Modified release compositions comprising tacrolimus

DESCRIPTION

SOLID DISPERSIONS UNDERSTANDING TACROLIMUS

The present invention relates to a pharmaceutical composition and / or unit oral dosage form comprising tacrolimus with modified release profiles when subjected to a conventional dissolution method which we think reflects the index and release time of the active ingredient in vivo. The new composition effectively reduces or even prevents the effects of CYP3A4 metabolism.

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

<img file="PT1663216E_D0001.tif" />

which corresponds to C44H69NO12. 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.

1/78

The preparation of tacrolimus is described in European Patent Application EP-A-0 184 162 and tacrolimus analogs are for example 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 wall and liver. Therefore, the medicines that

2/78 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.

Usually absorbed absorption is food.

tacrolimus tacrolimus is administered orally and therefore through the gastrointestinal tract. It was observed that negatively influenced by simultaneous ingestion

Thus, the rate and extent of absorption were higher under fasting conditions.

from of

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.

3/78

Absorption of tacrolimus into the gastrointestinal tract following oral administration is rapid with a mean time-to-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.

Most often 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 neurotoxicity have also been 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.

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

4/78 can be significantly reduced. In addition, increased bioavailability may also result in a more reproducible release profile (ie less variable compared to Prograf®).

International Patent Application WO 01/37808 A describes a formulation obtainable by spraying a solution of tacrolimus, PEG-24 cholesterol ether (Solulan C-24), monoglycerides and deoxycholic acid in organic solvent on non pareil seeds, and also refers to increased oral bioavailability.

EP-A-1064942 describes sustained release formulations obtainable by dissolving tacrolimus in fused glycerol monesterate or tetraglycerine triglyceride ester and mixing them with HPMC or lactose.

International Patent Application WO 03/004001 A describes a controlled agglomeration method for improving the bioavailability of poorly water soluble compounds in solid solutions or dispersions.

Honbo et al: The oral dosage form of FK-506 in Transplantion Proceedings, 1987, vol. 19, no. 5 suppl. 6, pp. 17-22 describes capsules comprising a solid dispersion of tacrolimus in HPMC prepared by a solvent method.

The inventors have found that tacrolimus bioavailability can be significantly increased when tacrolimus is administered to a mammal in a controlled release or modified composition providing a rate and time of release of the active ingredient, i.e., an in vivo release profile, which effectively reduces or even prevents the effects of CYP3A4 metabolism.

5/78

We believe that conventional in vitro dissolution methods correlate with or at least reflect the actual modified release profile in vivo in man. Accordingly, the present invention provides, in its first aspect, a solid pharmaceutical composition comprising tacrolimus, wherein at least 20% w / w tacrolimus is released within 0.5 hours when subjected to an in vitro dissolution test. using the USP paddle method and using 0.9 N HCl as dissolution medium, and less than 50% w / w tacrolimus is released within 8 hours when subjected to an in vitro dissolution test using the USP paddle method and pH 4.5 adjusted aqueous dissolution medium with 0.005% hydroxypropylcellulose.

This modified release profile is obtained by providing a pharmaceutical composition comprising a solid dispersion or solid solution of tacrolimus in a hydrophilic or water-miscible carrier and one or more modified release agents selected from the group consisting of water-miscible polymers, water-insoluble polymers. water, oils and oleaginous materials, and the carrier comprises polyethylene glycol and a poloxamer in a ratio of 1: 3 to 10: 1.

In another aspect, the invention relates to solid dosage forms, especially oral dosage forms, comprising the composition of the invention, the solid dosage forms exhibiting a modified release profile. Delayed release of tacrolimus in the distal part of the duodenum may reduce drug-related gastrointestinal side effects and the relatively high degree of metabolism in the proximal part of the gastrointestinal tract (CYP3A4 mediated metabolism). This can be done without losing systemic bioavailability due to the unique compositions of the invention, preferably compositions comprising the active substance fully or partially dissolved in a carrier to form a solid dispersion and / or a solid solution at room temperature.

6/78

In yet another aspect, the invention relates to the use of the present pharmaceutical composition in the preparation of medicaments, especially in the preparation of useful solid dosage forms.

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 function. from 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 context of the present invention, the term hydrophilic describes that something either water, i.e. a hydrophilic molecule or part of a molecule is one that is typically electrically polarized and capable of forming hydrogen bonds with the water molecules, allowing them to separate. 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).

In the context of the present invention, the term hydrophobic refers to a compound that tends to be electrically neutral and nonpolar, and

Thus preferring other neutral and non-polar solvents or molecular environments.

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.

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 becomes available in the target tissue upon administration. As used

In this document, the term bioequivalence indicates a scientific basis on which generic and branded drugs are compared with each other. For example, medicines are bioequivalent if 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, AUC₀-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. In addition, in the context of the present invention, two compositions are considered bioequivalent if the value of the parameter used is within 80-125% of Prograf® or a similar product containing commercially available tacrolimus used in the test.

In the context of the present invention_max indicates the time to reach the maximum plasma concentration (C_max) after administration; AUC-_Thenf infinite 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.

In the context of the present invention, the terms controlled release and modified release are equivalent terms that cover any type of tacrolimus release of a composition of the invention that is appropriate to achieve a specific prophylactic or therapeutic response after administration to a subject. . A skilled technician knows how to

Controlled release / modified release differs from the release of single tablets or capsules. The terms controlled release or modified release have the same meaning as set forth above. The terms include slow release (which results in a C_max lower et_max late but t₂/₂ unalterable), extended release (which results in a lower coax, a t_max late but apparently t₂/₂ is longer); delayed release (which results in a C_max invariable but the lapse time and hence t_max it's late, et₂/₂ invariable) as well as pulsatile release, immediate release, sustained release, prolonged release, chromo-optimized release, rapid release (for improved appearance of action), etc. Included in the terms is also for example the use of specific conditions in the body for example different enzymes or changes in pH to control the release of the drug substance.

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

one for respond modified compositions

The present invention provides pharmaceutical compositions and solid dosage forms for the improved treatment of conditions which to the treatment of tacrolimus, especially those and dosage forms which provide for the release of the active ingredient to improve bioavailability, the active ingredient in the compositions of the present invention. tacrolimus (aka FK-506 or FR-900506). However, within the scope of the present invention is tacrolimus in any physical form (crystals, amorphous powder, any possible polymorph, any possible solvate including hydrate, anhydrate, and complexes thereof etc.). Also included are any active tacrolimus derivative or metabolite, salts, solvates, complexes and prodrugs thereof

10/78 accepted in the Pharmaceutical Industry.

Thus, in a preferred embodiment, the present invention provides a solid pharmaceutical composition comprising tacrolimus, where less than 20% w / w of the active ingredient is released within 0.5 hours when subjected to an in vitro dissolution test using a USP paddle method and using 0.1 N HCl as dissolution medium, preferably where less than 20% w / w; more preferably less than 10% w / w of the active ingredient is released within 3 hours.

We believe that such a release profile significantly increases the bioavailability of tacrolimus in mammals, provided that all or most of the active ingredient is actually released into the gastrointestinal tract, so that CYP3A4 metabolism is substantially impaired or at least significantly reduced. . It is also contemplated that this effect correlates with, or at least is reflected in, the in vitro dissolution profile of the solid pharmaceutical composition and / or dosage forms of the invention, this profile is readily encountered when the composition and / or dosage form is subjected to a conventional in vitro dissolution method according to for example USP. We believe that any USP in vitro dissolution method is useful for the purpose of the present invention.

For example, the solid pharmaceutical composition of the invention releases at least 50% w / w of the active ingredient within 4 hours, preferably within 2.5 hours, when subjected to an in vitro dissolution test using a USP paddle method and using 0%. 0.1 N HCl as dissolution medium for the first 2 hours and then using a dissolution medium with a pH of 6.8.

Using a less conventional dissolution medium, the composition of the invention releases less than 50% w / w, especially less than 50% w / w.

40% w / w active ingredient in 8 hours, preferably in 15 hours

11/78 hours when subjected to an in vitro dissolution test using a USP paddle method and an aqueous dissolution medium adjusted to pH 4.5 with 0.005% hydroxypropylcellulose.

The desired modified release profile of the pharmaceutical composition may be provided using a pharmaceutical composition comprising a solid dispersion or solid solution of the active ingredient, ie tacrolimus or an analog thereof, in a hydrophilic or water miscible carrier and one or more agents. modified release

In one embodiment, a modified release pharmaceutical composition containing tacrolimus with the active ingredient dissolved or dispersed in a hydrophilic or water miscible carrier comprising polyethylene glycol mixed with a poloxamer is provided. A specific example of a useful mixture is a mixture of 70% w / w polyethylene glycol 6000 (PEG6000) and 30% w / w poloxamer 188.

The composition of the invention may after oral administration to a mammal in need thereof exhibit an AUC / AUC value._Prograf® of at least approximately 1.3, the AUC values ​​being determined under similar conditions.

As shown in the examples, the bioavailability obtained here after administration of a composition according to the invention is markedly improved. Thus, the value of AUC / AUCPrograf® is at least

<td colspan="3">less than approximately</td><td>1.5 at</td>

<td colspan="2">more approximately</td><td> 1,8</td><td>or ma</td>

<td>about</td><td> 2, 0</td><td>or</td><td>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>

yes as approximately 1.7 5 or Ls, approximately 1.9 or more,

<td>about</td><td> 2,5</td><td>or</td><td>more,</td>

<td>about</td><td> 3, 0</td><td>or</td><td>more,</td>

<td>about</td><td> 3,5</td><td>or</td><td>more,</td>

<td>about</td><td> 4,0</td><td>or</td><td>more,</td>

<td>about</td><td> 4,5</td><td>or</td><td>more,</td>

Approximately 4.75 or more or approximately 5.0 or more, with AUC values ​​determined under similar conditions.

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 period of time in which the plasma concentration is maintained in the therapeutic window (i.e. plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed.

The composition of the invention may release, upon oral administration to a mammal in need thereof, the controlled release of tacrolimus and exhibit a C_max which is when about 80% C_max for Prograf® tablets such as, for example, when very approximately 75%, when very approximately 70%, when very approximately 65%, when very approximately 60%, when very approximately 55%, when very approximately 50%, when very approximately 45% or at most about 40%.

In the context of the present invention, the terms controlled release and modified release are intended to be equivalent terms covering any type of tacrolimus release of a composition of the invention that is appropriate to elicit a specific prophylactic or therapeutic response following administration to a subject. One of ordinary skill in the art knows how controlled / modified release differs from single tablet or capsule release. The terms controlled release or modified release have the same meaning as set forth above.

The terms controlled release / modified release include slow release (which results in a C_max lower et_max delayed, but t / 2 is invariable, extended release (which results in a C_max

13/78 lower, t_max late, but apparently you /₂ longer), delayed release (which results in a C_max invariable but the reaction time and hence the_max is late, and you /₂ it is invariable) as well as pulsatile release, immediate release, sustained release, prolonged release, optimized chrono release, rapid release (for improved appearance of action) etc. Included in the terms is also for example the use of specific body conditions for example different enzymes or pH changes to control the release of the pharmaceutical substance.

To be more specific, upon oral administration to a mammal, including a human, of a pharmaceutical composition according to the present invention containing a 5 mg dose of tacrolimus, tacrolimus is released in a controlled manner and will exhibit a C_max which is at most about 30 ng / ml such as, for example, when at about 25 ng / ml or at most about 20 ng / ml.

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. Accordingly, the present invention also relates to a pharmaceutical composition, where W₅₀ is at least about 2 hours, such as for example at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.

<td>In addition or</td><td>on the other hand,</td><td>an</td><td>composition</td><td>according</td><td>with the</td>

<td>invention has a</td><td>Cdiff = [C_max - ct</td><td>(t = 12</td><td>hours)]</td><td>which is smaller</td><td>than</td>

14/78 ° of Prograf® under the same conditions. If Cdiff for Prograf® is set at 100, then Cdiff of a composition according to the invention is usually 90 or less such as, for example, approximately 85 or less, approximately 80 or less, approximately 75 or less, approximately 70 or less. approximately 65 or less, approximately 60 or less, approximately 55 or less, approximately 50 or less, approximately 45 or less, or approximately 40 or less.

More specifically, upon oral administration to a mammal, including a human, of a pharmaceutical composition of the invention with tacrolimus 5 mg, tacrolimus is released in a controlled manner and exhibits a Cdiff of approximately 20 ng / ml or less such as, e.g. for example, approximately 15 ng / ml or less, approximately 13 ng / ml or less or approximately 10 ng / ml or less.

A pharmaceutical composition according to the invention releases tacrolimus in a controlled manner to extend the therapeutic action of tacrolimus. In one aspect the release may be pH dependent, that is, the release predominantly occurs after passing through the stomach. This pH dependent release is mainly provided by the enteric coating material as described herein. The release may also be pH independent, for example by providing the composition with a controlled release coating, such as, for example, a cellulose-based coating such as ethyl cellulose, or by providing the composition as a matrix composition. such as, for example, a hydrophilic cellulose polymer matrix type for example based on HPMC. Of course a combination may also be employed.

In general, the change in bioavailability and / or changes in other related bioavailability parameters are usually determined by in vivo studies in a suitable animal model that may

15/78 test the compositions in question together Prograf® or a similar product available contains tacrolimus. The use of a model shows evidence of the bioavailability of certain general practice in the pharmaceutical industry.

with for example commercially that to establish the formulations is a

Studies relevant to tacrolimus are nonrandomized, crossover studies where each dog is its own control. Usually four dogs, and four treatments are applied. As no iv injections are given, the bioavailability obtained is relative.

Furthermore, it has surprisingly been found that the need for simultaneous food intake to ensure sufficient absorption of tacrolimus is significantly reduced or even completely abolished.

Thus, the pharmaceutical compositions according to the invention provide significantly higher bioavailability of tacrolimus, which may reduce the number of daily dose units administered, and reduce or abolish the need for administration along with food intake, which provides a higher degree of freedom for the recipient of the pharmaceutical compositions, and consequently patient acceptance and / or adaptability is significantly improved. In addition, the compositions provide a significant reduction in side effects, especially side effects related to high peak concentration (such as, for example, nephro and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc.) and provide an extended release of tacrolimus leading to better therapy.

As mentioned above, one of the biggest challenges regarding the formulation of tacrolimus compositions is to avoid an adverse effect of the food. Tacrolimus is generally much better absorbed when taken orally without food. A large variation in bioavailability is therefore observed after

16/78 administration with or without food. This dependence makes it difficult to give precise guidelines as to how large a dose should be administered and, furthermore, requires the patient to be informed about the dosage regimen. The present invention is intended to provide compositions in which the adverse effect of food is reduced. Thus, the present invention provides a composition which does not exhibit a significant adverse effect on food after administration of the composition to a mammal in need thereof as evidenced with a (AUCf) value._andd / AUCf_astand d) of at least approximately 0.85 with a lower 90% confidence limit of at least 0.75.

More specifically, a pharmaceutical composition according to the invention has a value of (AUCf_andd / AUCf_astand d) from 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, about about 1.1 or up to about 1.2.

Another advantage of a composition of the present invention is the ability to obtain an effective therapeutic response with a decreased dosage compared to traditional oral treatment. Accordingly, upon oral administration to a mammal in need thereof a pharmaceutical composition according to the invention releases tacrolimus or an analog thereof in a controlled manner and the composition is essentially bioequivalent to Prograf® or a similar commercially available tacrolimus product when administered in a dose which is approximately at very approximately 85% w / w such as, for example, when at approximately 80% w / w, at about 75%, at about 70% w / w, at about 65% w / w, at about 60% w / w, at about 55% w / w or at about 50% w / w of the dose of tacrolimus administered as Program® or a similar commercially available product containing tacrolimus.

17/78

The parameters often 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 should be applied when determining whether bioequivalence is present. Furthermore, in the context of the present invention, two compositions are considered bioequivalent if the value of the parameter used is within 80-125% of Prograf® or a similar commercially available product containing tacrolimus used in the test. In the context of the present invention_max indicates the time to reach the maximum plasma concentration (C_max) after administration; AUCo-range indicates the area under the plasma concentration curve versus time curve 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).

Two other major disadvantages associated with tacrolimus treatment or prophylaxis are the relatively high incidence of side effects and a relatively high interindividual variation. It is anticipated that a composition according to the invention will lead to a reduction in side effects. The reduction may be in terms of reduced frequency or in severity. Side effects include for example nephro and neurotoxicity, diarrhea, constipation, abdominal pain, nausea etc. In one aspect, the invention relates to a pharmaceutical composition in particulate form comprising tacrolimus or an analog thereof together with one or more pharmaceutically acceptable excipients, wherein the composition after oral administration to a mammal in need thereof releases tacrolimus or a controlled analogue and reduces side effects compared to those of Prograf® administered

18/78 under the same conditions and at a dose providing an equivalent therapeutic effect.

By increasing bioavailability, the Area Under the Curve will generally reduce the intra and inter variability related to 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 the area under the curve 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 modified, controlled and delayed release compositions.

Tacrolimus is extensively metabolised by the isoenzyme CYP3A4 in the intestinal wall and liver. Accordingly, a suitable controlled release composition may be a composition that is designed to release tacrolimus in a delayed manner to prevent or reduce CYP3A4 metabolism in the gastrointestinal tract.

Delayed release is mainly caused by some type of enteric coating. Although the semipermeable coating

Shows some kind of delayed release, it may not sufficiently slow the release 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 slight increment in the pH value, 1/10, the film changes properties and becomes permeable. Examples of pH sensitive polymers, which are relatively insoluble and impermeable 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 acidic phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, methylcellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate phthalate, sodium cellulose acetate phthalate, stearyl amide copolymer phthalate maleic acid phthalate; styrene polyvinyl acetate phthalate maleic acid copolymer; styrene and maleic acid copolymers; polyacrylic acid derivatives, such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and its esters, methacrylic polyacrylic acid copolymers, gum shell, and vinyl acetate and crotonic acid copolymers.

Preferred pH sensitive polymers include shellac;

phthalate derivatives, particularly cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate;

polyvinyl, and phthalate of polyacrylic acid derivatives, particularly polymethyl methacrylate mixed with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.

20/78

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.

Following oral administration to a mammal in need thereof, including a human, a controlled release pharmaceutical composition according to the present invention releases tacrolimus such that a plasma concentration of at least 5 ng / ml such as for example is obtained. at least about 7.5 ng / ml or at least about 10 ng / ml over a time period of at least about 24 hours. In a specific aspect of the invention the difference between the peak plasma concentration and the plasma concentration measured 24 hours after administration is at most approximately 20 ng / ml such as, for example, when at approximately 10 ng / ml, when very approximately 7.5 ng / ml or at most approximately 5 ng / ml.

The composition of the invention is designed to have a modified release of tacrolimus and may in particulate form comprise tacrolimus together with one or more pharmaceutically acceptable excipients, after oral administration to a mammal in need thereof, have a delayed release of tacrolimus and / or an analog thereof, so that at most 10% w / w such as, for example, at most approximately 7.5% w / w or at most about 5% w / w of the total amount of tacrolimus or an analog thereof is released within the first two hours such as, for example, the first hour after administration.

The following conditions are met for in vitro dissolution tests performed under acidic conditions:

(i) when much of approximately 30% w / w such as for example

21/78 when very approximately 25% w / w, when very approximately 20% w / w, when very approximately 15% w / w or when very approximately 10% w / w tacrolimus is released within 2 hours in an in vitro dissolution test employing a dissolution medium having a pH of at least about 5 such as for example when much from about 4,5, when much from about 4, when much from about 3,5, when much from about 3 , when much of about 2 or when much of about 1,5;

(ii) when much from approximately 10% w / w such as for example when much from approximately 7.5% w / w, when much from approximately 5% w / w or when much from approximately 2.5% w / w

<td>of tacrolimus</td><td>is released within</td><td>in</td><td> 2</td><td>hours on</td><td colspan="2">test</td><td>in</td>

<td>dissolution in</td><td>using a</td><td>kinda</td><td>in</td><td>dissolution</td><td>with</td><td>one</td><td>pH</td>

<td>at most</td><td>of approximately 5</td><td>such</td><td colspan="3">such as</td><td colspan="2">When</td>

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 with 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 of approximately 40% w / w such as for example when much of approximately 30% w / w when much of

Approximately 25% w / w or when much of approximately 20% w / w 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, Such as for example at most, from about 4.0, at most, from about 3.5, when from about 3, when from about 2 or when from 1.5.

such calcineurin organs

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 that are indicated for use in connection with transplantation such as steroids, and / or specific antiproliferative agents include prednisone, prednisolone, methylprednisone. , cyclosporine, mycophenolate, azathioprine, sirolimus, everolimus, mycophenolate sodium, and FTY720 (Novartis).

inhibitors of the examples

The pharmaceutical compositions may be prepared by any convenient method such as, for example, granulating, mixing, spray drying, etc. A particularly useful method is the method described in International Patent Application WO 03/004001. A process for the preparation of particulate material by a controlled agglomeration method, that is, a method that allows controlled growth of particle size, is described herein. The method involves spraying a first composition comprising for example tacrolimus and a carrier which has been melted into a second solid carrier medium. Typically, the fusible carrier has a melting point of at least 5 ° C but less than the tacrolimus melting point. The melting point of the carrier may be in the range from 10 ° C to 150 ° C, such as, for example, in the range from 30 ° C to 100 ° C or in the range from 40 ° C to 50 ° C. is most preferred.

23/78

It is among the skill of the average practitioner to select a suitable carrier that is accepted in the pharmaceutical industry, capable of dissolving or at least partially dissolving tacrolimus and having a melting point at the desired margin using general knowledge and routine experimentation. Suitable carrier candidates are described in International Patent Application WO 03/004001, which is incorporated herein by reference.

Suitable carriers in the present context are those mentioned for example as an oil or an oleaginous material (as discussed later herein) as well as those described in International Patent Application WO 03/004001.

An advantage of using the controlled agglomeration method described in International Patent Application WO 03/004001 is that it is possible to apply a relatively large amount of a melt to a particulate material without having an undesirable particle size growth. Accordingly, the particulate material of a pharmaceutical composition of the invention has a weight average diameter

<td colspan="2">geometric d_gw from% 10</td><td>pm such</td><td>such as,</td><td> &gt; 20</td><td>μιη,</td><td>in between</td>

<td>about</td><td> 20</td><td>up until</td><td>about</td><td> 2000,</td><td>in</td><td>in between</td>

<td>about</td><td> 30</td><td>up until</td><td>about</td><td> 2000,</td><td>in</td><td>in between</td>

<td>about</td><td> 50</td><td>up until</td><td>about</td><td> 2000,</td><td>in</td><td>in between</td>

<td>about</td><td> 60</td><td>up until</td><td>about</td><td> 2000,</td><td>in</td><td>in between</td>

<td>about 75</td><td>up until</td><td colspan="2">approximately 2000 such</td><td>how,</td><td>per</td><td>example,</td>

from about 100 to about 1500 pm, from about 100 to about 1000 pm or from about 100 to about 700 pm, or at most from about 400 pm or at most 300 pm such as, for example, from about 50 up to approximately 400 μιη

<td>such as</td><td colspan="2">example,</td><td>in</td><td>in between</td><td>about</td><td> 50</td><td>up until</td>

<td>about</td><td> 350</td><td>μιη,</td><td>in</td><td>in between</td><td>about</td><td> 50</td><td>up until</td>

<td>about</td><td> 300</td><td>μιη,</td><td>in</td><td>in between</td><td>about</td><td> 50</td><td>up until</td>

<td>about</td><td> 250</td><td>pm or</td><td>in</td><td>in between</td><td>about</td><td> 100</td><td>up until</td>

24/78 approximately 300 μιη when prepared using the controlled agglomeration method.

The particulate material obtained by the above-mentioned method has properties suitable for flowability and / or compressibility and is therefore suitable also for treatment in pharmaceutical dosage forms.

Solid dispersion and / or tacrolimus solid solution

The solid dispersion or solid solution used in a preferred embodiment of the invention comprises tacrolimus dispersed or dissolved in a hydrophilic or water miscible carrier with a melting point (freezing point or pour point) of at least 20 ° C in a concentration of between approximately 0.01% w / w and approximately 15% w / w, and whose dispersion forms a solid dispersion or solid solution at medium temperature (room temperature).

The concentration of the active ingredient in the hydrophilic or water-miscible carrier is at most 15% w / w, preferably when very 10% w / w, preferably when very 8% w / w, more preferably when very 6% w / w when even more preferably 5% w / w, when very 4% w / w, especially when very 3% w / w, in particular when very 2% w / w, and / or is at least approximately 0.05% w / w w, preferably at least approximately 0.1% w / w, more preferably at least about 0.5% w / w, especially at least about 0.7% w / w, in particular at least about 1% w / w.

Physically the combination of active ingredient and carrier may form a solid dispersion, that is, the active ingredient is dispersed in the carrier in particulate form, or may form a solid solution, that is, the active ingredient is dissolved in the carrier at a molecular level. The active ingredient and carrier may also form a solid dispersion having a portion of the

Active ingredient dissolved at a molecular level. The physical state of the dispersion and / or solution may be determined using various techniques such as hot plate microscopy (HSM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) optionally in combination with X-ray energy dispersion. (EDX), and X-ray powder diffraction. In a preferred embodiment, the active ingredient is completely dissolved in the vehicle to form a solid solution at room temperature.

Examples of hydrophilic or water miscible carriers useful for use in accordance with this invention are selected from the group consisting of polyethylene glycols, poloxamers, and mixtures thereof.

In a preferred embodiment, 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 ratio (on a weight / weight basis) of from 1: 3 to 10: 1, preferably from 1: 1 to 5: 1, more preferably from 3: 2 to 4: 1, especially from 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 the 7: 3 ratio.

For polyethylene glycols (PEG), the melting point (freezing point or pour point) increases as the average molecular weight increases. For example, PEG 400 is in the range of 4-8 ° C, PEG 600 is in the range of 20-25 ° C, PEG1500 is in the range of 44-48 ° C, PEG2000 is approximately 52 ° C, PEG 4000 is approximately 59 ° C, PEG 6000 is approximately 65 ° C and PEG 8000 is approximately 61 ° C.

26/78

Useful poloxamers (also called polyoxypropylene-polyoxyethylene block copolymers) are for example 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®. Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of approximately 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 from the series

Tetronic® 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 one of approximately such as, for example, approximately 600 to approximately 40,000. The viscosities given above are determined at 60 ° C for substances which are slurries at room temperature and at 77 ° C for substances which are solid at room temperature.

viscosity (Brookfield) approximately 45,000 cps,

500 even from between

In a preferred embodiment of the present invention, the poloxamer is poloxamer 188, which has an average molecular weight of approximately 8400 and a melting point of approximately 50-54 ° C.

Excipients accepted in the Pharmaceutical Industry

Examples of excipients suitable for use in a solid composition or dosage form according to the present invention include fillers, diluents, disintegrants, binders, lubricants and the like and mixtures thereof. As the composition or

The solid dosage form according to the invention may be used for different purposes, the choice of excipients is generally made having regard to these 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 and others.

Examples of suitable fillers, diluents and / or binders include lactose (e.g. spray dried lactose, α-lactose, βlactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), microcrystalline cellulose (various grades). from Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low substitution), hydroxypropylmethylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH Shin-Etsu, Ltd, such as, for example, Methocel E degrees 4,000 cps and Metolose 60 SH, Methocel F degrees 4,000 cps and Metolose 65 SH, Methocel K grades 4,000, 15,000 and 100,000 cps: and Metallose 90 SH grades 4,000, 15,000, 39,000 and 100,000), 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), basic calcium, hydrogen phosphate calcium sulphate calcium phosphate, (eg calcium phosphate, hydrated dicalcium phosphate), calcium carbonate, sodium alginate, collagen etc,

Specific examples of diluents are for example calcium carbonate, bibasic calcium phosphate,

Tribasic, calcium sulphate, microcrystalline cellulose, cellulose powder, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar, etc.

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

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

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 that may be included in a solid composition or dosage form of the invention are for example flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, moisture adjusters, surfactants, suspending agents, absorption enhancers, release modifying agents etc.

29/78

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, formaldehyde sulfoxylate sodium, 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 0.1% w / w to about 5% w / w.

A solid composition or dosage form according to the invention may also include one or more surfactants or substances with 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.

Suitable excipients for use in a composition or solid dosage form according to the invention are surfactants such as, for example, amphiphilic surfactants as set forth in International Patent Application WO 00/50007, whose holder is Lipocine, Inc Examples of suitable surfactants are

(i) polyethoxylated fatty acids such as, for example, polyethylene glycol mono- or diesters of fatty acid or mixtures thereof such as, for example, polyethylene glycol mono- or diesters with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid; and the 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 25, 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,

30/78

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, i.e. esters as mentioned above but in the form of glycerin esters of the individual fatty acids;

polyethylene glycol, PEG or, vegetable oils such as almond oil, apricot kernel oil, hydrogenated oil and the like;

iii) glycerol, polypropylene glycol, sorbitol esters such as hydrogenated castor oil, palm, castor oil, castor oil, olive oil, peanut oil, palm oil iv) polyglycerine fatty acids such as polyglycerol stearate; polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate;

v) polypropylene glycol fatty acid esters such as, for example, propylene glycol monolaurate, propylene glycol ricinoleate and others;

vi) mono- and diglycerides such as glycerine monooleate, glycerine dioleate, glycerine mono and / or dioleate, glycerine caprylate, glycerine caprate, etc .;

vii) sterol and sterol derivatives;

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

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

31/78

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

xi) polyethylene glycol alkylphenols such as for example the Triton® X or N series;

(xii) polyoxyethylene-polyoxypropylene block copolymers, such as, for example, the Pluronic® series, Synperonic®, Emkalyx®, Lutrol®, Supronic® series, etc. The generic term for these polymers is poloxamers and relevant examples in the context of the present invention are poloxamers 105, 108, 122, 123, 124, 181,

182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407;

xiii) sorbitan fatty acid esters such as Span® series or Ariacel® series such as for example sorbinane 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,

<td colspan="2">for example</td><td>salts</td><td>of acid</td><td>fat salts</td><td>gallstones,</td><td>phospholipids,</td>

<td>esters</td><td>in</td><td>acid</td><td>phosphoric,</td><td>carboxylates</td><td>sulfates</td><td>and sulfonates</td>

<td>etc.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>When</td><td>one</td><td>agent</td><td colspan="3">surfactant or a mixture</td><td>of agents</td>

<td colspan="3">surfactants is present in a</td><td colspan="2">composition or</td><td>in</td><td colspan="2">l form of</td>

<td>solid dosage</td><td>gives</td><td>invention,</td><td colspan="2">concentration</td><td>of (</td><td colspan="2">Agent (s)</td>

<td>surfactant (s)</td><td>it is</td><td>normally</td><td>in</td><td colspan="2">margin</td><td>in</td><td>in between</td>

<td>about</td><td> 0,1 -</td><td>80% w / w such</td><td>how,</td><td colspan="2">for example</td><td>, in</td><td>in between</td>

<td>about</td><td> 0, 1</td><td colspan="2">until about</td><td> 20%</td><td>w / w,</td><td>in</td><td>in between</td>

<td>about</td><td> 0, 1</td><td colspan="2">until about</td><td> 15%</td><td>w / w,</td><td>in</td><td>in between</td>

32/78

<td>about</td><td> 0,</td><td>5 up to about 10%</td><td>w / w,</td><td>or</td>

<td>alternatively,</td><td></td><td>from about 0</td><td> ,10</td><td>up until</td>

<td>about</td><td> 80%</td><td>w / w such as for example</td><td>in</td><td>in between</td>

<td>about</td><td> 10</td><td>up to approximately 70% w / w,</td><td>in</td><td>in between</td>

<td>about</td><td> 20</td><td>up to approximately 60% w / w or</td><td>in</td><td>in between</td>

about 30 to about 50% w / w.

One of one or more pharmaceutically acceptable excipients may be selected from the group consisting of silica acid or a derivative or salt thereof; including silicates, silicon dioxide and their polymers; magnesium aluminosilicate and / or magnesium aluminosilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite.

These materials are specifically useful as sorption materials for oils or oleaginous type materials in medicaments, cosmetics and / or edibles. In a specific embodiment, the material is used as a sorption material for oils or oleaginous materials in medicaments. Material that has the ability to function as a sorption material for oils or oilseed materials is also called an oil sorption material. Furthermore, in the context of the present invention the term sorption is used to mean absorption as well as adsorption. It will be understood that whenever one of the terms is used in the present invention, it is intended to cover the absorption as well as the adsorption phenomenon.

Notably, the pharmaceutically acceptable excipient may comprise a silica acid or a derivative thereof 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.

33/78

The solid composition or dosage form according to the invention may comprise a pharmaceutically acceptable excipient which is a silicon dioxide product having properties corresponding to Aeroperl® 300 (marketed by Degussa,

Frankfurt, Germany).

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 food 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 oil-like 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 oil-like materials using an oil sorption material according to the invention. In 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 while solubility in water has no suitable properties (eg, low solubility in water). ), stability in aqueous medium (ie degradation occurs in aqueous medium), 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, 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 absorbing material for use in processing in solid compositions usually absorbs approximately 5% w / w or more, such as, for example, approximately 10% w / w or more, approximately 15% w / w or more, approximately 20% w / w or more, approximately 25% w / w or more,

34/78

<td>about</td><td> 30%</td><td>p / p</td><td>or</td><td>more</td><td>, about</td><td> 35%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 40%</td><td>p / p</td><td>or</td><td>more</td><td>, about</td><td> 45%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 50</td><td>p / p</td><td>or</td><td>more,</td><td>about</td><td> 55%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 60%</td><td>p / p</td><td>or</td><td>more</td><td>, about</td><td> 65%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 70%</td><td>p / p</td><td>or</td><td>more</td><td>, about</td><td> 75%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 80%</td><td>p / p</td><td>or</td><td>more</td><td>, about</td><td> 85%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 90%</td><td>p / p</td><td>or</td><td>more</td><td colspan="2">or about 95^:</td><td>% w / w</td><td colspan="2">&gt; or more</td>

<td>of an oil or</td><td>in</td><td colspan="3">a material</td><td colspan="2">oilseed and it's still</td><td>one</td><td colspan="2">material</td>

solid.

Another aspect of the invention relates to solid dosage forms or compositions comprising an oil or an oleaginous material.

In the present context the term oils and oleaginous materials is used in a very broad sense including oils, waxes, semi-solid materials and materials that are commonly used as solvents (such as organic solvents) or co-solvents in the Pharmaceutical Industry, and the term also includes prophylactic and / or therapeutically active substances which are in liquid form at room temperature, the term further includes emulsions such as microemulsions and nanoemulsions and suspensions. Oils and oilseed materials which can normally be absorbed will be liquid at room or elevated temperature (for practical reasons the maximum temperature is approximately 250 ° C). They may be hydrophilic, lipophilic, hydrophobic, and / or amphiphilic materials.

Oil-like oils and materials which are suitable for use in the present context are substances or materials, which have a melting point of at least about 0 ° C and at most about 250 ° C.

In specific embodiments, the oil or oleaginous material has a melting point of approximately 5 ° C or more, such as, for example, approximately 10 ° C or more,

Approximately 15 ° C or higher, approximately 20 ° C or higher or approximately 25 ° C or higher.

In other embodiments, the oil or oleaginous material has a melting point of at least about 25 ° C such as, for example, at least about 30 ° C, at least about 35 ° C, or at least about 40 ° C. ° C. As a practical matter, the melting point may not normally be too high, so the oil or oleaginous type material usually has a melting point of at most about 300 ° C such as, for example, when at about 250 ° C, at about 200 ° C, at about 150 ° C or at about 100 ° C. If the melting point is higher than a relatively high temperature it may promote for example oxidation or other degradation of an active substance in those cases where for example the therapeutically and / or prophylactically active substance is included.

In the present context, the melting point is determined by DSC (differential scanning calorimetry). The melting point is determined as the temperature at which the linear increase of the DSC curve intersects the temperature axis.

Interesting oleaginous oils or materials are generally substances which are used in the manufacture of medicaments such as so-called melt binders or solid solvents (in solid dosage form form), or as co-solvents or ingredients in medicaments for topical use.

It may be hydrophilic, hydrophobic and / or have surfactant properties. In general, hydrophobic and / or hydrophilic oleaginous type oils or materials are suitable for use in the manufacture of a pharmaceutical composition comprising a therapeutic and / or prophylactically active substance having a

Relatively low water solubility and / or when the release of the active substance from the pharmaceutical composition is designed to be immediate or unmodified. On the other hand, hydrophobic oil or oil-like materials are commonly used in the manufacture of a modified release pharmaceutical composition. The considerations made above are simplified to illustrate general principles, but there are many cases where other combinations of oil or oil-like materials and other purposes are relevant and, therefore, the foregoing examples should in no way limit the invention.

Typically, a suitable hydrophilic oil or oleaginous material is selected from the group consisting of: polyether glycols such as, for example, polyethylene glycols, polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxamers and mixtures thereof, or may be selected from the group consisting of: : xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, other types Gelucire compounds such as, for example, Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05, Sucroster 7, Sucroster 11, Sucroster 15, Maltose, Mannitol and mixtures thereof.

A suitable hydrophobic oil or oleaginous material may be selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins, fats and oils such as cocoa butter, beef tallow, lard, glycol esters polyether; higher fatty acids such as, for example, stearic acid, myristic acid, palmitic acid, higher alcohols such as, for example, kethanol, stearyl alcohol, low melting waxes such as, for example, glycerine monostearate, glycerine, hydrogenated tallow, myristyl alcohol, stearyl alcohol, unsubstituted and / or substituted monoglycerides, diglycerides

Unsubstituted and / or substituted 37/78, unsubstituted and / or substituted triglycerides, yellow wax, white wax, carnauba wax, castor wax, Japan wax, acetylate monoglycerides, NVP polymers, PVP polymers, acrylic polymers, or mixtures of these.

In an interesting embodiment the oil or oleaginous type material is a polyethylene glycol having an average molecular weight in the range of from about 400 to about 35,000 such as, for example, from about 800 to about 35,000, from about 1,000 to about approximately 35,000 such as, for example, polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6000; polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000, polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000. In certain situations polyethylene glycol may be employed with a molecular weight of from about 35,000 to about 100,000.

In an interesting embodiment the oil or oleaginous material is polyethylene oxide with a molecular weight of from about 2,000 to about 7,000,000 such as

<td colspan="2">such as</td><td>in</td><td>in between</td><td>about</td><td> 2,000</td><td>up until</td>

<td>about</td><td> 100,000</td><td>, in</td><td>in between</td><td>about</td><td> 5, 000</td><td>up until</td>

<td>about</td><td> 75,000,</td><td>in</td><td>in between</td><td>about</td><td> 10,000</td><td>up until</td>

<td>about</td><td> 60,000,</td><td>in</td><td>in between</td><td>about</td><td> 15,000</td><td>up until</td>

<td>about</td><td> 50,000,</td><td>in</td><td>in between</td><td>about</td><td> 20,000</td><td>up until</td>

<td>about</td><td> 40,000,</td><td>in</td><td>in between</td><td>about</td><td> 100,000</td><td>up until</td>

<td>about</td><td colspan="4">7,000,000 such as, for example,</td><td>in</td><td>in between</td>

<td>about</td><td> 100,000</td><td>up until</td><td colspan="3">approximately 1,000,000 of</td><td>in between</td>

<td>about</td><td> 100,000</td><td>up until</td><td colspan="2">approximately 600,000</td><td>, in</td><td>in between</td>

<td>about</td><td> 100,000</td><td>up until</td><td colspan="2">approximately 400,000</td><td>or of</td><td>in between</td>

approximately 100,000 to approximately 300,000.

38/78

119 In another embodiment, the oil or oleaginous type material is a poloxamer such as, for example poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or other ethylene oxide and propylene oxide block copolymers such as the series. Pluronic® and / or Tetronic® series. Suitable block copolymers of the Pluronic® series include polymers with a molecular weight of approximately 3,000 or more such as, for example, approximately 4,000 to approximately 20,000 and / or a viscosity (Brookfield) of approximately 200 to approximately 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, 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 about 9,000 to about 35,000 and / or a viscosity (Brookfield) of from about 500 to about 45,000 cps such. such as from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances that are slurries at room temperature and at 77 ° C for substances that are solid at room temperature.

The oil or oleaginous material may also be a sorbitan ester such as, for example, sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monostearate, sorbitan monostearate, sorbitan sesquioleate, sorbitan monopalmitate, sorbitan sesqui-isostearate, sorbitan de sesqui-stearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan triestearate or mixtures thereof.

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 oils or oleaginous type materials may be semisolid solvents or excipients such as polypropylene glycol, polyglycoside glycerides including Gelucire 44/14, complex fatty materials of vegetable origin including cupuacu oil, carnauba wax, vegetable oils such as oil 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, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; natural fatty materials of animal origin, including beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric, palmitic myristic, stearic fatty alcohols; esters including glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate, liquid non-synthetic glycerides including interesterified including Miglycol 810/812; fatty acid starch or alkolamides including esteramide ethanol, coconut fatty acid diethanolamide, mono and diglyceride acetic acid esters, mono diglyceride citric acid esters, mono diglyceride lactic acid esters, mono diglycerides, polyglycerol esters fatty acids, polyglycerol polyvinylate, propylene glycol esters of fatty acids, sorbitan monostearates, sorbitan tristearates, sodium stearoyl lactylates, calcium stearoyl lactylate, diacetyl tartaric acid esters of mono and diglycerides, etc.

40/78

Typically, a pharmaceutical composition or solid dosage form according to the invention has a concentration of oil or oleaginous material in the composition of approximately 5% w / w

<td colspan="2">or more such as,</td><td>per</td><td colspan="2">example,</td><td>about 10%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 15%</td><td>p / p</td><td>or</td><td>more,</td><td>about 20%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 25%</td><td>p / p</td><td>or</td><td>more,</td><td>about 30%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 35%</td><td>p / p</td><td>or</td><td>more,</td><td>about 40%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 45%</td><td>p / p</td><td>or</td><td>more,</td><td>about 50</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 55%</td><td>p / p</td><td>or</td><td>more,</td><td>approximately 60%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 65%</td><td>p / p</td><td>or</td><td>more,</td><td>approximately 70%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 75%</td><td>p / p</td><td>or</td><td>more,</td><td>approximately 80%</td><td>p / p</td><td>or</td><td>more,</td>

<td>about</td><td> 85%</td><td>p / p</td><td>or</td><td>more,</td><td>about 90%</td><td>p / p</td><td>or</td><td>more</td>

or approximately 95% w / w or more.

The concentration of the oil or oleaginous material in a composition or solid dosage form of the invention may range from about 20% to about 80% w / w, such as, for example, from about 25% to about 75% w / w. /P.

One of the advantages is that it is possible to incorporate a relatively large amount of oil and oil-like 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 absorbing material according to the invention. In the pharmaceutical field it is an advantage to be able to incorporate a relatively large amount of an oil or an oleaginous material into a solid composition especially in that situation where the active substance does not have adequate water solubility properties (e.g. low water solubility ), stability in aqueous medium (ie degradation occurs in aqueous medium), 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 delivery

Controlled, delayed, sustained and / or pulsed active substance.

Another advantage is that the particulate material obtained is a free flowing powder so it is easily processable in for example solid dosage forms such as tablets, capsules or sachets. Typically, the particulate material has properties that are suitable for producing direct compression tablets without adding large amounts of other additives. A suitable test for examining the flowability of particulate matter is the method described in Ph.Eur. and measuring the material flow velocity of a nozzle funnel with a diameter (hole) of 10.0 mm.

At least a portion of tacrolimus is present in the composition in the solid including a molecular dispersion and typically 10% or more, such as by 50% or more, 40% or more, 50% or more, 60% 70 or more, 80% or more, 90% or more, such as by

<td>form of</td><td>an</td><td colspan="2">solution</td>

<td colspan="2">a scatter</td><td colspan="2">solid.</td>

<td>example,</td><td> 20% &lt;</td><td>or</td><td>more,</td>

<td>or more,</td><td> 70%</td><td>or</td><td>more,</td>

<td>example,</td><td> 95%</td><td>or</td><td>more</td>

<td colspan="2">is present</td><td>at</td><td>make up</td>

A solid dispersion may be obtained by different means, for example by using organic solvents or by dispersing or dissolving the active substance in another suitable medium (for example, an oil or an oleaginous type material which at ambient or elevated temperatures is in liquid form). .

Solid dispersions (solvent method) may for example be prepared by dissolving a physical mixture of the active substance (eg a pharmacological substance) and the carrier in a common organic solvent, followed by evaporation of the solvent. Most of the time the carrier is a hydrophilic polymer. Suitable organic solvents include a pharmaceutically acceptable solvent where 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, polyoxyethylene stearates, polycaprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinylacetate copolymer (Kollidon VAudr) polymers (RS) polymers , Eudragit NE, Eudragit E) and polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, and poly (ethylene oxide) (PEO).

Polymers containing functional acidic groups may be suitable for solid dispersions, which release the active substance within a preferred pH range providing acceptable absorption in the intestines. These polymers may be one or more selected from the group comprising hydroxypropyl methylcellulose phthalate (HMPCP), polyvinylacetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacritic acid copolymer (Eudragit) S), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacryline, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimelitate.

With respect to the amount of active substance and polymer in the solid dispersion, the weight ratio of active substance to polymer may range from about 3: 1 to about 1:20. However, narrower margins from about 3: 1 to about 1: 5 may also be used, such as, for example, from about 1: 1 to about 1: 3.

43/78

The solid dispersion is preferably formed by spray drying, controlled agglomeration, freeze drying or coating onto carrier particles or any other solvent removal process. The dried product contains the active substance present as a solid dispersion including a molecular dispersion and a solid 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 at least partially in the form of a solid dispersion or solution may be prepared using any suitable procedure for preparing the pharmaceutical compositions known in the art.

In addition to using the solvent-based organic method, solid dispersion or tacrolimus solid solutions may be obtained by dispersing and / or 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.

In another aspect, the invention relates to a method for the preparation of a pharmaceutical composition according to the invention. In general, any suitable method of the pharmaceutical field may be used. However, to allow incorporation of a relatively high amount of an oil or oleaginous material the method described in International Patent Application WO 03/004001 has been shown to be useful. The method comprises spraying a first composition in liquid form, said composition comprising a first carrier or carrier and having a melting point above 5 ° C in a second composition comprising a second carrier or carrier material, said composition being a first carrier or carrier.

For example in the fluidized state and having a temperature below the melting point of the first carrier or carrier. The active substance may be present in the first carrier or carrier composition and / or the second carrier or carrier composition. However, in those cases where tacrolimus is present, at least partially, as a solid dispersion, it is advantageous to incorporate or dissolve tacrolimus in the first carrier or carrier composition.

Solid Dosage 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 dosage forms including tablets, capsules and sachets and the like. A solid dosage form according to the invention may be a unit dosage form or may be in polydeposited dosage form several individual units such as, for example, tablets, beads and / or granules.

Typically, a pharmaceutical composition or solid dosage form of the invention is for oral, buccal or sublingual administration.

The invention also relates to the above mentioned embodiment. Within the field of the invention there are solid dosage form compositions / forms which are intended to release tacrolimus and / or analogs thereof in a rapid release, delayed release or modified release manner. All of these ways are considered as a controlled way. In addition, a pH dependent release is also covered by the expression controlled manner.

45/78

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 main aspect of the invention are applied mutatis mutandis to other aspects of the invention. Consequently, properties regarding 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.

Usually, the concentration of the pharmaceutical composition in the form

<td>particulate matter is</td><td>in</td><td>gamma</td><td colspan="3">from approximately 5 to</td><td> 100%</td><td>p / p</td>

<td>such as</td><td colspan="2">example,</td><td>in</td><td>in between</td><td>about</td><td> 10%</td><td>up until</td>

<td>about</td><td> 90%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 15%</td><td>up until</td>

<td>about</td><td> 85%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 20%</td><td>up until</td>

<td>about</td><td> 80%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 25%</td><td>up until</td>

<td>about</td><td> 80%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 30%</td><td>up until</td>

<td>about</td><td> 80%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 35%</td><td>up until</td>

<td>about</td><td> 80%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 40%</td><td>up until</td>

<td>about</td><td> 75%</td><td>w / w,</td><td>in</td><td>in between</td><td>about</td><td> 45%</td><td>up until</td>

<td>about</td><td> 75%</td><td>p / p</td><td>or of</td><td>in between</td><td>about</td><td> 50%</td><td>up until</td>

<td>about</td><td> 70%</td><td>p / p</td><td colspan="2">in the form of</td><td colspan="2">dosage. For example,</td><td>The</td>

<td>concentration of</td><td colspan="2">composition</td><td colspan="2">pharmaceutical</td><td colspan="2">in particulate form is</td><td>in</td>

50% w / w or more of the dosage form.

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

46/78

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

<td>0 typical level during</td><td> 1-3</td><td>months is</td><td>in</td><td> 7-20</td><td>ng / ml and 4-12</td>

<td colspan="2">months the levels should be</td><td>from 5 -</td><td> 15</td><td>ng / ml.</td><td>These are only</td>

<td>guiding values ​​and</td><td>may</td><td>vary</td><td>we</td><td>types</td><td>transplantation and</td>

<td>ethnicity.</td><td></td><td></td><td></td><td></td><td></td>

<td>Were discovered</td><td>Dice</td><td colspan="2">following</td><td>for</td><td>patients with</td>

kidney transplant:

<td></td><td colspan="2">Caucasian n = 114</td><td colspan="2">Negro n = 56</td>

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

Expected dose recommendations for the products of the present invention will be from 0.02 mg / kg / day to 0.15 mg / kg / day once daily.

47/78

The solid composition or dosage form according to the invention may also be coated with a film coating, an enteric coating, a modified release coating, a protective coating, an anti-adhesive coating, etc.

A solid dosage form according to the invention may also be coated to obtain suitable properties for example with respect to controlled release of the active substance. The coating may be applied in individual unit dosage forms (e.g., tablets, capsules) or may be applied in a polydeposited dosage form or in individual units thereof.

Suitable coating materials are for example methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylalcohol, sodium carboxymethylcellulose, cellulose acetate, phthalate acetate , methacrylic acid copolymer, polyethylene glycol, gum shell, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, glycerine monostearate, zein.

To the coating material, plasticizers and other ingredients may be added. The same or a different active substance may also be added to the coating material.

In preferred embodiments, solid dosage forms are designed to release tacrolimus and / or an analog thereof in a controlled manner. In the present context, the term controlled manner is intended to include all release types that differ from single tablet release. Thus, the term includes so-called controlled release, sustained release, extended release, pulsed release, modified release, rapid release,

Slow release, extended release, as well as the terms delayed release and pH dependent release. However, a specific aspect of the invention relates to a delayed release composition or dosage form, which in this context is intended to indicate a composition or dosage form which upon release of 10% w / w of the active substance upon release. hours after administration and / or after the initiation of a dissolution test employing a dissolution medium with a pH of at most approximately 3.

Modified Release Systems

A first modified release system includes matrix systems in which tacrolimus is embedded or dispersed in a matrix of other material which serves to retard the release of tacrolimus in an aqueous medium (i.e. the luminal fluid of the G1 tract). When tacrolimus is dispersed in such a matrix, drug release occurs primarily from the surface of the matrix. Thus, the medicament is released from the surface of a device, which incorporates the matrix after it diffuses through the matrix or when the surface of the device wears off, exposing the medicine. In some embodiments, both mechanisms may operate simultaneously. Matrix systems can be long, ie tablet size (approximately 1 cm), or small (&lt;0.3 cm). The system may be unitary (e.g., a bolus), may be divided by virtue of being comprised of several subunits (e.g., several single dose capsules) which are substantially administered simultaneously, or may comprise several particles, also called a multiparticulate. A multiparticulate may have numerous formulation applications. For example, a multiparticulate may be used as a powder to fill a capsule shell, or used per se to be mixed with food for ease of ingestion.

49/78 other matrix polymers may be hydrophobic, which

A useful multiparticulate matrix comprises a plurality of tacrolimus particles, each tacrolimus particle and / or an analog thereof, for example, in the form of a solid solution / dispersion with one or more excipients selected to form a matrix capable of controlling the rate of dissolution. of tacrolimus in an aqueous medium. Matrix materials are generally hydrophobic materials such as waxes, some cellulose derivatives, or hydrophobic ones. If necessary, the materials optionally formulated with materials may be used as binders or as enhancers. Matrix materials useful for the production of these dosage forms such as: ethylcellulose, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, and others, as well as synthetic polymers such as poly ( vinyl chloride), polyvinyl acetate, vinyl ethylene acetate copolymers, polystyrene, and the like. Hydrophilic or water-soluble binders or modified release agents which may optionally be formulated in the matrix include hydrophilic polymers such as hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, poly (N-vinyl-2-pyrrolidinone) (PVP), poly (ethylene oxide) (PEO), polyvinyl alcohol (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials. Additionally, materials whose function as release modifying agents include water soluble materials such as sugars or salts. Preferred water soluble materials include lactose, sucrose, glucose, and mannitol, as well as hydrophilic polymers such as HPC, HPMC, and PVP.

A multiparticulate product may also be treated by controlled agglomeration. In this case tacrolimus is dissolved or partially dissolved in a suitable fusible carrier and sprayed onto the carrier particles comprising matrix substance. Suitable fusible carriers have been previously mentioned herein.

50/78

Alternatively, tacrolimus is dissolved in an organic solvent together with the matrix substance and atomized or applied to the carrier particles, cf. below. Solvents typically employed for the process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

Once formed, the tacrolimus multiparticulate matrix can be mixed with compressible excipients such as lactose, microcrystalline cellulose, dicalcium phosphate, and the like, and the mixture is compressed into a tablet. Disintegrants such as sodium starch glycolate or cross-linked poly (vinyl) pyrrolidone are also commonly employed. Tablets prepared by this method disintegrate when placed in an aqueous medium (such as the GI tract), thereby exposing the multiparticulate matrix, which thereafter releases tacrolimus.

The matrix system may also be in the form of a tacrolimus hydrophilic matrix tablet and / or an analog thereof (e.g., as a solid dispersion) as a multiparticulate product and an amount of hydrophilic polymer sufficient to provide a useful degree of control. on the dissolution of tacrolimus. Hydrophilic polymers useful for matrix formation include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), poly (ethylene oxide), poly (vinyl alcohol), xanthan gum, carbomer, carrageenan, and zooglan. A preferred material is HPMC. Other similar hydrophilic polymers may also be employed. In use, the hydrophilic material is swollen and eventually dissolved in water. Tacrolimus is released by matrix diffusion as well as matrix erosion. The dissolution rate of tacrolimus of these hydrophilic matrix tablets may be controlled by the amount, molecular weight and gel forces of the hydrophilic polymer employed. In general, using a larger amount of hydrophilic polymer reduces the rate of dissolution as

If we were using a higher molecular weight polymer. Using a smaller molecular weight polymer usually increases the rate of dissolution. A matrix tablet typically comprises from about 20 to 90% by weight of tacrolimus and about 80 to 10% by weight of polymer.

A preferred matrix tablet comprises by weight from about 30% to about 80% of solid dispersion with tacrolimus and / or an analog thereof, from about 15% to about 35% of matrix former (such as, for example, HPMC ), from 0% to about 35% lactose, from 0% to about 20% microcrystalline cellulose, and from about 0.25% to about 2% lubricant (such as, for example, magnesium stearate) .

Matrix systems as a class often exhibit non-constant drug release from the matrix. This result may be a consequence of the diffusive mechanism of drug release, and modifications to the dosage form geometry may be advantageously used to make the rate of drug release more constant.

A second class of tacrolimus controlled release dosage forms of this invention include mild membrane or depot systems. In this class, a tacrolimus deposit for example in a solid solution / dispersion as a multiparticulate product is surrounded by a velocity limiting membrane. Tacrolimus crosses the membrane by mass transport mechanisms well known in the art, including but not limited to membrane dissolution followed by diffusion through the membrane or diffusion through the liquid filled pores in the membrane. These individual dispensing system dosage forms can be large, as in the case of a single large tablet, or multiparticulate, as in the case of a

Multi-deposition polydeposited capsule or tablets each coated with a membrane. The coating may be non-porous but permeable to tacrolimus (e.g. tacrolimus may diffuse directly through the membrane), or may be porous. As with the other embodiments of this invention, we think that the particular transport mechanism is not critical.

Sustained release coatings as known in the art may be employed to fabricate the membrane, especially polymeric coatings such as a cellulose ester or ether, an acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be applied as a solution in an organic solvent or as an aqueous or latex dispersion. The coating operation may be performed on Standard equipment such as a fluid bed liner, a Wurster liner, or a rotary fluid bed liner.

If desired, the permeability of the coating may be adjusted by mixing two or more materials. A particularly useful process for making the porosity of the coating comprises adding a predetermined amount of a finely divided water soluble material such as sugars or water soluble salts or polymers to a solution or dispersion (e.g. an aqueous latex) of the polymer to the membrane formation to be used. When the dosage form is ingested in the aqueous medium of the G1 tract, these water-soluble membrane additives are filtered through the membrane, leaving pores that facilitate drug release. The membrane coating may also be modified by the addition of plasticizers as is known in the art.

53/78

A particularly useful variation of the process for applying a membrane coating comprises dissolving the coating polymer in a mixture of chosen solvents so that the coating dries, an inversion phase takes place in the applied coating solution, resulting in a membrane with a porous structure.

In general, a support is not required to mechanically reinforce the membrane.

Membrane morphology is not of critical importance provided that the permeability characteristics set forth herein are met. The membrane may be amorphous or crystalline. It may have any category of morphology produced by any particular process and may be, for example, an interfacial polymerized membrane (comprising a speed limiting thin skin on a porous support), a hydrophilic porous membrane, a hydrophobic porous membrane, a membrane. hydrogel, an ionic membrane, and other materials of this type which are characterized by the controlled permeability of tacrolimus.

It is a goal to reduce GI tract exposure higher than high tacrolimus concentrations. Accordingly, suitable dosage forms include those forms, which incorporate specific latency prior to the emergence of tacrolimus controlled release. An exemplary embodiment may be illustrated by a tablet (or particulate material) comprising a tacrolimus core coated with a first coat of a polymeric material of the type useful for sustained release of tacrolimus and a second coating of a type useful for delayed release of medicines when the dosage form is taken. The first coating is applied on and around the tablet or individual particles. 0 The second coating is applied on and around the first coating.

54/78

A tablet may be prepared by techniques well known in the art and contains a therapeutically useful amount of tacrolimus plus the excipients that are required to form the tablet by these techniques.

The first coating may be a sustained release coating as known in the art, especially membrane-forming polymeric coatings, such as those previously treated for depot systems. Or this could be a controlled release matrix core, which is coated a second time with a delayed release material.

Materials useful for preparing the second tablet coating include polymers known in the art as enteric coatings for delayed release of medicaments. These are very commonly pH-sensitive materials such as cellulose acetate phthalate, cellulose acetate trimelitate, hydroxypropylcellulose phthalate, polyvinyl acetate phthalate) and acrylic copolymers such as Eudragit L-100 (Rohm Pharma) and related materials such as more fully detailed below on delayed release. The thickness of the delayed release coating is adjusted to give the desired latency property. In general, thicker coatings are more resistant to erosion and therefore produce a longer and more effective delay. Preferred coatings range from approximately 30 μπι thick to approximately 3 mm thick.

When a hydrophobic matrix material such as glycerine monostearate is used, no delay coating is required. The tablet will not release tacrolimus until an area of ​​enzymatic degradation has been reached, specifically after the duodenum.

55/78

When ingested, the twice-coated tablet passes through the stomach, where the second coating prevents the release of tacrolimus under the acidic conditions prevailing there. When the tablet leaves the stomach and enters the small intestine, where the pH is higher, the second coating degrades or dissolves according to the physiochemical properties of the chosen material. After erosion or dissolution of the second coating, the first coating prevents the immediate or rapid release of tacrolimus and modulates the release to prevent the production of high concentration peaks, thereby minimizing side effects.

Another example is a multiparticulate where each particle is double coated as described above for tablets, first with a polymer designed to produce sustained release of tacrolimus and then coated with a polymer designed to delay the onset of release into the GI tract when The dosage form is ingested.

The tacrolimus release rate of sustained release multiparticulates (i.e. multiparticulates prior to receiving the delayed release coating) and coating modification methods are also controlled by the previously discussed tacrolimus deposition system factors.

for multiparticulate

The second double-coated multiparticulate membrane or coating is a delayed release coating that is applied over the first sustained release coating as described above for tablets and may be formed of the same materials. It should be noted that the use of so-called enteric materials to practice this embodiment differs significantly from their use to produce conventional enteric dosage forms. With conventional enteric forms, the object is to delay drug release until the dosage form has passed through the stomach and then

56/78 deliver the dose in the duodenum. Dosing tacrolimus directly and completely to the duodenum may be undesirable, however, due to the side effects we seek to minimize or prevent with this invention. Therefore, if conventional enteric polymers are to be used to practice this embodiment, it may be necessary to apply them significantly thicker than in conventional practice to retard drug release until the dosage form reaches lower GI tract. However, controlled or sustained delivery of tacrolimus can also be performed after the delayed release coating has dissolved or degraded, so the benefits of this embodiment can be realized with an appropriate combination of delayed release character and sustained release, and the delayed release part alone may or may not necessarily fit the USP enteric criterion. The thickness of the delayed release coating is adjusted to give the desired latency property. In general, thicker coatings are more resistant to erosion and therefore produce a longer delay.

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 sufficient polymer to ensure

There is substantially no release of tacrolimus in the dosage form until the dosage form has left the stomach and approximately 15 minutes of small intestine has remained for more, preferably or approximately 30 minutes or more, thereby ensuring that a tacrolimus minimum was released in 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 from about 15% to about 50% of the core weight of the tacrolimus tablet.

PH-sensitive polymers that are very insoluble and impermeable to stomach pH, ​​but which are more soluble and small colon include polyacrylamide intestinal pH-permeable phthalate derivatives such as carbohydrate acid phthalates, amylose acetate phthalate, phthalate cellulose acetate, 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 copolymer, maleic acid styrene phthalate phthalate copolymer, maleic acid and styrene, 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.

Coating amounts, latency time before tacrolimus release, after the pH-dependent coated tablet dosage form has left the stomach, can be controlled by choosing Eudragit-L® and Eudragit-S® relative in and with the choice of coating thickness. Eudragit-L® films dissolve at a pH above pH 6.0, and 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®, more preferably from about 9: 1 to about 1: 4 Eudragit-L® / EudragitS®. The coating may comprise from about 3% to about 70% of the weight of the uncoated tablet core. Preferably, the coating comprises from about 5% to about 50% of the tablet core weight.

59/78

Uses

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 pharmaceutical composition is used in the preparation of an immediate release solid dosage form or a delayed release solid dosage form.

A further advantage of a composition of the present invention is the ability to obtain an effective therapeutic response with a dosage reduction as 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 in the form of Prograf® or a similar commercially available product containing tacrolimus and which is essentially bioequivalent to Prograf® or a product similar commercially available product containing tacrolimus.

Any of the tacrolimus-containing dosage forms and compositions of the invention may improve treatment of conditions responsive to 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. slender,

60/78 limb, muscle, nerve, intervertebral disc, trachea, myoblast, the

that of diseases, atopic mediated dermatitis, bullous dermatitis, cartilage, etc .; graft-versus-host reactions after bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis

Hashimoto, multiple sclerosis, myasthenia gravis, type I diabetes, etc .; infections caused by pathogenic microorganisms (eg Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroids, etc.); inflammatory or hyperproliferative skin diseases or skin manifestations immunologically (for example psoriasis contact dermatitis, eczematous, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, lupus erythematosus, acne, erythematosus areata); autoimmune diseases of the eye (eg keratoconjunctivitis, vernal conjunctivitis, keratosis-associated uveitis, herpetic keratosis, keratosis Behcet's disease, conical, epithelial corneal dystrophy, keratoleukoma, pemphigus, Mooren's ulcer, scleritis, ophthalmopathy VogtKoyanagi-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); diseases

Renal impairment (eg, intestinal nephritis, Goodpasture syndrome, uremic hemolytic syndrome, and diabetic nephropathy); nerve diseases (e.g. multiple myositis, Guillain Barre's syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and radiculopathy); ischemic brain disease (eg 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 diseases (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 (eg cataracts, siderosis bulbi), retinitis, retinitis pigmentosa, senile plaques, vitreous scarring, alkaline corneal burns); dermatosis (e.g. erythema multiforme, bullous dermatosis linear immunoglobulin A, contact dermatitis with cement); and other diseases (e.g. gingivitis, periodontitis, sepsis, pancreatitis, and diseases caused by environmental pollution (eg air contamination), aging, carcinogen, carcinoma metastases, and hypobaropathy)]; diseases caused by the release of histamine or leukotriene C4 coronary artery restenosis after angioplasty and prevention of postoperative adhesions; autoimmune diseases and inflammatory conditions (eg, primary mucosal edema, autoimmune atrophic gastritis, premature menopause, 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.

Additionally, tricyclic macrolides such as tacrolimus have liver regenerating activity and / or activities to stimulate hypertrophy and hyperplasia. Therefore, the pharmaceutical composition of the present invention is useful for enhancing the effect of treatment and / or prophylaxis of liver disease. [e.g. immune diseases (e.g. chronic autoimmune liver diseases such as hepatocytes invention is

63/78 autoimmune liver disease, 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 acute-to-chronic liver failure (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 enhancing chemotherapy effect activity, 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 n² . 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)

Glycerin Monostearate, Rylo® MD50, (from Danisco Cultor), Ph.Eur .; lot n². 4010056276

Avicel PH200 (Microcrystalline Cellulose) (from FMC)

64/78

Lactose DCL 11 (from DMV)

Magnesium stearate

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

Eudragit® L30D.55 (from Degussa)

Triethyl Citrate (from Merck)

Anti-Foam Emulsion (from Unikem)

Micro Talc

HPMC refers to ShinEtsu Metallose 90SH (Type 2910, 2208) or ShinEtsu Metolose 60SH (Type 2910) available in various polymerization grades (viscosity 3-100, OOOcP).

Tablets, capsules or granules may be enteric coated with different types of polymers such as hydroxypropyl methylcellulose acetate succinate (Aqoat), CAP cellulose acetate phthalate, HP-MCP hydroxypropyl methylcellulose phthalate or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100 / S, Eudragit 100 / L.

Comparison of the prior art tacrolimus formulation:

Prograf © Hard Gelatin Capsules, manufactured by Fujisawa Ireland Ltd.

Ingredients Tacrolimus, anhydrous mg

1,0

Gelatine

Hypromellose

6, 9 1,0

65/78

Lactose monohydrate

24,7

Magnesium stearate

0,3

Shellac

Soybean Seed Lecithin Red Iron Oxide (E172) Titanium Dioxide (E171) Dimeticone (E900)

what? b q. B

what

what

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

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 of the apparatus.

Determination of disintegration time

The time for a tablet to disintegrate, that is, to break down into particles or clumps, is determined according to Ph. Eur.

Determination of mean geometric diameter d_gw

The mean geometric weight diameter was determined by employing the laser diffraction method by dispersing the obtained particulate material (or starting material) in air. Measurements were performed at 1 bar dispersive pressure on a Sympatec device.

66/78

Helos, which records the distribution of the equivalent spherical diameter. This distribution is adjusted to a normal logarithmic volume-size distribution.

When used herein, mean diameter of geometric weight means the mean diameter of the normal logarithmic volume-size distribution.

In vitro dissolution tests

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 paddle method; rotation speed: 50 rpm; 37 ° C; after 2 hours in the acidic medium, the medium is changed to a phosphate pH 6.8).

Test 2:

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

The pharmaceutical compositions and dosage forms of the invention are exemplified in Examples 1 to 7. The results of the in vitro dissolution tests of the compositions and dosage forms of the invention are found in Example 8.

EXAMPLE 1

67/78

Modified-release polydeposited capsule based on an expandable hydroxypropylcellulose hydrocolloid matrix

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

<td>Tacrolimus</td><td> 0,50</td><td> 1,00</td>

<td>HPMC</td><td> 20,00</td><td> 40,00</td>

<td>Lactose Mesh 200</td><td> 30,00</td><td> 60,00</td>

<td>PEG 6000</td><td> 34, 65</td><td> 69, 30</td>

<td>Poloxamer 188</td><td> 14, 85</td><td> 29,70</td>

<td>Total</td><td> 100,00</td><td> 200,00</td>

<td colspan="3">Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer</td>

<td>188 (at a 70:30 p / p ratio) to</td><td> 70 ²C. A</td><td>solution was sprayed</td>

<td>in a mixture of 150 g lactose</td><td colspan="2">and 100 g HPMC in a fluid bed</td>

<td>Strea-1. The granular product was</td><td>sifted</td><td>in a 0.7 mm sieve</td>

<td>and filled in gelatin capsule</td><td>lasts (200</td><td>mg).</td>

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

<td>Release matrix tablet</td><td colspan="2">modified matrix-based</td>

expandable hydroxypropylcellulose hydrocolloid

<td>Substance</td><td>O 0</td><td></td><td colspan="2">mg</td>

<td>Tacrolimus</td><td> 0,</td><td> 50</td><td> 1,</td><td> 00</td>

<td>HPMC</td><td> 19,</td><td> 90</td><td> 40,</td><td> 00</td>

<td>Lactose Mesh 200</td><td> 29,</td><td> 85</td><td> 60,</td><td> 00</td>

<td>PEG 6000</td><td> 34,</td><td> 48</td><td> 69,</td><td> 30</td>

<td>Poloxamer 188</td><td> 14,</td><td> 85</td><td> 29,</td><td> 70</td>

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

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

tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (in a 70:30 w / w ratio) at 70 ° C ²C. The solution was sprayed onto 250 g of lactose in a Strea-1 fluid bed. The resulting granular product was sieved through a 0.7 mm sieve and

Mixed with HPMC and magnesium stearate for 0.5 minutes in a Turbula mixer.

The mixture was compressed into 8 mm tablets with 1 mg of active ingredient (200 mg tablet) with the compound as a cup.

Average disintegration time: 20 minutes. Hardness: 45 N.

EXAMPLE 3

Enteric coating

The capsules and tablets of examples 1 and 2 were further coated with the following enteric coating to obtain delayed release of the active ingredient after administration.

<td>Ingredients</td><td>O 0</td>

<td>Eudragit® L30D</td><td> 40</td>

<td>Purified water</td><td> 52</td>

<td>Triethyl Acetylcitrate</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 coating suspension was prepared by mixing triethyl acetylcitrate, antifoam emulsion and purified water in the Ultra Turrax apparatus at 9500 rpm for 30 min. After 1 minute talc was added. The mixture was passed through the No.² . 300 ° C and stirred with a magnetic stirrer. Eudragit was passed through the sieve n². 300 µl and added to the mixture which was stirred for 5 minutes.

69/78

The process conditions of the coating process were as follows, an inlet temperature of 40 ° C, an outlet temperature of 31 ° C, an air inlet of 140 cbm per hour and a coating time of approx. 50 minutes (300 g of coating material). Approx. 400g tablets, or 200g capsules were coated.

The film-coated tablets and capsules were polymerized for 48 hours at 30 ° C prior to the dissolution test.

EXAMPLE 4

Enteric coated tablet with PEG 6000 / Poloxamer 188 based core and Eudragit L30D 55 based enteric coating

Tablet core composition

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

<td>Tacrolimus</td><td> 1, 98</td><td> 2,00</td>

<td>Lactose Monohydrate, Lactose 200 Mesh</td><td> 40,50</td><td> 40, 91</td>

<td>PEG 6000</td><td> 33,26</td><td> 33, 60</td>

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

<td>Magnesium stearate</td><td> 0,50</td><td> 0,51</td>

<td>Baby powder</td><td> 4,50</td><td> 4,55</td>

<td>Sodium Croscamellose, Ac-di-sol</td><td> 5, 00</td><td> 5, 05</td>

<td>Total</td><td> 100,00</td><td> 101,01</td>

The tacrolimus tablet core was produced by dissolving in PEG 6000 at a temperature above 80 ° C. Poloxamer 188 was added and the solution was heated to a temperature above 80 ° C.²C. Using the Phast FS1.7 food unit, the solution was sprayed onto 200 g lactose monohydrate in a Phast FB100 fluid bed. The resulting granulate was passed through a co70 / 78 grinder, sieve 1397, 4500 rpm, and mixed with croscarmellose sodium for 3 minutes in a Turbula mixer.

Magnesium stearate and talc were sieved through sieve 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 the compound as a cup.

Average disintegration time: 7 minutes. Hardness: 65 N

Enteral coating:

The enteric coating is based on an 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 with pH values ​​below 5.0 and easily soluble with pH values ​​above 6.0. The composition of the film coating is:

<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 pm.

A check of the applied film thickness is based on the

71/78 measurement with a digital micrometer of increase in tablet height. The film coating process was performed on a Phast FB100 fluid bed equipped with a Wurster insert. The process conditions were: inlet air temperature 50 ° C; 100 cm inlet air flow³ per hour;

product temperature 38 ° C; 15 g / min feed speed.

After coating appropriate film formation requires polymerization of the coated tablets, i.e. 30 ° C within 48 hours in an oven. Alternatively, the coated tablets could be polymerized more effectively at 40 ° C in 24 hours.

EXAMPLE 5

PEG6000 / Poloxamer 188 controlled-release tablet based on an HPMC matrix.

Tablet Composition:

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

<td>Tacrolimus</td><td> 1,21</td><td> 2,00</td>

<td>Lactose Monohydrate, Lactose 200 Mesh</td><td> 24,75</td><td> 40,91</td>

<td>PEG 6000</td><td> 20,33</td><td> 33, 60</td>

<td>Poloxamer 188, Lutrol 68</td><td> 8,71</td><td> 14,40</td>

<td>Magnesium stearate</td><td> 0,50</td><td> 0,83</td>

<td>Baby powder</td><td> 4,50</td><td> 7,44</td>

<td>Hydroxypropyl methylcellulose, Metolose 90SH 15000</td><td> 40,00</td><td> 66,12</td>

<td></td><td> 100,00</td><td> 165,29</td>

Tacrolimus was dissolved in PEG 6000 at a temperature above 80 ° C. ²C. Poloxamer 188 was added and the solution was heated to a temperature above 80 ° C. ²C. Using the Phast FS1.7 food unit, the solution was sprayed onto 200 g lactose monohydrate in a Phast FB100 fluid bed. The product

The granules were sieved through a co-grinder, sieve 1397, 4500 rpm, and mixed with hydroxypropyl methylcellose for 3 minutes in a Turbula mixer.

Magnesium stearate and talc were sieved through sieve 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 mixture was compressed into 8 mm tablets with a strength of 2 mg (165 mg tablet with cup-shaped compound).

Average disintegration time: 2 hours and 34 minutes. Hardness: 50 N

EXAMPLE 6

HPMC erosion matrix-based controlled release tablet formulation, HPMC added as part of intragranular phase. Fusion Granulation s

Tablet Composition:

<td>Ingredient</td><td>mg</td>

<td>Tacrolimus</td><td> 2</td>

<td>Lactose</td><td> 80</td>

<td>PEG 6000</td><td> 15</td>

<td>Poloxamer 188</td><td> 6</td>

<td>Metolose SH 90</td><td> 80</td>

<td>Avicel PH200</td><td> 60</td>

<td>Magnesium stearate</td><td> 2</td>

<td>Total</td><td> 245</td>

The tablet formulation was based on melt granulation in a Pellmix 1/8 high shear mixer. 16g of

Micronized tacrolimus was mixed with 640 g lactose, mesh 125 and 120 g.

Polyethylene glycol 6000, 48g of poloxamer 188 and 640g of hydroxypropyl methylcellulose Metolose SH 90 15,000 cP in the high shear mixer. The jacket of the blender vessel was heated to 80 ° C and the mixture was heated to an impeller rotation speed of 1000 rpm to the melting point of PEG and poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm. The granulate was sieved through the 0.7 mm sieve and cooled in a tray. The granulate was mixed with 480 g of Avicel PH200 for 3 minutes and after the addition of 16 g of magnesium stearate for another 0.5 minutes. The mixture was compressed into tablets on a Diaf TM20 monopuncture tabletting machine. Diameter of the tablet: 8 mm. Tablet shape: Round, cup-shaped compound.

EXAMPLE 7

Enteric coated tablet formulation (melt granulation and enteric coated tablets)

Tablet Composition:

<td>Ingredient</td><td>mg</td>

<td>Tacrolimus</td><td> 2</td>

<td>Lactose</td><td> 80</td>

<td>PEG 6000</td><td> 15</td>

<td>Poloxamer 188</td><td> 6</td>

<td>Avicel PH200</td><td> 60</td>

<td>Magnesium stearate</td><td> 2</td>

<td>Total</td><td> 165</td>

The tablet formulation was based on melt granulation in a Pellmix 1/8 high shear mixer. 16g of tacrolimus

Micronized 74/78 was mixed with 640 g lactose, mesh 125 and 120 g. Polyethylene glycol 6000, 48g of poloxamer 188 in the high shear mixer. The jacket of the blender vessel was heated to 80 ° C and the mixture was heated to an impeller rotation speed of 1000 rpm to the melting point of PEG and poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm. The granulate was sieved through the 0.7 mm sieve and cooled in a tray. The granulate was mixed with 480 g of Avicel PH200 for 3 minutes and after the addition of 16 g of magnesium stearate for another 0.5 minutes. The mixture was compressed into tablets on a Diaf TM20 monopuncture tabletting machine. Tablet diameter: 7 mm. Tablet shape: Round, cup-shaped compound.

Enteric coating of the tablets was performed according to the procedure described in example 11.

Example 8

In vitro Dissolution Data

The compositions and dosage forms according to the previous examples were subjected to in vitro dissolution tests using two different dissolution media / tests.

A. Using medium / dissolution test: 900 ml of aqueous medium with 0.005% HPC (hydroxypropylcellulose) adjusted to pH = 4.5 (USP paddle method; rotation speed: 50 rpm), the following profiles of dissolution:

<td></td><td colspan="4">% Release</td>

<td>Time (hours)</td><td>Ex. 1</td><td>Ex. 2</td><td>Ex4 - EC (% Rsd)</td><td>Ex. 5 (% Rsd)</td>

<td> 0</td><td> 0</td><td> 0</td><td> 0 (0)</td><td> 0 (0)</td>

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

75/78

<td> 1</td><td></td><td></td><td></td><td></td>

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

<td> 2</td><td> 0</td><td> 0</td><td></td><td></td>

<td> 3</td><td></td><td></td><td></td><td></td>

<td> 4</td><td> 1</td><td> 3</td><td> 0,8 (32,3)</td><td> 7,4 (9,8)</td>

<td> 5</td><td></td><td></td><td></td><td></td>

<td> 6</td><td> 3</td><td> 4</td><td></td><td></td>

<td> 8</td><td> 5</td><td> 7</td><td> 0,4 (61,1)</td><td> 13,3 (16,5)</td>

<td> 10</td><td> 20</td><td> 14</td><td></td><td></td>

<td> 15</td><td> 40</td><td></td><td> 11,0 (17,3)</td><td> 36,0 (5,8)</td>

<td> 16</td><td></td><td> 38</td><td></td><td></td>

<td> 17</td><td></td><td></td><td> 13,2 (12,1)</td><td> 44,5 (5,4)</td>

<td> 20</td><td></td><td></td><td></td><td></td>

<td> 24</td><td></td><td></td><td></td><td></td>

dissolution profile for Example 4 tablet cores in dissolution medium: 900 ml, aqueous medium with 0.005% HPC (hydroxypropylcellulose) adjusted to pH = 4.5. USP blade method.

Rotation Speed: 50 rpm:

<td>Time (hours)</td><td>% 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> 8,0</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>

Dissolution profile of the enteric coated tablets of example 4 in the dissolution medium according to USP Method A, delayed release articles. USP shovel method. Rotation Speed: 50 rpm:

76/78

<td>Time (hours)</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>

Lisbon, February 2012

77/78

This list of references cited by the Holder is intended solely to assist the reader and is not part of the European patent document. Even though the utmost care has been taken in its preparation, errors or omissions cannot be excluded and EPO assumes no responsibility in this regard.

Patent Application Documents cited in description

REFERENCES REFERRED TO IN THE DESCRIPTION

<td> •</td><td>EP</td><td> 0184162</td><td>THE</td><td>• EP</td><td>1064942 A</td>

<td> •</td><td>EP</td><td> 0444659</td><td>THE</td><td>• WO</td><td>03004001 A</td>

<td> •</td><td>US</td><td> 6387918</td><td>B</td><td>• WO</td><td>0050007 A</td>

<td> •</td><td>WO</td><td> 0137808</td><td>THE</td><td></td><td></td>

Literature Cited in Non-Patent Application Description

HONBO et al. The oral dosage form of FK-506. Transplantation Procedings, 1987, vol. 19 (5), 17-22

DEW et al. Br. J. Clin. Pharmac., 1982, vol. 14, 405-408