fillers, disintegrants, binders and / or lubricants.

Preferably, the pharmaceutical composition of the invention is in particulate form, for example in powder form. Preferably, the particulate material obtained is a free flowing powder and is therefore easily processable in for example solid dosage forms such as tablets, capsules or sachets. Typically, the particulate material has properties that are suitable for making tablets by direct compression without the addition of large amounts of other additives. A suitable test for testing the flowability of particulate material is the method described in Ph. Eur. And measures the flow rate of material leaving a funnel with a nozzle (orifice) having a diameter of 10.0 mm.

The particles may have an average diameter of geometric weight d_gwfrom about 10 μπι to about 2,000 μπι,

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<td>preferably</td><td>since</td><td>about 20</td><td>μιη</td><td>up until</td>

<td>about</td><td>2000 μπι,</td><td colspan="2">more preferably</td><td>since</td>

<td>about</td><td>3 0 μπι to</td><td>about 2000</td><td>μπι,</td><td>more</td>

<td>preferably</td><td>since</td><td>about 50</td><td>μιη</td><td>up until</td>

<td>about</td><td>2000 μπι,</td><td colspan="2">more preferably</td><td>since</td>

<td>about</td><td>6 0 μπι to</td><td>about 2000</td><td>μιη,</td><td>more</td>

<td>preferably</td><td>since</td><td>about 75</td><td>μπι</td><td>up until</td>

<td>about</td><td>2000 μπι,</td><td colspan="2">more preferably</td><td>since</td>

<td>about</td><td>100 μπι to</td><td>about 1500</td><td>μιη,</td><td>more</td>

<td>preferably</td><td>since</td><td>about 100</td><td>μιη</td><td>up until</td>

<td>about</td><td>1000 μπι,</td><td colspan="2">more preferably</td><td>since</td>

<td>about</td><td colspan="2">100 μπι to approximately 70 0</td><td>μιη,</td><td>more</td>

<td>preferably</td><td>since</td><td>about 50</td><td>μιη</td><td>up until</td>

<td>about</td><td>40 0 μπι,</td><td colspan="2">more preferably</td><td>since</td>

<td colspan="3">approximately 50 μπι to approximately 350 μπι,</td><td>still</td><td>more</td>

<td>preferably</td><td>since</td><td>about 50</td><td>μιη</td><td>up until</td>

<td colspan="4">approximately 300 μπι, especially since approximately</td><td>5 0 μιη</td>

<td colspan="2">up to approximately 250</td><td colspan="2">μπι or in particular</td><td>since</td>

<td colspan="3">approximately 100 μπι to approximately 300 μπι.</td><td>In</td><td>form</td>

<td colspan="3">preferred embodiment of the invention, the particles have</td><td colspan="2">a diameter</td>

<td colspan="2">geometric weight average d_gw</td><td>since approximately</td><td colspan="2">5 0 μιη to</td>

<td colspan="2">approximately 300 μπι.</td><td></td><td></td><td></td>

<td>The examples of</td><td>excipients</td><td>suitable to be i</td><td>roasts</td><td>in</td>

The solid composition or dosage form according to the invention includes fillers, diluents, disintegrants, binders, lubricants etc. or a mixture thereof. As the solid composition or dosage form according to the invention may be used for different purposes, the choice of excipients is generally made having regard to such different uses. Other excipients accepted in the Pharmaceutical Industry for suitable use are for example acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents,

Chelating agents, coloring agents, binding agents, emulsifying and / or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents, etc.

<td>(in</td><td>low</td>

<td>(per</td><td>example</td>

<td>such</td><td>how put</td>

<td>and 60</td><td>SH, the 4</td>

<td> 000,</td><td>15 000 and</td>

Examples of suitable fillers, diluents and / or binders include lactose (eg spray dried lactose, α-lactose, βlactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose replacement), hydroxypropyl methylcellulose (HPMC)

Methocel E, F and K, Shin-Etsu Metolose SH, Ltd, such as for example the 4,000 cps degrees Methocel E and Metolose 60 SH, the 4,000 cps degrees Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps degrees Methocel K; and 4,000, 15,000, 39,000 and 100,000 degrees of Metolose 90 SH), methylcellulose polymers (such as for example Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl -hydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, malto-dextrins, modified starches or starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, hydrogen calcium phosphate, hydrated dicalcium phosphate), calcium sulphate, calcium carbonate, sodium alginate, collagen etc.

Specific examples of diluents are for example calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.

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Specific examples of disintegrants are for example alginic acid or hydroxypropylcellulose croscarmellose sodium, carboxymethyl starch glycolate starch (by alginates, microcrystalline cellulose, and other cellulose derivatives, crospovidone, potassium polacryline, sodium, starch, pregelatinized starch, for example Primogel® and Explotab®) etc.

Specific examples of binders are for example acacia, alginic acid, agar, sodium carboxymethylcellulose carrageenan, dextrin cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.

calcium, microcrystalline,

The composition may also include sliders and lubricants. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glycerol behenate, colloidal silica, hydrogenated vegetable oils, cornstarch, sodium stearyl fumarate. , polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in a solid composition or dosage form of the invention are for example flavoring agents, coloring agents, pH masking agents, antioxidant, moisture agents, buffering agents, flavoring agents, preservative adjusting agents, stabilizers, humectants, surfactant adjusting agents, suspending agents, absorption enhancing agents, release modifying agents etc.

Other additives in a solid composition or dosage form according to the invention may be antioxidants such as ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl gallate, 20/58. sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may for example also contain stabilizing agents. The concentration of an antioxidant and / or stabilizing agent in the carrier composition is usually from about 0.9% w / w to about 5% w / w.

The pharmaceutical composition or solid dosage form according to the invention may also include one or more surfactants or substances having surfactant properties. It is contemplated that these substances are involved in the humidification of the slightly soluble active substance and thus contribute to the increased solubility characteristics of the active substance. Excipients suitable for use in a solid composition or dosage form according to

<td>invention are</td><td>the</td><td>surfactants such as,</td><td>per</td><td>example,</td>

<td>surfactants</td><td colspan="2">amphiphiles as exposed</td><td>at the</td><td>Request</td>

<td>International</td><td>in</td><td>WO 00/50007 whose holder</td><td>and the</td><td>Lipocine,</td>

<td>Inc.</td><td></td><td></td><td></td><td></td>

<td>The examples</td><td>in</td><td>suitable suitable substances</td><td>how</td><td>agents</td>

<td>surfactants</td><td>are</td><td> •</td><td></td><td></td>

<td colspan="2">i) fatty acids</td><td colspan="2">polyethoxylates such as for example</td><td>mono or</td>

polyethylene glycol fatty acid diesters or mixtures thereof such as, for example, polyethylene glycol mono- or diesters with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000,

Ii) polyethylene glycol glycerol fatty acid esters, ie esters as mentioned above but in the form of glycerine esters of the individual fatty acids;

(iii) glycerol, polypropylene glycol, ethylene glycol, PEG or sorbitol esters with for example vegetable oils such as hydrogenated castor oil, almond oil, palm oil, castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palm oil and others, iv) polyglycerated fatty acids such as polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate,

v) polypropylene glycol fatty acid esters such as for example polypropylene glycol monolaurate, polypropylene glycol ricinoleate and others, vi) mono and diglycerides such as glycerine monooleate, glycerine dioleate, glycerine monoleate and / or caprylate dioleate glycerin, glycerine caprate etc .;

vii) sterol and sterol derivatives;

viii) polyethylene glycol sorbitan fatty acid esters (sorbitan-PEG fatty acid esters) such as PEG esters of the various molecular weights listed above, and the various Tween® series;

ix) polyethylene glycol alkyl ethers such as for example PEG oleic ether and PEG lauryl ether;

x) sugar esters such as sucrose monopalmitate and sucrose monolaurate;

Xi) polyethylene glycol alkylphenols such as Triton® X or N series;

xii) block copolymers such as, for example, the Emkalyx®, Lutrol®, Supronic® series polymers are poloxamers and context are poloxamers 183, 184, 185, 188, 212, 215, 284, 288, 331, 333, 334, 335, polyoxypropylene-polyoxyethylene such as Pluronic®, Synperonic® series, etc. The generic term for these relevant examples in the present

<td> .05, 108,</td><td> 122,</td><td> 123,</td><td> 124,</td><td> 181,</td><td> 182</td>

<td> 217, 231,</td><td> 234,</td><td> 235,</td><td> 237,</td><td> 238,</td><td> 282</td>

<td> 338, 401,</td><td> 402,</td><td colspan="2">403 and 407;</td><td></td><td></td>

xiii) sorbitan fatty acid esters such as the Span® series or Ariacel® series such as for example sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate etc .;

xiv) lower alcohol fatty acid esters such as oleate, isopropyl myristate, isopropyl palmitate etc. ;

xv) ionic surfactants including cationic, anionic and zwitterionic surfactants such as, for example, fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates etc.

When a surfactant or a mixture of surfactants is present in a solid composition or dosage form of the invention, the concentration of the surfactant (s) approximately approximately approximately is approximately 0.1 - 80%.

0.1 to from normally within a w / w range such as for example from about 20% w / w, from

0.1 to about 0.5 to about

15% w / w, from 10% w / w, or alternatively from about 0.10 to about

80% w / w such as for example from about 10 to 23/58 about 70% w / w, from about 20 to about 60% w / w or from about 30 to about 50% w / w.

In a specific aspect of the invention, at least one of one or more pharmaceutically acceptable excipients is selected from the group consisting of silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof; magnesium aluminosilicate and / or magnesium aluminosilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite.

These materials are especially useful as a sorption material for oils or oilseeds in pharmaceuticals, cosmetics and / or food products. In a specific embodiment used as an oilseed material in the invention products the material is sorption for oils or pharmaceutical materials. Material which has the ability to function as a sorption material for oils or oilseeds is also called an oil sorption material. Furthermore, in the present context the term sorption absorption as well as adsorption.

where in the present invention one of the terms is used, it is intended to encompass the phenomenon of absorption as it is used to mean that adsorption should be understood.

Notably, the pharmaceutically acceptable excipient may comprise a silica acid or a derivative or salt thereof such as for example silica dioxide or a polymer thereof as a pharmaceutically acceptable excipient. Depending on the quality employed, a silica dioxide may be a lubricant or may be an oil sorption material. The qualities that fulfill this last function seem to be the most important.

24/58

In a specific embodiment, the composition or solid dosage form according to the invention comprises a pharmaceutically acceptable excipient which is a silicon dioxide product having properties corresponding to Aeroperl®300 (marketed by Degussa, Frankfurt, Germany ). As is evident from the examples of the present invention, a very suitable material is Aeroperl® 300 (including materials having the same or corresponding properties as Aeroperl® 300).

The use of an oil sorption material in the compositions or dosage forms according to the invention is very advantageous for the preparation of pharmaceutical, cosmetic, nutritional and / or nutritional compositions, wherein the composition comprises oil or an oleaginous material. One of the advantages is that it is possible to incorporate a relatively large amount of oil and oleaginous material and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high load of oil or oleaginous materials using an oil sorption material according to the invention. Within the pharmaceutical field, it is an advantage to be able to incorporate a relatively large amount of an oil or oleaginous material into a solid composition especially in those situations where the active substance as long as its solubility in water does not have adequate properties (for example poor solubility). in water), stability in aqueous media (ie degradation occurs in aqueous media), oral bioavailability (eg low bioavailability) etc., or in those situations where it is desirable to modify the release of an active substance from a composition to achieve controlled, delayed, sustained and / or pulsed delivery of the active substance. Thus, in a specific embodiment of the invention it is used in the preparation of pharmaceutical compositions.

The oil sorption material for use in processing solid compositions usually absorbs approximately 5% w / w or more, such as for example approximately 10% w / w or 25/58 plus, approximately 15% w / w or more, approximately 20% w / w or more, approximately 25% w / w or more, approximately 30% w / w or more, approximately 35% w / w or more, approximately 40% w / w or more, approximately 45 % w / w or more, approximately 50% w / w or more, approximately 55% w / w or more, approximately 60% w / w or more, approximately 65% ​​w / w or more, approximately 70% w / w or more, approximately 75% w / w or more, approximately 80% w / w or more, approximately 85% w / w or more, about 90% w / w or more or about 95% w / w or more of oil or oleaginous material and is further a solid material.

As is evident from the examples of the present invention, the bioavailability obtained after administration of a composition according to the invention is markedly increased. Thus, in specific embodiments of the invention, the value AUC / AUC_Prograf® is at least approximately 1.5 such as approximately 1.75 or more, approximately 1.8 or more, approximately 1.9 or

<td colspan="2">more approximately</td><td> 2,0</td><td>or more</td>

<td>about</td><td> 2, 75</td><td>or</td><td>more,</td>

<td>about</td><td> 3,25</td><td>or</td><td>more,</td>

<td>about</td><td> 3, 75</td><td>or</td><td>more,</td>

<td>about</td><td> 4,25</td><td>or</td><td>more,</td>

<td>about</td><td> 4, 75</td><td>or</td><td>more hi</td>

the AUC values ​​being determined

<td>, approximately 2.5</td><td>or</td><td>more,</td>

<td>approximately 3.0</td><td>or</td><td>more,</td>

<td>about 3.5</td><td>or</td><td>more,</td>

<td>about 4.0</td><td>or</td><td>more,</td>

<td>approximately 4.5</td><td>or</td><td>more,</td>

<td>approximately 5.0</td><td>or</td><td>more,</td>

<td colspan="2">under identical conditions.</td><td></td>

Following oral administration of a pharmaceutical composition according to the present invention, it is contemplated that the plasma concentration versus time profile shows an extended time period in which the plasma concentration is maintained in the therapeutic window (i.e. of plasma leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration can be observed.

26/58

However, a reduction in peak concentration may not lead to a decrease in therapeutic effect as long as the tacrolimus plasma concentration is maintained in the therapeutic window.

It is contemplated that the need for simultaneous food intake to ensure sufficient intake of tacrolimus is significantly reduced or even completely suppressed when administered in a pharmaceutical composition or a dosage form of the present invention.

Thus, the pharmaceutical compositions of the invention provide significantly higher bioavailability of tacrolimus, which may reduce the number of dosage units administered daily, and reduce or suppress the need for administration in connection with food intake, which provides a higher degree. receptor freedom of the pharmaceutical compositions, and consequently patient acceptance and / or consent may be significantly increased. In addition, the compositions provide a significant reduction in side effects, especially side effects related to a high peak concentration (such as, for example, nephro and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc.). provide extended release of tacrolimus leading to better treatment.

One of the biggest challenges with formulating tacrolimus compositions is to avoid an adverse food effect. Tacrolimus is generally much better absorbed when taken orally without food. A large variation in bioavailability was therefore seen after administration with or without food. This dependence makes it difficult to give precise guidance on how large the administered doses should be and furthermore it requires the patient to be informed about the dosing regimen. The present invention aims to provide compositions in which the adverse food effect is reduced. Thus, the present invention provides a composition which does not exhibit a significant adverse food effect upon administration of the composition to a mammal in need of such treatment as evidenced with a fasting (AUC-fed-VAUC) value of at least approximately 0.8. 5 with a 90% lower confidence limit of at least 0.75.

More specifically, a pharmaceutical composition according to the invention has a value of (AUC_Theii_mentado-VAUC_andfasting) of about 0.9 or more, such as for example about 0.95 or more, about 0.97 or more or about 1 or more, such as for example up to about 1.1 or up to about 1.2 .

In addition to tacrolimus, the composition of the invention may comprise a therapeutic, prophylactic and / or diagnostically active substance. Notably, combinations of tacrolimus with at least one of the following active substances are of interest: Substances which are intended to be used in connection with organ transplantation such as, for example, steroids, calcineurin inhibitors and / or antiproliferative agents. Specific examples include prednisone, prednisolone, methylprednisone, cyclosporine, mycophenolate, azathioprine, sirolimus, everolimus, mycophenolate sodium, and FTY720 (developed by the Pharmaceutical Company Novartis).

Dosage forms

Useful dosage forms of the invention are solid oral dosage forms comprising the solid solution and one or more pharmaceutically acceptable excipients, preferably unit dose forms.

The pharmaceutical composition according to the invention is in particulate form and may be employed as such. However, in many cases it is more convenient to present the composition in the form of granules, granules, microspheres, nanoparticles and the like or in solid dose forms including tablets, capsules and sachets and others.

A solid dose form according to the invention may be a single unit dose form or in a multi-purpose dose form, may contain a multiplicity of individual units such as, for example, granules, beads and / or granules.

Dosage forms may also comprise suitable additives in the Pharmaceutical Industry such as flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, moisture adjusting agents. surfactants, suspending agents, absorption enhancing agents and release modifying agents.

In a preferred embodiment, the dosage form comprises silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof; and / or magnesium aluminosilicate and / or magnesium aluminosilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite. A particularly useful excipient for inclusion in dosage forms is any silicon dioxide product having properties corresponding to Aeroperi® 300 (available from Degussa, Frankfurt, Germany).

A solid dosage form according to the present invention comprises a pharmaceutical composition in particulate form as described above. The details and specifications set forth in this principal aspect of the invention are applied mutatis mutandis to other aspects of the invention. Accordingly, the properties with respect to increased bioavailability, changes in bioavailability parameters, reduction in adverse food effect as well as the release of tacrolimus and / or an analog thereof etc. described and / or claimed in the present invention for pharmaceutical compositions in particulate form are analogous to a solid dosage form according to the present invention.

Typically, the concentration of the pharmaceutical composition in particulate form is in a range of from about 5 to 100% w / w such as for example from about 10% to about 90% w / w, from about 15% to about 85% w / w ,

<td colspan="3">from approximately 20%</td><td>up to approximately 80%</td><td>w / w,</td><td>since</td>

<td>about</td><td> 25%</td><td>up until</td><td>approximately 80%</td><td>w / w,</td><td>since</td>

<td>about</td><td> 30%</td><td>up until</td><td>approximately 80%</td><td>w / w,</td><td>since</td>

<td>about</td><td> 35%</td><td>up until</td><td>approximately 80%</td><td>w / w,</td><td>since</td>

<td>about</td><td> 40%</td><td>up until</td><td>approximately 75%</td><td>w / w,</td><td>since</td>

<td>about</td><td> 45%</td><td>up until</td><td colspan="2">approximately 75% w / w or</td><td>since</td>

<td>about</td><td> 50%</td><td colspan="2">up to approximately 70% w / w</td><td colspan="2">in the form of</td>

<td colspan="2">dosage. In a form</td><td colspan="4">of carrying out the invention, the concentration of</td>

<td colspan="3">pharmaceutical composition in</td><td>particulate form is of</td><td> 50%</td><td>p / p or</td>

more of the dosage form.

A solid dosage form according to the invention is obtained by processing the particulate material by techniques well known to a skilled person. Typically, it involves the additional addition of one or more of the pharmaceutically acceptable excipients mentioned in the present invention.

The solid composition or dosage form according to the invention may be designed to release tacrolimus in any suitable manner whenever and when increased bioavailability is provided. Thus, the active substance may be released relatively rapidly to obtain an increased onset of action, may be released to zero or first order kinetics, or may be modified-modified to obtain a predetermined release pattern. All of these modes are

30/58 considered controlled ways. Simple formulations are also within the scope of the present invention.

The recommended dosage range for Prograf® is 0.1 to 0.2 mg / kg / day every 12 hours in two divided doses. Most importantly blood levels have to be monitored. The typical level for 1-3 months is 7 - 20 ng / ml and at 4 - 12 months the levels should be 5 - 15 ng / ml. These are only

<td>guiding values ​​and ethnicity.</td><td>may</td><td colspan="2">vary in the types of</td><td>transplantation and</td>

<td>Were discovered</td><td>Dice</td><td>following</td><td>for</td><td>patients with</td>

<td>kidney transplant:</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Cauchasic</td><td></td><td>Black</td>

<td></td><td></td><td>n = 114</td><td></td><td>n = 56</td>

<td>Time after transplantation</td><td>doses</td><td>Concentrations</td><td>doses</td><td>Concentrations</td>

<td></td><td>(mg / kg)</td><td>minimum (ng / ml)</td><td>(mg / kg)</td><td>minimum (ng / ml)</td>

<td>Day 7</td><td> 0, 18</td><td> 12, 0</td><td> 0,23</td><td> 10, 9</td>

<td>Month 1</td><td> 0, 17</td><td> 12, 8</td><td> 0,26</td><td> 12, 9</td>

<td>Month 6</td><td> 0, 14</td><td> 11,8</td><td> 0,24</td><td> 11,5</td>

<td>Month 12</td><td> 0, 13</td><td> 10, 1</td><td> 0, 19</td><td> 11,0</td>

<td colspan="3">The recommendation of the contemplated dosage of</td><td colspan="2">gift products</td>

The invention is 0.02 mg / kg / day to 0.15 mg / kg / day, dosed once daily.

Enteric Coatings - Delayed Release

It has been found that the efficacy of oral tacrolimus treatment can be greatly enhanced by appropriate tacrolimus release profile design. On the one hand, relatively high doses of tacrolimus are required to prevent transplant rejection, and on the other hand, often side effects become too pronounced even when at therapeutically relevant levels. So the effects

Secondary symptoms such as acute nausea, vomiting, nephrotoxicity and neurotoxicity are directly linked to high peak plasma concentrations. This binding has been demonstrated in dogs. In those cases where a lower dose was used to avoid high peak levels, dose-dependent side effects almost cease to occur at a certain threshold level and, if they occurred, would be much less pronounced. However, due to dose reduction (without increasing bioavailability) the therapeutically effective level was only maintained for a short time. The present invention solves this problem by providing a tacrolimus-containing pharmaceutical composition or dosage form wherein the release of tacrolimus is designed to prevent high peak concentrations and at the same time the composition is designed such that overall bioavailability is maintained or increased compared to commercially available tacrolimus-containing dosage forms. In addition, by delaying the release of tacrolimus while providing a composition wherein tacrolimus is at least partially in dissolved form, significant absorption in the distal part of the gastrointestinal tract can be achieved.

Thus, the dosage form of the invention may further comprise one or more release modifying agents selected from the group consisting of water-miscible polymers, water-insoluble polymers, oils and oleaginous materials.

Water insoluble polymer may be ethyl cellulose, cellulose acetate, cellulose nitrate, and mixtures thereof. 0 Water miscible polymer may also be a cellulose derivative selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, poloxamers, polyoxyethylene stearates, poly-8-caprolactone, polyvinylpyrrolid (polyvinylpyrrolid) , polyvinylpyrrolidone32 / 58 polyvinyl acetate copolymer PVP-PVA, polymethacrylic polymers and polyvinyl alcohol (PVA), poly (ethylene oxide) (PEO) and mixtures thereof. Examples of especially useful polymethacrylic polymers are Eudragit® RS, Eudragit® RL, Eudragit® NE and Eudragit®.

AND.

Oil or oils may be hydrophilic and hydrophobic oils or oleaginous materials.

hydrophilic oil or oleaginous material may be polyether glycols such as polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers; polyglycosylated glycerides such as Gelucire®, for example Gelucire® 50/13, Gelucire® 44/14, Gelucire® 50/10, Gelucire® 62/05 and mixtures thereof.

The hydrophobic oil or oleaginous material may have a melting point of at least about 20 ° C. Useful examples are straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils such as cocoa butter, beef tallow, lard, polyether glycol esters; higher fatty acids such as stearic acid, myristic acid, palmitic acid, higher alcohols such as kethanol, stearic alcohol, low melting waxes such as glyceryl monostearate, glyceryl monooleate, unsubstituted tallow alcohol, hydrogenated, myristyl alcohol, substituted and / or unsubstituted substituted monoglycerides and / or diglycerides, substituted and / or unsubstituted triglycerides, yellow wax, white wax, carnauba wax, castor wax, Japan wax, acetylate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, and mixtures thereof.

The oil or oleaginous type material may also be a sorbitan ester such as, for example, sorbitan distearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan, sorbitan sesquiisoestearate, sorbitan sesquioleate, sorbitan sesquiestearate, sorbitan triestearate, sorbitan trioleate, sorbitan triestearate or mixtures thereof.

The oil or oil-like material may of course comprise a mixture of different oils or oil-like materials such as, for example, a mixture of hydrophilic and / or hydrophobic materials.

Other suitable oleaginous oils or materials may be semisolid solvents or excipients such as propylene glycol, polyglycolised glycerides including Gelucire

44/14, complex fatty materials of vegetable origin including cupuacu oil, carnauba wax, vegetable oils such as almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil , olive oil, castor oil, palm oil, peanut oil, rapeseed oil, grape seed oil etc., hydrogenated vegetable oils such as, for example hydrogenated peanut oil, hydrogenated palm oil, cottonseed oil hydrogenated, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; natural fatty materials of animal origin including beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric, myristic, palmitic, stearic fatty alcohols; esters including glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate;

semi-synthetic liquid interesterified glycerides including Miglycol 810/812; fatty acid starch or alkolamides including sorbitan triisostearate, coconut fatty acid diethanolamide, mono and diglyceride acetic acid esters, mono and diglyceride citric acid esters, mono and diglyceride lactic acid esters, mono and diglycerides , polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propylene glycol esters of 34/58 fatty acids, sorbitan monostearates, sorbitan tristearates, sodium stearoyl lactylate, calcium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides etc.

Delayed release of the active ingredient is desirable to increase the bioavailability of the active ingredient delivering the ingredient to the gastrointestinal tract, i.e. the release predominantly occurs after the passage of the stomach. For example, the dosage form of the present invention may be designed to release upon oral administration to a mammal.

<td>that needs it,</td><td>When</td><td>much</td><td>in</td><td>about</td><td> 10%</td><td>w / w,</td>

<td>preferably</td><td colspan="2">when much of</td><td colspan="2">approximately 7.5%</td><td>w / w,</td><td>more</td>

<td>preferably</td><td>When</td><td>much</td><td>in</td><td>about</td><td> 5%</td><td>w / w,</td>

especially when very approximately 2% w / w of the total amount of active ingredient within the first 3 hours, preferably within 2 hours, more preferably within 1 hour, in particular approximately 30 minutes after administration.

In addition, the solid dosage form of the invention may, upon oral administration to a mammal in need thereof, release at least about 50% w / w of the active ingredient within 24 hours, preferably within approximately 20 hours, more preferably within approximately 18 hours, especially within approximately 15 hours, in particular within approximately 12 hours.

Delayed release is mainly caused by some type of enteric coating. Although the semipermeable coating shows some type of delayed release, it may not slow the release sufficiently advantageously.

Additionally, it requires a certain amount of time to release its content. The coating sought for this invention is a pH dependent coating. This type of coating is very resistant to releasing the drug until a certain pH is reached. With a small increase in the pH value, this with a pH increase of approximately 0.2 becomes permeable.

0.4, the movie changes the properties

Accordingly, the solid dosage forms of the invention may exhibit delayed release of the active ingredient by means of an enteric coating using a water miscible polymer which has a pH dependent solubility in water. Examples of pH-sensitive polymers, which are relatively insoluble and impervious to stomach pH, ​​but which are more soluble and permeable to small intestine and colon pH include, but are not limited to, polyacrylamides; phthalate derivatives such as carbohydrate acid phthalates including amylose acetate phthalate, cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, phthalate hydroxypropylcellulose acetate, hydroxypropylethylcellulose phthalate, hydroxypropyl methylcellulose phthalate (HMPCP), methylcellulose phthalate, methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydrogen polyvinyl acetate phthalate, sodium cellulose acetate phthalate, starch acid phthalate; phthalates of other compounds including polyvinyl acetate phthalate (PVAP); Others including (HPMCAS), cellulose;

hydroxypropyl methylcellulose cellulose derivatives trimellitate carboxymethylcellulose acetate succinate acetate, alginates; carbomers;

polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and its esters, methacrylic polyacrylic acid copolymers, methacrylic acid copolymers (for example Eudragit® L and

Eudragit® S); styrene dibutyl phthalate maleic acid copolymer; styrene maleic acid polyvinyl acetate styrene phthalate copolymer; styrene and maleic acid copolymers; gum shell, starch glycolate; polacryline; vinyl acetate and crotonic acid copolymers and mixtures thereof. PH sensitive polymers 36/58 of specific interest include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate mixed with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.

A first delayed release embodiment according to the invention is a pH dependent coated dosage form such as, for example, a tablet or capsule. In the case of a tablet, it comprises a tablet core comprising tacrolimus for example in a solid solution / dispersion as a multiparticulate product, a controlled release matrix of for example HPMC, a disintegrant, a lubricant, and one or more pharmaceutical carriers, the core being coated with a material, preferably a polymer, which is substantially insoluble and impermeable to stomach pH, ​​and which is more soluble and permeable to small intestine pH. Preferably, the coated polymer is substantially insoluble and impermeable at pH &lt;5.0, and water soluble at pH&gt; 5.0. The tablet core may be coated with a sufficient amount of polymer to ensure that substantially no tacrolimus release from the dosage form occurs until the dosage form has left the stomach and resided in the small intestine for approximately 15 minutes or more. preferably approximately 30 minutes or more, thereby ensuring that a minimum of tacrolimus has been released into the duodenum. Mixtures of a pH-sensitive polymer with a water-insoluble polymer may also be employed. The tablets are coated with an amount of polymer comprising from about 10% to about 80% of the core weight of the tacrolimus-containing tablet. Preferred tablets are coated with an amount of polymer comprising approximately

37/58

15% to approximately 50% of the core weight of the tacrolimus tablet.

PH-sensitive polymers that are very insoluble and impervious to stomach pH, ​​but which are more soluble and permeable to small intestine and colon pH include polyacrylamides, phthalate derivatives such as carbohydrate acid phthalates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, hydrogen polyvinyl acetate phthalate, sodium cellulose acetate phthalate, starch acid phthalate, maleic acid styrene-phthalate phthalate, polyvinyl acetate styrene phthalate phthalate, maleic acid and styrene copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, methacrylic polyacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

Preferred pH sensitive polymers include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate mixed with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.

The time delay prior to tacrolimus release, after the pH-dependent coated tablet dosage form has left the stomach, can be controlled by choosing relative amounts of Eudragit-L® and Eudragit-S® in the coating, and choosing of coating thickness. Eudragit-L® films dissolve at a pH above pH 6.0, and 38/58 Eudragit-S® films dissolve at a pH above pH 7.0, and mixtures dissolve at an intermediate pH. Because the pH of the duodenum is approximately 6.0 and the pH of the colon is approximately 7.0, the composite coatings of the Eudragit-L® and Eudragit-S® mixtures provide duodenum protection for tacrolimus. If it is desirable to delay the release of tacrolimus until the tacrolimus-containing pH-dependent coated tablet has reached the colon, as a coating material Eudragit-S® as described by Dew et al. (Br. J. Clin. Pharmac. 14 (1982) 405-408). To delay the release of tacrolimus for approximately 15 minutes or more, preferably 30 minutes or more, after the dosage form has been withdrawn from the stomach, preferred coatings comprise from about 9: 1 to about 1: 9 Eudragit-L® / Eudragit-S®, plus approximately L® / Eudragit-S®.

preferably from 9: 1 to about 1: 4 Eudragit The coating may comprise from about 3% to about 70% of the weight of the uncoated tablet core. Preferably, the coating comprises from approximately

5% to approximately 50% of the tablet core weight,

Release of the active substance from a composition having a delayed release coating may also be an enzymatic reaction, if for example zein or mono / diglyceride mixtures are employed as a coating material.

Manufacture of the compositions and dosage forms of the invention

The present invention also provides a method for preparing the solid solution of the invention, which method comprises dissolving tacrolimus in a polyethylene glycol and poloxamer to obtain a solid solution at room temperature.

The pharmaceutical compositions of the invention may be prepared by any convenient method such as, for example granulation, mixing, spray drying etc. An example of a useful method is the controlled agglomeration method described in International Patent Application WO 03/004001, that is a method that allows for controlled growth in particle size. The method involves spraying a first composition comprising an active ingredient and a molten carrier onto a second solid carrier. Typically, the fusible carrier has a melting point of at least 5 ° C, but the melting point preferably will be below the melting point of tacrolimus. The melting point of the vehicle may range from 10 ° C to 150 ° C.

An advantage of using the controlled agglomeration method described in International Patent Application WO 03/004001 is that with this it is possible to apply a relatively large amount of a melt to a particulate material without having an undesired particle size growth.

The solid solution may also be obtained by employing for example organic solvents or by dissolving the active substance in another suitable medium (for example an oil or an oleaginous material which at room temperature or at elevated temperatures is in liquid form).

Solid dispersions (solvent method) are prepared by dissolving a physical mixture of the active substance (for example a pharmacological substance) and the carrier or carrier in a common organic solvent, followed by evaporation of the solvent. Suitable organic solvents include a pharmaceutically acceptable solvent in which the active substance is soluble such as methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone or mixtures thereof.

Suitable water soluble carriers include polymers such as polyethylene glycol, poloxamers.

40/58 by freeze drying techniques or any other dry contains the solid solid dispersion.

The solid dispersion is preferably formed by spray drying, controlled agglomeration, coating on carrier particles or solvent removal process. The active substance product present as one including a molecular dispersion and a solution

As an alternative to the use of organic solvents, the medicament and polymer may be ground together or extruded at elevated temperatures (melt extrusion).

In principle, pharmaceutical compositions comprising tacrolimus in the form of a solid solution may be prepared using any suitable procedure for preparing pharmaceutical compositions known in the art.

In addition to using the solvent-based organic method, tacrolimus solid solutions can be obtained by dissolving tacrolimus in the carrier composition used in the controlled agglomeration method. Stabilizing agents etc. may be added to ensure stability of the dispersion / solid solution.

Uses

The crystallized solution of the invention or the pharmaceutical composition of the invention may be used in the preparation of an oral solid dosage form such as tablets, capsules or sachets; or for the preparation of granules, granulates, microspheres or nanoparticles.

Preferably, the solid dispersion or solid solution is used in the preparation of an immediate release solid dosage form or a delayed release solid dosage form.

41/58

Other uses of the solid dispersion or solid solution of the invention is the preparation of a topical dosage form.

Another advantage of a composition of the present invention is the ability to obtain an effective therapeutic response at a decreased dosage compared to traditional oral treatment. Thus, it is contemplated that the solid dosage form of the invention, when administered orally to a mammal in need thereof at a dose which is at most approximately 85% w / w such as for example when at most approximately 80% w / w , when much from approximately 75%, when much from approximately 70% w / w, when much from approximately 65% ​​w / w, when much from approximately 60% w / w, at most about 55% w / w or at most about 50% w / w of the dose of tacrolimus administered as Prograf® or a similar commercially available product containing tacrolimus and which is essentially bioequivalent to Prograf® or a product commercially available similar product containing tacrolimus.

Any of the tacrolimus-containing dosage forms, compositions, dispersions or solutions of the invention may improve the treatment of conditions responsive to the treatment of tacrolimus.

Tacrolimus is indicated (or recommended) for the treatment of diseases such as, for example, organ or tissue transplant rejection reactions such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, intestines. thin, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc .; graft-versus-host reactions after bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc .; infections caused by pathogenic microorganisms (eg Aspergillus fumigatus, 42/58

Fusarium oxysporum, Trichophyton asteroids, etc.); inflammatory or hyperproliferative skin diseases or skin manifestations of immunologically mediated diseases (eg psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema dermal eosinophilia, lupus erythematosus, acne, and alopecia areata); autoimmune eye diseases (eg keratoconjunctivitis, vernal conjunctivitis, Behcet's disease-associated uveitis, keratosis, herpetic keratosis, conical keratosis, epithelial corneal dystrophy, keratoleukoma, pemphigus, Mooren's ulcer, scleritis, ophthalmopathy Vogt-Koyanagi-Harada, keratoconjunctivitis sicca (dry eye), fictenulose, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, etc.); reversible diseases of airway obstruction (asthma (eg bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or inveterate asthma (eg late asthma and airway hyperreactivity) bronchitis, etc. .; mucosal or vascular inflammation (eg gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel disease, enteritis, necrotizing enterocolitis, intestinal damage associated with thermal burns, leukotriene B4 mediated diseases); intestinal inflammation / allergies (eg celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis); food-related allergic diseases with remote symptomatic manifestation of the gastrointestinal tract (eg migraine, rhinitis and eczema);

renal diseases (e.g. intestinal nephritis, Goodpasture syndrome, uremic hemolytic syndrome, and diabetic nephropathy); nerve diseases (eg multiple myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and ischemic brain disease (eg 43 Radiculopathy);

head trauma, cerebral hemorrhage (eg subarachnoid hemorrhage, intracerebral hemorrhage), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, ischemic transient attack (TIA), hypertensive encephalopathy, cerebral infarction); endocrine disorders (e.g. hyperthyroidism, and Basedow's disease); blood disorders (e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and aneritroplasia); bone diseases (e.g. osteoporosis); respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis, and interstitial idiopathic pneumonia); skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity and cutaneous T-cell lymphoma); circulatory diseases (e.g. atherosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, and myocardosis); collagen disease (e.g. scleroderma, Wegener's granuloma, and Sjogren's syndrome); adipose; eosinophilic fasciitis; periodontal diseases (eg gum, periodontal, alveolar bone or substantia ossea dentis damage); nephrotic syndrome (eg glomerulonephritis); male pattern alopecia, senile alopecia; muscular dystrophy; pyoderma and Sézary's syndrome; diseases associated with chromosomal abnormalities (eg Down syndrome); Addison's disease; active oxygen-mediated diseases (eg organ damage (eg ischemic organ disease (eg heart, liver, kidney, digestive tract, etc.) associated with conservation, transplantation, or ischemic disease (eg thrombosis) , heart infarction, etc.)); intestinal disorders (eg endotoxic shock, pseudomembranous colitis, and drug or radiation induced colitis); renal diseases (eg acute ischemic renal failure, chronic renal failure); lung diseases (e.g. lung oxygen toxicosis or medications (e.g. paracort, bleomycin, etc.), lung cancer, and pulmonary emphysema);

eye diseases (e.g. cataracts, storage disease retinitis aging, hypobaropathy)];

iron (siderosis bulbi), retinitis, retinitis pigmentosa, senile plaques, vitreous scarring, corneal alkaline burn); dermatosis (e.g. erythema multiforme, bullous dermatosis linear immunoglobulin A, contact dermatitis with cement); and other diseases (eg gingivitis, periodontitis, sepsis, pancreatitis, and diseases caused by environmental pollution (eg air contamination), carcinogen, carcinoma metastases, and diseases caused by the release of histamine or leukotriene C4 after coronary artery restenosis angioplasty and prevention of postoperative adhesions; autoimmune diseases and inflammatory conditions (eg, mucous membranes, autoimmune atrophic gastritis, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis , discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g., deforming arthritis), or polychondritis); human immunodeficiency virus (HIV) infection, AIDS; allergic conjunctivitis; hypertrophic scar and keloid due to trauma, burn, or surgery.

primary edema of premature menopause,

In addition, tricyclic macrolides such as tacrolimus have liver regenerating activity and / or activities to stimulate hypertrophy and hyperplasia of hepatocytes. Therefore, the pharmaceutical composition of the present invention is useful for enhancing the effect of treatment and / or prophylaxis of liver diseases [e.g. immunogenic diseases (e.g. chronic autoimmune liver diseases such as autoimmune liver diseases, primary biliary cirrhosis or sclerosing cholangitis), partial liver resection, acute liver necrosis (eg toxin necrosis, viral hepatitis, shock, or anoxia), hepatitis B, non-non-B hepatitis, hepatocirrosis, and liver failure (eg fulminant hepatitis, late-onset hepatitis and

45/58 acute-to-chronic liver disease (acute liver failure in chronic liver disease))].

In addition, the composition of the present invention is useful for enhancing the effect of preventing and / or treating various diseases due to the useful pharmacological activity of tricyclic macrolides, such as the activity for increasing the chemotherapy effect activity, the infection activity of the cytomegalovirus, antiinflammatory activity, inhibiting activity against peptidyl propyl isomerase or rotamase, antimalarial activity, antitumor activity and so on.

Materials and methods

Materials

Tacrolimus (provided by Eurotrade); lot no RD 03-111

200 Mesh Lactose Monohydrate (DMV)

Granulated silicon oxide, Aeroperl® 300, (Degussa)

Polyethylene glycol 6000, Pluracol® E6000 (from BASF)

Poloxamer 188, Pluronic® F-68 (from BASF)

Glyceryl Monostearate, Rylo® MD50, (from Danisco Cultor), Ph.Eur. lot no 4010056276

Avicel PH200 (Microcrystalline Cellulose) (from FMC)

Lactose DCL 11 (from DMV)

Magnesium stearate

46/58

Croscarmellose Sodium, Ac-Di-Sol® (from FMC)

Eudragit® L30D.55 (from Degussa); lot no 1220314079

Triethyl (from Merck) citrate; lot no RD03-122

Anti-Foam Emulsion (from Unikem)

Micro talc hydroxypropyl methylcellulose acetate phthalate

Both tablets, capsules or granules may be enteric coated with different types of polymers such as hydroxypropyl methylcellulose acetate succinate (Aqoat), CAP cellulose, phthalate of

HPMCP or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100 / S, Eudragit 100 / L.

Comparison of prior art tacrolimus formulation for in vivo studies:

Prograf © Gelatin Capsules

Ingredients

Tacrolimus, anhydrous

Gelatine

Hypromellose

Lactose monohydrate

Magnesium stearate

Shellac

Soybean Lecithin

Red Iron Oxide (E172)

Titanium Dioxide (E171)

Dimethicone (E900) hard, manufactured mg 1.0 6.9 1.0 24, 7 0.3 q. b qb q. b qbq b by

Fuj Isawa

47/58

Methods

Determination of weight variation

The tablets prepared in the examples of the present invention were subjected to a weight variation test performed according to Ph. Eur.

Determination of average tablet hardness

The tablets prepared in the examples of the present invention were subjected to a tablet hardness test using the Schleuniger model 6D apparatus and performed according to the general instructions for the apparatus.

Determination of disintegration time The time for a tablet to disintegrate, that is to say decomposition into particles or agglomerates, is determined according to Ph. Eur.

Determination of mean geometric diameter d_gw The mean geometric diameter was determined by employing the laser diffraction method by dispersing the obtained particulate material (or starting material) into the air. Measurements were performed at 1 bar of dispersive pressure on a Sympatec Helos equipment, which records the distribution of the equivalent spherical diameter. This distribution is adjusted to a normal logarithmic volume-size distribution.

When used in the present invention, geometric means the normal logarithmic diameter of volume-size.

In vitro dissolution tests Mean distribution weight average diameter

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The following test methods were applied to the compositions and dosage forms of the present invention.

Test 1:

In vitro dissolution test according to USP Method A, delayed release articles (USP pallet method; rotation speed: 50 rpm; 37 ° C; after 2 hours in acidic medium the medium is changed to a buffer phosphate pH 6.8).

Test 2:

In vitro dissolution test in pH 4.5 adjusted aqueous dissolution medium (900 ml water with 0.005% HPC (hydroxypropylcellulose) adjusted pH 4.5, 37 ° C; USP pallet method; rotation speed: 50 rpm).

In vivo studies in Beagle dogs

In vivo studies to determine the bioavailability of the compositions of the present invention with respect to the bioavailability of the commercially available tacrolimus product, ie Prograf®, were performed using Beagle dogs.

The experimental work was carried out in Denmark using male Beagle dogs each having a body weight between 12 and 18 kg (initial weight). The studies were conducted as open, nonrandomized crossover studies. The dogs had been previously treated with Primperan inj. 5 mg / ml (antiemetic) and were given an oral dose of 0.5 to 4 mg tacrolimus.

Dogs were fasted for 10 hours before dosing (water ad libitum) and were fed 5 hours after dosing (water ad libitum). Each dog was dosed with the dose

49/58 of tacrolimus without consideration of the weight of the dog.

Blood samples were collected from the external jugular vein at the following time points: Pre-dose, 1, 1.5; 2, 3, 4, 6, 8, 12 and 24 hours after dosing. 4 ml of blood was collected, mixed with EDTA, and the samples were frozen (-80 ° C). Blood samples were analyzed using on-line LC / MS extraction and results are given in ng / ml.

Determined tacrolimus total blood concentration profiles were treated using WinNonlin® softwear pharmacokinetic software (Pharsight, California; USA) to calculate pharmacokinetic parameters. All data were dose adjusted.

The following examples are illustrative of the invention and are not intended to limit the scope of the present invention.

The pharmaceutical compositions and dosage forms of the invention are exemplified in examples 1 to 4 including the results of in vitro dissolution tests. Results of in vivo comparison studies on Beagle dogs (blood plasma concentration) are shown in examples 5 and 6.

EXAMPLE 1

Increased immediate release tablet with bioavailability

Tablet Composition% mg

Tacrolimus

Lactose Mesh 200

PEG 6000

0,50 49, 75 34, 48

1,00

100,00

69,30

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<td>Poloxamer 188</td><td> 14, 78</td><td> 29, 70</td>

<td>Magnesium stearate</td><td> 0,50</td><td> 1, 01</td>

<td>Total</td><td> 100,00</td><td> 201,01</td>

tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (in a 70:30 w / w ratio) at 70 ° C. The solution was sprayed onto 250 g of lactose in a Strea-1 fluid bed. The granular product was sieved through sieve No. 0.7 mm and mixed with magnesium stearate for 0.5 minutes in a Turbula mixer. The mixture was compressed into 8

<td>mm with 1 mg of the active ingredient (tablet compound and cup-shaped.</td><td>in</td><td>200 mg) with</td>

<td>Average disintegration time: 20 minutes. Toughness:</td><td> 45</td><td>N.</td>

<td>EXAMPLE 2</td><td></td><td></td>

<td>PEG-based immediate release tablet</td><td colspan="2">6 0 0 0 / Poloxamer</td>

<td> 188</td><td></td><td></td>

<td>Pill Composition</td><td></td><td></td>

<td>Substance %</td><td></td><td>mg</td>

<td>Tacrolimus 1.98</td><td></td><td> 2,00</td>

<td>Lactose monohydrate 200 mesh 40,50</td><td></td><td> 40, 91</td>

<td>PEG 6000 33.26</td><td></td><td> 33,60</td>

<td>Poloxamer 188, Lutrol 68 14.40</td><td></td><td> 14, 40</td>

<td>Magnesium Stearate 0.50</td><td></td><td> 0,51</td>

<td>Talc 4.50</td><td></td><td> 4,55</td>

<td>Croscarmellose Sodium, Ac-Di-Sol 5.00</td><td></td><td> 5, 05</td>

<td>Total 100.00</td><td></td><td> 101,01</td>

<td>Tacrolimus was dissolved in PEG 6000 at</td><td>an</td><td>temperature</td>

<td>above 80 ° C. Poloxamer 188 has been added</td><td>and the</td><td>solution was</td>

<td colspan="2">heated to a temperature above 80 ° C. Using</td><td>the unit of</td>

<td>Phast FS1.7, the solution was sprayed</td><td colspan="2">about 200 g of</td>

51/58 lactose monohydrate in a Phast FB100 fluid bed. The resulting granulate was passed through a co-grinder, sieve No. 1397, 4500 rpm, and mixed with croscarmellose sodium for 3 minutes in a Turbula mixer.

Magnesium stearate and talc were sieved through sieve No. 300 and mixed in a Turbola mixer for 3 minutes. The granulate was mixed with magnesium stearate: talc (1: 9) for 0.5 minutes in a Turbula mixer.

The resulting mixture was compressed into 6 mm tablets with 2 mg of active ingredient (100 mg tablet) with cup-shaped compound.

Average disintegration time: 7 minutes. Hardness: 65 N

The tablets were subjected to an in vitro dissolution test in the dissolution medium: 900 ml, 0.005% HPC (hydroxypropylcellulose) aqueous medium adjusted to pH = 4.5, USP pallet method; rotation speed: 50 rpm; and the following dissolution profiles were found:

<td>Time (minutes)</td><td>% of release</td><td>% Rsd</td>

<td> 0</td><td> 0</td><td> 0</td>

<td> 5</td><td> 27,2</td><td> 15, 1</td>

<td> 10</td><td> 49, 1</td><td> 10,9</td>

<td> 20</td><td> 80, 7</td><td>CO O</td>

<td> 35</td><td> 98,9</td><td> 5, 4</td>

<td> 42</td><td> 102, 7</td><td> 3,6</td>

<td> 52</td><td> 104, 9</td><td> 2,0</td>

EXAMPLE 3

Enteric coating of Example 2 immediate release tablets

Enteric coating is based on Eudragit L30D-55 acrylic polymer. Eudragit L30D is supplied as an aqueous latex suspension creating a water insoluble film when water evaporates during coating. The polymer is insoluble at pH values ​​below 5.0 and readily soluble at pH values ​​above 6.0. Tablets prepared as described in example 2 were coated with the following coating film composition:

<td>Substance</td><td>% w / w</td>

<td>Eudragit L30D-55</td><td> 40</td>

<td>Water</td><td> 52</td>

<td>Triethyl Citrate</td><td> 1,8</td>

<td>Foam Emulsion</td><td> 0,2</td>

<td>Talc (micro)</td><td> 6</td>

<td>Total</td><td> 100</td>

The amount of polymer film applied (Eudragit) is based on a calculation of mg of polymer film per cm² of the tablet surface. The thickness of the enteric coating was 80 μιη. A check of the applied film thickness is based on a digital micrometer measurement of the increase in tablet height. The film coating process was performed on a Phast FB100 fluid bed equipped with a Wurster insert using an inlet air temperature of 50 ° C, inlet air flow of 100 cbm per hour, product temperature of 38 ° C. C and feed speed of 15 g / min.

The coated tablets were cured in an oven at 30 ° C for 48 hours. Alternatively, the coated tablets may be more effectively cured at 40 ° C for 24 hours.

Enteric coating tablets were subjected to in vitro dissolution tests using two different dissolution media / tests.

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Using the test / dissolution medium: 900 ml of the 0.005% HPC (hydroxypropylcellulose) aqueous medium adjusted to pH = 4.5 (USP pallet method; rotation speed: 50 rpm), the following dissolution profile was found:

<td>Time (hours)</td><td>% of release</td><td>% Rsd</td>

<td> 0</td><td> 0</td><td> 0</td>

<td> 4</td><td>O co</td><td> 32,3</td>

<td> 8</td><td> 0,4</td><td> 61, 1</td>

<td> 15</td><td> 11, 0</td><td> 17,3</td>

<td> 17</td><td> 13,2</td><td> 12, 1</td>

Using dissolution medium / test: USP Method A, Delayed Release Articles (USP Pallet Method; Rotation Speed: 50 rpm), the following dissolution profile was found:

<td>Time (minutes)</td><td>% of release</td><td>% Rsd</td>

<td> 0</td><td> 0</td><td>AT</td>

<td> 120</td><td> 0</td><td>AT</td>

<td> 155</td><td> 84, 8</td><td> 12,8</td>

<td> 165</td><td> 102,9</td><td>AT</td>

<td> 175</td><td> 101, 0</td><td> 3,5</td>

EXAMPLE 4

The following tacrolimus formulation was prepared as described in example 2:

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<td>Substance</td><td>O 0</td><td>mg</td>

<td>Tacrolimus</td><td> 2,09</td><td> 2,10</td>

<td>Lactose monohydrate 200 mesh</td><td> 42, 75</td><td> 42, 95</td>

<td>PEG 6000</td><td> 35, 11</td><td> 35,28</td>

<td>Poloxamer 188, Lutrol 68</td><td> 15, 05</td><td> 15, 12</td>

<td>Magnesium stearate</td><td> 0,50</td><td> 0,50</td>

<td>Baby powder</td><td> 4,50</td><td> 4,52</td>

<td>Total</td><td> 100,00</td><td> 100,48</td>

The mixture was compressed into 6 mm tablets with 2.1 mg of active ingredient (100 mg of tablet with compound in cup form). Average tablet hardness: 41 N.

EXAMPLE 5

In vivo test on dogs of immediate release formulations

The following tacrolimus formulation was prepared as described in example 2:

<td>Substance</td><td>O, 0</td><td>mg</td>

<td>Tacrolimus</td><td> 0, 76</td><td> 0,5</td>

<td>Lactose Mesh 200</td><td> 49, 14</td><td> 32,43</td>

<td>PEG 6000</td><td> 34, 73</td><td> 22,92</td>

<td>Poloxamer 188</td><td> 14, 88</td><td> 9,82</td>

<td>Magnesium stearate</td><td> 0,50</td><td> 0,33</td>

<td>Total</td><td> 100,00</td><td> 66,00</td>

mg granules were weighed into hard gelatin capsules.

<td>A study</td><td>in vivo</td><td>of this formulation</td><td>with 0.5 mg in a</td><td>Beagle dog,</td>

<td>executed</td><td>as the</td><td>above described</td><td>in Methods, in</td><td>regarding</td>

<td>Prograf®,</td><td>4x1</td><td>mg (lot no.⁰: 1</td><td>C56050), gave the</td><td>results</td>

<td>following:</td><td></td><td></td><td></td><td></td>

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Blood concentrations (ng / ml) in dog No F1182 after administration of the formulation:

<td rowspan="2">Time (hours)</td><td colspan="2">Formulation</td>

<td>Prograf (4 mg)</td><td>Dose of the invention adj. at 4mg</td>

<td></td><td></td><td></td>

<td> 0</td><td> 0</td><td> 0,0</td>

<td> 0,5</td><td> 0,5</td><td> 10,5</td>

<td> 1,0</td><td> 5,5</td><td> 44, 1</td>

<td> 1,5</td><td> 4, 1</td><td> 34,3</td>

<td> 2,0</td><td> 4,0</td><td> 21,0</td>

<td> 3,0</td><td> 4,6</td><td> 10,5</td>

<td> 4,0</td><td> 4,0</td><td> 9,1</td>

<td> 6,0</td><td> 2, 7</td><td> 4, 9</td>

<td> 8,0</td><td> 2,0</td><td> 4,2</td>

<td> 12,0</td><td> 2,0</td><td> 3,5</td>

<td> 24, 0</td><td> 0, 7</td><td> 2,1</td>

Relative bioavailability based on AUC (invention / Prograf): 293%.

EXAMPLE 6

In vivo dog testing of immediate release formulations

The following tacrolimus formulation of the invention was prepared as described in example 2:

<td>Substance</td><td>O O</td><td>mg</td>

<td>Tacrolimus</td><td> 1,86</td><td> 0,50</td>

<td>Lactose monohydrate 200 mesh</td><td> 43,56</td><td> 11, 72</td>

<td>PEG 6000</td><td> 31,21</td><td> 8,40</td>

<td>Poloxamer 188, Lutrol 68</td><td> 13,37</td><td> 3,60</td>

<td>Magnesium stearate</td><td> 0,50</td><td> 0,13</td>

56/58

<td>Baby powder</td><td> 4,50</td><td> 1,21</td>

<td>Croscarmellose Sodium, Ac-Di-Sol</td><td> 5, 00</td><td> 1,35</td>

<td>Total</td><td> 100,00</td><td> 26,92</td>

This was compressed into 4 mm tablets with 0.5 mg active ingredient (27 mg tablet with cup-shaped compound).

An in vivo study of this 0.5 mg formulation in a Beagle dog, performed as described above in Methods, for Prograf® 0.5 mg capsules (lot #: OC512OD), gave the following results: blood (ng / ml) in dog # 1 after administration of the formulation:

<td>Time</td><td colspan="2">Formulation</td>

<td>(hours)</td><td>Prograf (0.5 mg)</td><td>Formulation B (0.5 mg)</td>

<td></td><td></td><td></td>

<td> 0</td><td> 0</td><td> 0,0</td>

<td> 0,5</td><td> 0,95</td><td> 0,04</td>

<td>I—¹O</td><td> 0,84</td><td> 1,56</td>

<td> 1,5</td><td> 0,55</td><td> 4,68</td>

<td> 2,0</td><td> 0,40</td><td> 9, 11</td>

<td> 3,0</td><td> 0,26</td><td> 2,82</td>

<td> 4,0</td><td> 0,18</td><td> 2,46</td>

<td> 6,0</td><td> 0,18</td><td> 1, 10</td>

<td> 8,0</td><td> 0, 14</td><td> 1,25</td>

<td> 12,0</td><td> 0, 11</td><td> 0, 74</td>

<td> 24, 0</td><td> 0,06</td><td> 0,40</td>

<td> 25, 00</td><td> 0,06</td><td> 0, 44</td>

Lisbon, October 7, 2010

Relative bioavailability based on AUC (invention vs.

Prograf): 742%.