Modified release compositions comprising tacrolimus

The present invention relates to a pharmaceutical composition and / or dosage forms, preferably oral dosage unit forms, containing tacrolimus, having modified release profiles when subjected to a standard dissolution method which is believed to reflect the actual rate and time course of release of the active substance in vivo where this new composition effectively reduces or even prevents the effects of CYP3A4 metabolism.

BACKGROUND OF THE INVENTION [0002] Tacrolimus, also known as FK-506 or FR-900506, has a chemically tricyclic structure, as follows:

<img file="PL1663216T3_D0001.tif" />

corresponding to C44H69NO12. Tacrolimus is in the form of white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol and well soluble in methanol and chloroform.

[0003] The production of tacrolimus is described in EP-A-0184162, and tacrolimus analogues are disclosed e.g. in EP-A-0444659 and US 6,387918.

[0004] Tacrolimus is a macrolide compound with useful immunosuppressive, antimicrobial and other pharmacological effects and is useful in the treatment or prophylaxis of rejection reactions in organ and tissue transplantation, graft versus host diseases, autoimmune diseases and infectious diseases. Tacrolimus prolongs host and transplant survival in animal models of liver, kidney, heart, bone marrow and small intestine and pancreas, lungs and trachea, skin, cornea and limb transplants.

[0005] Tacrolimus has been shown to inhibit to some extent humoral resistance and, to a greater extent, cell-mediated responses such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and transplant diseases. against the host.

[0006] Tacrolimus inhibits T cell activation, although the exact mechanism of action is unknown. Experimental evidence suggests that tacrolimus binds to intracellular FKBP-12 protein. The tacrolimus-FKBP-12, calcium, calmodulin and calcineurin complex is then formed and the phosphatase activity of calcineurin is inhibited. This action can prevent the dephosphorylation and translocation of the nuclear factor of activated T cells, a nuclear component that is thought to initiate transcription of the lymphokine forming gene. As a result, T lymphocyte activation is inhibited, i.e., immunosuppression.

[0007] Tacrolimus is significantly metabolised by CYP3A4 in the intestinal wall and liver. Therefore, drugs that affect this isoenzyme may affect the absorption and subsequent removal of systemically absorbed tacrolimus. CYP3A4 inhibitors may increase tacrolimus levels, while CYP3A4 inducers may increase tacrolimus metabolism and lower tacrolimus levels. Therefore, tacrolimus may be co-administered with one or more CYP3A4 inhibitors to improve its overall bioavailability.

[0008] Typically, tacrolimus is administered orally and is then absorbed from the gastrointestinal tract. It has been observed that absorption is adversely affected by the simultaneous intake of food. Therefore, the rate and extent of tacrolimus absorption were greatest under fasting conditions.

[0009] It is well known that, when administered orally, the absorption and bioavailability of a therapeutically active substance may be influenced by various factors. Such factors include the presence of food in the gastrointestinal tract and, in general, the residence time of the drug substance in the stomach is significantly longer in the presence of food than in the fasted state. When the presence of food in the digestive tract exceeds a certain point on the bioavailability of a drug substance, the drug substance is defined as having a gastrointestinal effect. Food effects are important because absorption and therefore plasma levels become highly variable depending on food intake. Adverse effects on the absorption into the bloodstream may result in a condition presenting the patient with insufficient absorption risk for the treatment of the condition to be treated with the drug administered. On the other hand, the very high peak levels sometimes seen under fasting conditions can also cause significant side effects of nephro- or neurotoxic origin as well as side effects of GI (gastrointestinal) and others.

[0010] Absorption of tacrolimus from the gastrointestinal tract after oral administration is rapid with the average time to reach a peak concentration (tmax) about 1-2 hours after administration to healthy subjects or patients with kidney or liver transplantation, but is incomplete and variable. The bioavailability is usually low, at most around 20% after oral administration.

[0011] Commonly observed side effects include vomiting and nausea, but side effects such as tremor, headache, hypertension, renal failure, hyperkalemia, hypomagnesaemia, hyperglycemia, insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity and neurotoxicity are also observed.

[0012] For oral administration, tacrolimus is currently formulated and marketed in the form of soft gelatin capsules containing the equivalent of 0.5, 1 or 5 mg of anhydrous tacrolimus and is commercially available under the trade names Prograf® and Protropic®. The recommended initial oral dose for the patient is about 0.1 to 0.2 mg / kg / day. The dose is designed to provide some minimum plasma level of about 5 to about 20 ng / ml. Prograf^® is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants.

[0013] There remains a need for new pharmaceutical compositions and / or dosage forms containing tacrolimus that show increased bioavailability. Increased bioavailability may allow the dosage units taken by the patient to be reduced, e.g. to a single daily dose, and may also reduce or exclude the need to take food simultaneously with the dosage form, thus providing greater freedom for patients as to when the drug is being taken. In addition, it is contemplated that fluctuations in the plasma concentration profile as a function of time can be significantly reduced. In addition, increased bioavailability can also provide a more reproducible (i.e. less variable compared to Prograf®) release profile.

[0014] WO 01/37808 A discloses a preparation obtainable by spraying a solution of tacrolimus, PEG-24-cholesterol ether (Solulan C-24), monoglycerides and deoxycholic acid in an organic solvent for micro-droplets (embryos) ), and also relates to improving oral bioavailability.

[0015] EP-A-1064942 discloses sustained release preparations obtainable by dissolving tacrolimus in molten glycerol monostearate or a tetragglerol fatty acid triester and mixing with HPMC or lactose.

[0016] WO 03/004001 A discloses a method of controlled agglomeration to improve the bioavailability of poorly water-soluble compounds in solid solutions or dispersions.

[0017] Honbo et al .: "The oral dosage form of FK-506" in Transplantation Proceedings, 1987, volume 19, No. 5 supl. 6, pp. 17-22 discloses capsules containing a tacrolimus solid dispersion in HPMC using a solvent method.

[0018] The inventors have found that the bioavailability of tacrolimus is significantly increased when tacrolimus is administered to a mammal in a modified or controlled release composition that provides the rate and time course of release of the active substance, i.e. an in vivo release profile that effectively reduces or even prevents the effects of CYP3A4 metabolism.

[0019] Standard in vitro dissolution methods are considered to correlate with or at least reflect the actual modified release profile in vivo in humans. Accordingly, the present invention provides, in its first aspect, a solid pharmaceutical composition comprising tacrolimus, of which less than 20% w / w. tacrolimus is released within 0.5 hour when it is subjected to an in vitro dissolution test using the USP paddle method and with 0.9 N HCl as the dissolution medium, and less than 50% w / w. Tacrolimus is released within 8 hours in an in vitro dissolution test using the USP paddle method and an aqueous dissolution medium adjusted to pH 4.5 with 0.005% hydroxypropyl cellulose.

[0020] This modified release profile is obtained by providing a pharmaceutical composition that comprises a solid dispersion or solid solution of tacrolimus in a hydrophilic or water miscible carrier, and one or more release modifying agents selected from the group consisting of water miscible polymers, insoluble polymers water, oils and oily materials, and the carrier contains polyethylene glycol and poloxamer in a ratio between 1: 3 and 10: 1.

[0021] In another aspect, the invention relates to solid dosage forms, particularly oral dosage forms, containing the composition of the invention, wherein said solid dosage forms exhibit a modified release profile. Delaying the release of tacrolimus into the distal duodenum may reduce drug-related gastrointestinal side effects and a relatively high degree of metabolism in the proximal gastrointestinal tract (CYP3A4 mediated metabolism). This can be achieved without losing systemic bioavailability due to the unique compositions of the invention, preferably compositions containing the active ingredient completely or partially dissolved in the carrier to form a solid dispersion and / or a solid solution at ambient temperature.

[0022] In still further aspects, 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 [0023] As used herein, the term "active substance" or "pharmaceutically active ingredient" means any ingredient that is intended to provide pharmacological or other direct action in the diagnosis, healing, alleviation, treatment or prevention of a disease, or affect the structure or any function of the human body or other animals. The term includes ingredients that may undergo chemical change during the manufacture of the drug product and are present in the drug product in a modified form intended to provide a particular action or effect.

[0024] In the present context, the term "hydrophilic" describes that something "likes water", i.e. a hydrophilic molecule or part of a molecule is one that is usually electrically polarized and is capable of forming hydrogen bonds with water molecules, thereby dissolving more easily in water than in oil or other "non-polar" solvents.

[0025] In the present context, the term "amphiphilic" refers to a molecule (such as a surfactant) having a polar, water-soluble group attached to a water-insoluble hydrocarbon chain. Therefore, one end of the molecule is hydrophilic (polar) and the other is hydrophobic (non-polar).

[0026] In the present context, the term "hydrophobic" means a compound that is prone to being electrically neutral and nonpolar, and thus prefers other inert and nonpolar solvents or molecular environments.

[0027] As used herein, the term "carrier" means any solvent or carrier fluid in a pharmaceutical product that does not play a pharmacological role. For example, water is a carrier for xylocaine and propylene glycol is a carrier for many antibiotics.

[0028] In the present context, the term "solid dispersion" means a drug or active ingredient or substance dispersed at the level of particles in an inert excipient, carrier, diluent or matrix in solid form, i.e. typically a dispersion of fine particles. [0029] In the present context, the term "solid solution" refers to a drug or active ingredient or substance dissolved at the molecular level in an inert excipient, carrier, diluent or matrix in the solid state.

[0030] As used herein, the term "analog" means a chemical compound that is structurally similar to another.

[0031] The term "drug" means a compound for use in diagnosing, healing, alleviating, treating or preventing a disease in a human or other animal.

[0032] In this context, the term "dosage form" means the form in which the drug is administered to the patient. It can be parenteral, topical, as a tablet, oral (liquid or dissolved powder), as a suppository, inhaled, transdermal, etc.

[0033] As used herein, the term "bioavailability" means the degree to which a drug or other substance becomes available to the target tissue after administration. As used herein, the term "bioequivalence" means the scientific basis on which generic and generic names are compared. For example, drugs are bioequivalent if they enter circulation at the same rate when given at similar doses under similar conditions. Parameters often used in bioequivalence studies are tmax, Cm, AUC0-infinity, AUC0-t. Other relevant parameters may be W50, W75 and / or MRT. Therefore, at least one of these parameters can be used to determine if bioequivalence exists. In addition, in the present context, two compositions are considered bioequivalent if the value of the parameter used is within 80-125% of the value for Prograf® or a similar commercially available tacrolimus-containing product used in the test.

[0034] In the present context, "tmax" means the time to reach maximum plasma concentration (Cmax) after administration; AUC0-infinity means the area under the plasma concentration-time curve as a function of time from time 0 to infinity; AUC0-t is the area under the plasma concentration curve versus time from time 0 to time t; W50 is the time when the plasma concentration is 50% or more of Cmax; W75 is the time when the plasma concentration is 75% or more of Cmax; and MRT means the average residence time of tacrolimus (and / or its analogue).

[0035] In the present context, the term "drug" means a compound used to treat a disease, injury or pain. The drug is correctly attributed to "prophylactic" e.g. in the field of maintaining health, and "therapeutic", e.g. in the field of restoring health.

[0036] In the present context, the terms "controlled release" and "modified release" are intended to be equivalent terms, including any type of tacrolimus release from the composition of the invention that is suitable to achieve a particular therapeutic or prophylactic response after administration to a patient. One skilled in the art knows how controlled release / modified release differs from release from ordinary tablets or capsules. The terms "controlled release" or "modified release" have the same meaning as described above. These terms include slow release (which results in lower C_max and later vol_max, but 1: ½ does not change), prolonged release (which results in lower Cmax, later t_maxbut observed 1½ is longer); delayed release (which results in unchanged Cmax, but with time delay and consequently t_max is delayed and you₂ does not change) as well as pulsatile release, burst release, sustained release, prolonged release, time-optimized release, rapid release (to achieve enhanced onset of action), etc. These terms also include e.g. use of specific conditions within the body, e.g. various enzymes or pH changes to control drug release.

[0037] In the present context, the term "erosion" or "eroding" means the gradual degradation of the surface of a material or structure, for example tablets or tablet coatings. [0038] The present invention provides pharmaceutical compositions and solid dosage forms for improved treatment of conditions that respond to tacrolimus treatment, particularly compositions and dosage forms that provide modified release of the active ingredient to increase its bioavailability.

[0039] The active substance in these inventive compositions is tacrolimus (also known as FK-506 or FR-900506). However, the scope of the present invention includes tacrolimus in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates, including hydrate, anhydrate, its complexes, etc.). Any derivative or active metabolite of tacrolimus, its pharmaceutically acceptable salts, solvates, complexes and prodrugs are also included.

[0040] In a preferred embodiment, the present invention thus provides a solid pharmaceutical composition comprising tacrolimus, of which less than 20% w / w. the active substance is released within 0.5 hour in an in vitro dissolution test using the paddle method according to USP using 0.1 N HCl as a dissolution medium; preferably, of which less than 20% w / w, more preferably less than 10% w / w the active substance is released within 3 hours.

[0041] This release profile is believed to significantly increase the bioavailability of tacrolimus in mammals, as the majority of the active substance is actually released in the digestive tract in a way that prevents or at least significantly reduces CYP3A4 metabolism. Furthermore, it is believed that this effect is correlated or at least reflects the in vitro dissolution profile of the solid pharmaceutical composition and / or dosage forms of the invention, which profile can be easily determined after subjecting the composition and / or dosage form to the standard in vitro dissolution method according to e.g. USP. Any USP in vitro dissolution method is considered useful for this purpose.

[0042] For example, the solid pharmaceutical composition of the invention releases at least 50% w / w. active substance within 4 hours, preferably within 2.5 hours in an in vitro dissolution test using the paddle method according to USP and using 0.1N HCl as the dissolution medium in the first 2 hours, followed by the use of a pH 6 dissolution medium 8.

[0043] Using a less standard dissolution medium, the composition according to the invention releases less than 50% w / w, especially less than 40% w / w, of the active substance within 8 hours, preferably within 15 hours when subjected to an in vitro dissolution test using the USP paddle method and an aqueous dissolution medium adjusted to pH 4.5 with 0.005% hydroxypropyl cellulose.

[0044] The desired modified release profile of the pharmaceutical composition can be achieved by using a pharmaceutical composition comprising a solid dispersion or solid solution of the active substance, i.e. tacrolimus or an analogue thereof, in a hydrophilic or water-miscible carrier and one or more release modifying agents.

[0045] In one embodiment of the invention, there is provided a modified release pharmaceutical composition comprising tacrolimus, which contains the active substance dissolved or dispersed in a hydrophilic or water-miscible carrier that comprises polyethylene glycol in a mixture with a poloxamer. A specific example of a useful mixture is a 70% w / w mixture polyethylene glycol 6000 (PEG6000) and 30% w / w poloxamer 188.

[0046] The composition of the invention may, after oral administration to a mammal in need thereof, exhibit an AUClAUCPrograf® value of at least about 1.3, where AUC values ​​are determined under similar conditions.

[0047] As can be seen from the examples herein, the bioavailability obtained after administration of the compositions of the invention is significantly improved. Thus, the AUC / AUCPrograph® value is about 1.5, such as about 1.75 or more, about 1.8 or more, about 1.9 or more, about 2.0 or more, about 2.5 or more, about 2.75 or more, about 3.0 or more, about 3.25 or more, about 3.5 or more, about 3.75 or more, about 4.0 or more, about 4.25 or more, about 4 , 5 or more, about 4.75 or more, or about 5.0 or more, where AUC values ​​are determined under similar conditions.

[0048] It is believed that after oral administration of the pharmaceutical composition of the present invention, the plasma concentration profile as a function of time shows an extended period of time during which the plasma concentration persists in the therapeutic window (i.e. the plasma concentration produces a therapeutic effect), without inducing serious side effects. Therefore, a decrease in peak concentration is also observed.

[0049] The composition of the invention after oral administration to a mammal in need thereof may release tacrolimus in a controlled manner and exhibit a Cmax that is at most 80% of the Cmax for Prograf® tablets, such as e.g. at most about 75%, at most about 70% , at most about 65%, at most about 60%, at most about 55%, at most about 50%, at most about 45%, or at most about 40%.

[0050] In the present context, the terms controlled release and modified release are intended equivalent terms, including any type of tacrolimus release from the composition of the invention that is suitable to achieve a particular therapeutic or prophylactic response when administered to a patient. One skilled in the art knows how controlled release / modified release differs from release from ordinary tablets or capsules. The terms "controlled release" or "modified release" have the same meaning as described above.

[0051] The terms controlled release / modified release include slow release (which results in lower C_max and later vol_max, but t / does not change), prolonged release (which results in lower Cmax, later tmax, but observed t / is longer); delayed release (which results in unchanged C_max, but with time delay and consequently t_max is delayed, at_/ does not change) as well as pulsatile release, burst release, sustained release, prolonged release, time-optimized release, rapid release (to achieve enhanced onset of action), etc. These terms also include, e.g., the use of specific conditions within the body, e.g. various enzymes or pH changes to control drug release.

[0052] In detail, after oral administration to a mammal, including a human, of the pharmaceutical composition of the present invention containing a 5 mg dose of tacrolimus, tacrolimus is released in a controlled manner and will show a Cmax of at most about 30 ng / ml, such as e.g. at most about 25 ng / ml or at most about 20 ng / ml.

[0053] However, a decrease in peak concentration may not lead to a decrease in the therapeutic effect provided that the plasma concentration of tacrolimus remains within the therapeutic window. Accordingly, the present invention also relates to a pharmaceutical composition wherein the W50 is at least about 2 hours, such as e.g. 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, at least about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or more or about 14 hours or more.

[0054] Furthermore or moreover, the composition according to the invention has Cdiff = [Cmax - Ct (t = 12 hours)] smaller than Prograf^® under the same conditions. If Cdiff for Prograf^® is defined as 100, then the Cdiff of the composition of the invention is usually 90 or less, such as e.g. about 85 or less, about 80 or less, about 75 or less, about 70 or less, about 65 or less, about 60 or less, about 55 or less, about 50 or less, about 45 or less or about 40 or less.

In particular, after oral administration to a mammal, including a human, of a pharmaceutical composition according to the invention containing 5 mg tacrolimus, tacrolimus is released in a controlled manner and exhibits a Cdiff of about 20 ng / ml or less, such as e.g. about 15 ng / ml or less, about 13 ng / ml or less or about 10 ng / ml or less. [0056] The pharmaceutical composition of the invention releases tacrolimus in a controlled manner to prolong the therapeutic effect of tacrolimus. In one aspect, release may be pH-dependent, i.e. release predominantly occurs after passage through the stomach. This pH-dependent release is mainly obtained with the aid of an enteric coating material as described herein. Release may also be pH independent, e.g. by providing a composition with a controlled release coating, such as e.g. a cellulose based coating, e.g. from ethyl cellulose, or by providing the composition in the form of a composition in a matrix, such as e.g. a type of matrix of a hydrophilic cellulose polymer, e.g. based on HPMC. Of course, you can also use a combination.

[0057] In general, the change in bioavailability and / or changes in other parameters related to bioavailability are usually determined in vivo in an appropriate animal model by testing the tested compositions together with e.g. Prograf® or a similar commercially available tacrolimus product . The use of a dog as a model organism to obtain evidence of the bioavailability of certain preparations is a common practice in the pharmaceutical industry.

[0058] The studies relevant for tacrolimus are non-randomized alternation studies in which each dog is its own control. Four dogs and four types of treatment are usually used. Since no iv injections are given, the bioavailability values ​​obtained are relative.

[0059] It has also surprisingly been found that the need for simultaneous food intake to ensure sufficient absorption of tacrolimus is significantly reduced or even completely removed.

[0060] Thus, the pharmaceutical compositions of the invention provide a significantly higher bioavailability of tacrolimus, which allows a reduction in the number of unit doses administered daily, and reduces or abolishes the need for administration in combination with food, which provides the recipient of the pharmaceutical composition with a greater degree of independence and, as a consequence, patient acceptance and compliance significantly improved. In addition, these compositions provide a significant reduction in side effects, and especially side effects associated with high peak concentrations (such as e.g. nephro- and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc.) and provide sustained release of tacrolimus leading to better therapy.

[0061] As mentioned above, one of the main challenges in formulating the tacrolimus composition is to avoid an undesirable food effect. In general, tacrolimus is much better absorbed when given orally without food. Therefore, a large difference in bioavailability is observed after administration with or without food. This relationship makes it difficult to give precise guidelines on the dose that should be administered and, moreover, requires the patient to be informed about the dosage regimen. The object of the present invention is to provide compositions for which the undesirable food effect is reduced. The present invention therefore provides a composition that does not exhibit a significant undesirable food effect upon administration of the composition to a mammal in need of such treatment, as evidenced by a value (AUCfed / AUCfasted) of at least about 0.85 with a lower limit of 90% confidence interval of at least 0.75 .

[0062] In particular, the pharmaceutical composition of the invention has a (AUCfed / AUCfasted) value of about 0.9 or more, such as, e.g., about 0.95 or more, about 0.97 or more, or about 1 or more, such as e.g. up to about 1.1 or up to about 1.2. [0063] Another advantage of the compositions of the present invention is the possibility of obtaining an effective therapeutic response at reduced dosing compared to traditional oral treatment. Accordingly, after oral administration to a mammal in need thereof, the pharmaceutical composition of the invention releases tacrolimus or an analogue thereof in a controlled manner and this composition is essentially bioequivalent to Prograf® or a similar commercially available tacrolimus product after administration at a dose of at most about 85 % w / w, such as e.g. at most about 80% w / w, at most about 75%, at most about 70% w / w, at most about 65% w / w, at most about 60% w / w, at most about 55% w / w or at most about 50% w / w a dose of tacrolimus administered as Program® or a similar commercially available tacrolimus containing product.

[0064] Parameters often used in bioequivalence studies are tmax, cmax, AUC0-infinity, AUC0-t. Other relevant parameters may be W50, W75 and / or MRT. Therefore, at least one of these parameters may be used to determine if bioequivalence is present. In addition, in the present context, two compositions are considered to be bioequivalent if the value of the parameter used is within 80125% of the value for Prograf® or a similar commercially available tacrolimus containing product used in the test.

[0065] In the present context, "tmax" means the time to reach maximum plasma concentration (cmax) after administration; AUC0-infinity means the area under the plasma concentration-time curve as a function of time from time 0 to infinity; AUC0-t is the area under the plasma concentration curve versus time from time 0 to time t; W50 is the time when the plasma concentration is 50% or more of Cmax; W75 is the time when the plasma concentration is 75% or more of Cmax; and MRT means the average residence time of tacrolimus (and / or its analogue).

[0066] Two other major disadvantages associated with tacrolimus treatment or prevention are the relatively high incidence of side effects and the relatively high inter-individual variability. It is anticipated that the composition of the invention will lead to a reduction in side effects. This may be a reduction in frequency reduction or in terms of severity. Considered side effects include e.g. nephro- and neurotoxicity, diarrhea, constipation, stomach ache, nausea etc. In one aspect, the invention relates to a pharmaceutical composition in the form of particles comprising tacrolimus or an analogue thereof with one or more pharmaceutically acceptable excipients, wherein the composition, when administered to a mammal in need thereof, releases tacrolimus or an analogue thereof in a controlled manner and reduces side effects as compared to side effects Prograf® given under the same conditions and in doses that provide an equivalent therapeutic effect.

[0067] Increasing bioavailability, the area under the curve (AUC), will usually reduce intrinsic and inter-individual variability in drug absorption. This is especially true, especially when low and poor bioavailability is due to poor water solubility. It is believed that the compositions of the invention will show CV (coefficient of variation) for the resulting area under the curve that is significantly lower than for Prograf® and similar products.

[0068] As mentioned above, one of the basic features of the present invention is that it makes it possible to achieve an improvement in bioavailability when the compositions of the present invention are administered orally. Typically, the low oral bioavailability of a drug substance is a barrier to the design of controlled or modified release of drug substance compositions due to the fact that it is almost impossible to achieve effective drug levels over a prolonged period. However, a significant improvement in bioavailability and thus the possibility of designing controlled, modified or delayed release compositions can be achieved using this technology.

[0069] Tacrolimus is extensively metabolised by CYP3A4 in the intestinal wall and liver. In this regard, a convenient controlled release composition may be a composition designed to release tacrolimus in a delayed manner to avoid or reduce metabolism by CYP3A4 in the gastrointestinal tract.

[0070] Delayed release is mainly accomplished by using some type of enteric coating. While the semi-permeable coating will exhibit delayed release to some extent, it does not "delay" release sufficiently advantageously. In addition, it requires a certain amount of time to release the content. The coating sought for this invention is a pH-dependent coating. This type of coating is very resistant to drug release until it reaches a certain pH. In the range of a few 1/10 of the pH, the coating changes properties and becomes permeable. Examples of pH sensitive polymers that are relatively insoluble and impermeable at gastric pH but which are more soluble and permeable at the pH of the small intestine and colon include, but are not limited to, polyacrylamides, phthalate derivatives such as acid carbohydrate phthalates, acetate phthalate amylose, cellulose acetate phthalate, other cellulose phthalate esters, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid copolymer, dibutyl phthalate, styrene-maleic acid, polyvinyl acetate, maleic acid, polyvinyl acetate such as copolymers of acrylic acid and acrylic esters, poly methacrylic acid and its esters, poly (acrylic methacrylic acid) copolymers, shellac and copolymers of vinyl acetate and crotonic acid.

[0071] Particularly interesting pH sensitive polymers include shellac; phthalate derivatives, in particular cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropyl methylcellulose phthalate; polyacrylic acid derivatives, in particular poly (methyl methacrylate) in combination with acrylic acid and acrylic ester copolymers; and copolymers of vinyl acetate and crotonic acid.

[0072] The release of the active ingredient from a composition having a delayed release coating may also be an enzymatic reaction if, for example, zein or mono / diglyceride mixtures are used as the coating material.

[0073] After oral administration to a mammal in need thereof, including a human, the controlled release pharmaceutical composition of the present invention releases tacrolimus in such a way that a plasma concentration of at least about

5 ng / ml, such as e.g. at least about 7.5 ng / ml or at least about 10 ng / ml for a period of at least about 24 hours. In a particular aspect of the invention, the difference between peak plasma concentration and plasma concentration measured 24 hours after administration is at most about 20 ng / ml, such as e.g. at most about 10 ng / ml, at most about 7.5 ng / ml or at most about 5 ng / ml.

[0074] The composition of the invention is designed to release tacrolimus in a modified manner and may, in the form of particles comprising tacrolimus together with one or more pharmaceutically acceptable excipients, after oral administration to a mammal in need thereof, exhibit delayed release of tacrolimus and / or its analogue such that at most 10% w / w, such as e.g. at most about 7.5% w / w or at most about 5% w / w the total amount of tacrolimus or its analogue is released within the first two hours, such as e.g. within the first hour after administration.

[0075] The following conditions may be met with regard to in vitro dissolution tests carried out under acidic conditions:

i) at most about 30% w / w, such as e.g. at most about 25% w / w, at most about 20% w / w, at most about 15% w / w. or at most about 14% w / w Tacrolimus is released within 2 hours in an in vitro dissolution test using a dissolution medium with a pH of at most about 5, such as at most about 4.5, at most about 4, at most about 3.5, at most about 3 , at most about 2 or at most about 1.5;

ii) at most about 10% w / w, such as e.g. at most about 7.5% w / w, at most about 5% w / w or at most about 2.5% w / w Tacrolimus is released within 2 hours in an in vitro dissolution test using a dissolution medium with a pH of at most about 5, such as at most about 4.5, at most about 4, at most about 3.5, at most about 3 , at most about 2 or at most about 1.5;

iii) at most about 60% w / w, such as e.g. at most about 50% w / w, at most about 40% w / w or at most about 30% w / w tacrolimus is released within 15 hours, such as e.g. around 12 hours, when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5, such as e.g. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5;

iv) at most about 40% w / w, such as e.g. at most about 30% w / w, at most about 25% w / w or at most about 20% w / w Tacrolimus is released within 6 hours when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5, such as e.g. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5, and / or

v) at most about 30% w / w, such as e.g. at most about 25% w / w, at most about 20% w / w or at most about 15% w / w tacrolimus is released within 4 hours when tested in an in vitro dissolution test using a dissolution medium with a pH of at most about 4.5, such as e.g. at most about 4.0, at most about 3.5, at most about 3, at most about 2 or at most about 1.5.

[0076] In addition to tacrolimus, the composition of the invention may also contain another therapeutically, prophylactically and / or diagnostically active substance. Combinations of tacrolimus with at least one of the following active substances are of particular interest: Substances indicated for use in connection with organ transplantation, such as e.g.

steroids, calcineurin inhibitors and / or antiproliferative agents. Specific examples include prednisone, prednisolone, methylprednisone, cyclosporin, mycophenolate, azathioprine, sirolimus, everolimus, mycophenolate sodium and FTY720 (Novartis).

[0077] The pharmaceutical compositions can be prepared in any convenient manner, such as, e.g., granulation, mixing, spray drying, etc. A particularly useful method is the method described in WO 03/004001. Described herein is a process for producing particulate material by controlled agglomeration, i.e., a method that allows a controlled increase in particle size. The method comprises spraying a first composition comprising e.g. tacrolimus and the carrier, which has been molten, to a second solid carrier medium.

Typically, the meltable carrier has a melting point of at least 5 ° C but lower than the melting point of tacrolimus. The carrier melting point may be in the range of 10 ° C to 150 ° C, such as e.g. in the range of 30 ° C to 100 ° C or in the range of 40 ° C to 50 ° C, which is most preferred.

[0078] It is within the skill of the average practitioner to select a suitable carrier that is pharmaceutically acceptable, capable of dissolving or at least partially dissolving tacrolimus and has a melting point within the desired range using general knowledge and routine experimentation. Suitable carrier candidates are those described in WO 03/004001, which are incorporated herein by reference.

[0079] In the present context, suitable carriers are e.g. those mentioned as oil or oily material (as discussed hereinafter) as well as those disclosed in WO 03/004001. [0080] The advantage of using the controlled agglomeration method described in WO 03/004001 is that it is possible to apply a relatively large amount of molten material to the particulate material without obtaining an undesirable increase in particle size. Accordingly, the particulate material in the pharmaceutical composition of the invention has a geometric weighted average diameter d_g &gt; 10 μm, such as e.g.&gt; 20 μm, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000, such as e.g. from about 100 to about 1500 pm, from about 100 to about 1000 μm or from about 100 to about 700 μm, or at most about

400 μm or at most about 300 pm, such as e.g. from about 50 to about 400 pm, such as e.g. from about 50 to about 350 μm, from about 50 to about 300 pm, from about 50 to about 250 μm or from about 100 to about 300 μm, when produced using a controlled agglomeration method.

[0081] The particulate material obtained as described above has suitable properties with respect to fluidity and / or compressibility and is therefore suitable for further processing into pharmaceutical dosage forms.

Solid dispersion and / or tacrolimus solid solution.

[0082] The solid dispersion or solid solution used in the preferred embodiment of the invention comprises tacrolimus dispersed or dissolved in a hydrophilic or water miscible carrier with a melting point (freezing point or freezing point) of at least 20 ° C at a concentration between about 0.01% w. and about 15% w / w, and wherein the dispersion forms a solid dispersion or solid solution at ambient temperature (room temperature).

[0083] The concentration of the active substance in the hydrophilic or water miscible carrier is at most 15% w / w, preferably at most 10% w / w, preferably at most 8% w / w, more preferably at most 6 % w / w, even more preferably at most 5% w / w, at most 4% w / w, especially at most 3% w / w, and especially at most 2% w / w .; and / or is at least about 0.05% w / w, preferably at least about 0.1% w / w, more preferably at least about 0.5% w / w, especially at least about 0 , 7% w / w, and especially at least about 1% w / w

[0084] The combination of the active substance and the carrier can physically form either a solid dispersion, i.e. the active substance is dispersed in the particulate carrier or a solid solution, i.e. the active substance is dissolved in the carrier at the molecular level. The active substance and the carrier can also form a solid dispersion containing the part of the active substance dissolved at the molecular level. The physical state of the dispersion and / or solution can be determined using a variety of methods such as high temperature microscopy (HSM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) optionally in combination with X-ray energy dispersion (EDX) and X-ray analysis powder diffraction. In a preferred embodiment, the active substance is completely dissolved in the carrier to form a solid solution at ambient temperature.

[0085] Examples of useful hydrophilic or water miscible carriers for use in accordance with this invention are selected from the group consisting of polyethylene glycols, poloxamers and mixtures thereof.

[0086] In a preferred embodiment, the carrier is polyethylene glycol (PEG), especially PEG with an average molecular weight of at least 1500, preferably at least 3000, more preferably at least 4000, especially at least 6000, mixed with the poloxamer in a ratio (by weight) between 1: 3 and 10: 1, preferably between 1: 1 and 5: 1, more preferably between 3: 2 and 4: 1, especially between 2: 1 and 3: 1, especially about 7: 3. A specific example of a useful mixture is a mixture of PEG6000 and poloxamer 188 in a ratio of 7: 3.

[0087] For polyethylene glycols (PEG), the melting point (freezing point or freezing point) increases as the average molecular weight increases. For example, for PEG 400 is in the range of 4-8 ° C, for PEG 600 is in the range of 2025 ° C, for PEG1500 is in the range of 44-48 ° C, for PEG2000 is about 52 ° C, for PEG 4000 is about 59 ° C, for PEG 6000 it is about 65 ° C, and for PEG 8000 it is about 61 ° C.

[0088] Suitable poloxamers (also referred to as polyoxypropylene-polyoxyethylene block copolymers) include, for example, poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407, or other block copolymers of ethylene oxide and propylene oxide, such as from the Pluronic® and / or Tetronic® series . Suitable block copolymers of the Pluronic® series include polymers with a molecular weight of about 3,000 or more, such as e.g. from about 4,000 to about 20,000 and / or viscosities (Brookfield) from about 200 to about 4,000 cP, such as e.g. from about 250 to about 3,000 cP. Useful 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. Tetronic® block copolymers include polymers with a molecular weight of about 8,000 or more, such as from about 9,000 to about 35,000 and / or viscosities (Brookfield) from about 500 to about 45,000 cP, such as e.g. from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances, which are pastes at room temperature and at 77 ° C for substances that are solid at room temperature.

[0089] In a preferred embodiment of the present invention, the poloxamer is poloxamer 188, with an average molecular weight of about 8400 and a melting point of about 50-54 ° C. Pharmaceutically acceptable excipients [0090] Examples of suitable excipients for use in the composition or solid dosage form of the present invention include fillers, diluents, disintegrants, binders, lubricants and the like or mixtures thereof. Because the composition or solid dosage form of the invention can be used for a variety of purposes, excipients are typically selected for such different uses. Other pharmaceutically acceptable excipients for suitable use are e.g. acidulants, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and / or solubilizing agents, flavoring and flavoring agents, humectants, sweetening agents, wetting agents and the like.

[0091] Examples of suitable fillers, diluents and / or binders include lactose (e.g. spray dried lactose, α-lactose, β-lactose, Tabletose®, various grades Pharmatose®, Microtose® or Fast-Floc®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc^®), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methyl cellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH from Shin-Etsu, Ltd, such as e.g. 4,000 cP Methocelu E and Metolose 60 SH grades , 4,000 cP Methocelu F and Metolose 65 SH grades, 4,000, 15,000 and 100,000 cP Methocelu K grades; and 4,000, 15,000, 39,000 and 100,000 Metolose 90 SH grades, methyl cellulose polymers (such like for example. Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, starch, maltol, skeleton, dextrose rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc. [0092] Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.

[0093] Specific examples of disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, potassium polacrylate, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch^® and Explotab^®) etc. [0094] Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethyl cellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, methylcellulose povidone, pregelatinized starch etc. [0095] The composition may also include lubricants and lubricants. Examples include stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, sodium sulphate , sodium acetate etc.

[0096] Other excipients that may be included in the composition or solid dosage form of the invention are e.g. flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, agents wetting agents, moisture regulating agents, surfactants, suspending agents, absorption enhancers, release modifying agents etc.

[0097] Other additives in the composition or solid dosage form according to the invention may be antioxidants such as, e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulphite, propyl gallate, sodium formaldehyde sulfosulfate sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives etc. The carrier composition may also contain e.g. stabilizing agents. The concentration of antioxidant and / or stabilizing agent in the carrier composition is usually from about 0.1% w / w. up to about 5% w / w

[0098] The pharmaceutical composition or solid dosage form of the invention may also contain one or more surfactants or surfactants. It is believed that such substances play a role in wetting the slightly soluble active substance and therefore contribute to improving the solubility characteristics of the active substance.

[0099] Suitable excipients for use in the composition or solid dosage form of the invention are surfactants, such as, e.g., amphiphilic surfactants, such as those disclosed in WO 00/50007 on behalf of Lipocine, Inc. Examples of surfactants include

i) polyethoxylated fatty acids, such as, for example, mono or diesters of polyethylene glycol fatty acids or mixtures thereof, such as, e.g., mono or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, with glycol polyethylene can be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, 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, 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) fatty acid esters with polyethylene glycol and glycerin, e.g. esters as mentioned above, but in the form of individual fatty acid glyceryl esters;

iii) esters of glycerol, propylene glycol, ethylene glycol, PEG or sorbitol e.g. with vegetable oils, e.g. with hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot seed oil, olive oil, peanut oil, hydrogenated oil from palm kernels and the like, iv) polyglycerized fatty acids, such as e.g. polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linolate,

v) fatty acid esters of propylene glycol, such as e.g. propylene glycol monolaurate, propylene glycol ricinolate and the like, vi) mono- and diglycerides such as e.g. glyceryl monooleate, glyceryl dioleate, glyceryl mono- and / or dioleate glyceryl, glyceryl caprate etc .;

vii) sterol and sterol derivatives;

viii) polyethylene glycol sorbitan fatty acid esters (PEG sorbitan fatty acid esters) such as PEG esters with different molecular weights given above and different esters from the Tween® series;

ix) polyethylene glycol alkyl ethers, such as, for example, PEG-oleyl ether and PEG-lauryl ether;

x) sugar esters such as, for example, sucrose monopalmitate and sucrose monolaurate;

xi) polyethylene glycol ethers with alkylphenols, such as e.g. from the Triton® X or N series;

xii) polyoxyethylene-polyoxypropylene block copolymers, such as e.g. from the Pluronic® series, Synperonic® series, Emkalyx®, Lutrol®, Supronic® etc. The general term for these polymers is "poloxamers" and relevant examples in this context are Poloksamer 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 and fatty acid esters, such as from the Span® series or the Ariacel® series, such as, e.g., sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like;

xiv) fatty acid esters with lower alcohols, such as, for example, oleate, isopropyl myristate, isopropyl palmitate, etc .;

xv) ionic surfactants, including cationic, anionic and amphoteric surfactants, such as e.g. fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates etc.

[0100] When the surfactant or surfactant mixture is present in the composition or solid dosage form of the invention, the concentration of surfactant (surfactants) is usually in the range of about 0.1-80% w / w, such as e.g. from about 0.1 to about 20% w / w, from about 0.1 to about 15% w / w, from about 0.5 to about 10% w / w. or alternatively, from about 0.10 to about 80% w / w, such as e.g. from about 10 to about 70% w / w, from about 20 to about 60% w / w or from about 30 to about 50% w / w

[0101] One of the one or more pharmaceutically acceptable excipients may be selected from the group consisting of silicic acid or a derivative or salt thereof, including silicates, silicon dioxide and its polymers; magnesium aluminum silicate and / or magnesium aluminum silicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite. [0102] Such materials are particularly useful as material for the sorption of oil or oily materials in pharmaceuticals, cosmetics and / or food. In a specific embodiment, the material is used as a sorption material for oils or oily materials in pharmaceuticals. A material that has the ability to act as a sorption material for oils or oily materials is also referred to as "oil absorbing material". Furthermore, in the present context, "absorption" as used herein means "absorption" as well as "adsorption". It is important to recognize that when one of these terms is used, it is intended to include the phenomenon of absorption as well as adsorption.

In particular, the pharmaceutically acceptable excipient may be silicic acid or a derivative or salt thereof, such as, e.g., silicon dioxide or a polymer thereof, as a pharmaceutically acceptable excipient. Depending on the quality of the silicon dioxide used, it can be a lubricant or it can be an oil-absorbing material. The types fulfilling the latter function seem to be the most important.

[0104] The composition or solid dosage form according to the invention comprises a pharmaceutically acceptable excipient, which is a silicon dioxide product with properties corresponding to the Aeroperl agent^® 300 (available from Degussa, Frankfurt,

Germany).

[0105] The use of oil-absorbent material in the compositions or dosage forms of the invention is very advantageous in the preparation of pharmaceutical, cosmetic, nutritional and / or food compositions when the composition comprises an oil or oily material. One advantage is that you can incorporate a relatively large amount of oil and oily material and you will still be dealing with a material that is solid. Accordingly, solid compositions with a relatively high oil or oily-like material content can be prepared by using the oil-absorbing material according to the invention. In the pharmaceutical field, it is convenient to incorporate a relatively large amount of oil or oily material into the solid composition, especially in those situations where the active substance does not have adequate water solubility properties (e.g. has poor water solubility), stability in the aqueous medium (i.e. degradation in the aqueous medium), oral bioavailability (i.e. has low bioavailability) etc., or in those situations where it is desired to modify the release of the active substance from the composition to achieve controlled, delayed, prolonged and / or pulsed delivery of the active substance. Therefore, in a preferred form, it is used in the preparation of pharmaceutical compositions.

[0106] The oil absorbing material for use in processing into solid compositions absorbs typically about 5% w / w. or more, such as e.g. about 10% w / w or more, about 15% w / w or more, about 20% w / w or more, about 25% w / w or more, about 30% w / w or more, about 35% w / w or more, by about 40% w / w or more, about 45% w / w or more, about 50 w / w or more, about 55% w / w or more, about 60% w / w or more, about 65% w / w or more, about 70% w / w or more, about 75% w / w or more, about 80% w / w or more, about 85% w / w or more, about 90% w / w or more or about 95% w / w or more oil or oily material and remains a solid material.

[0107] Another aspect of the invention relates to compositions or solid dosage forms comprising an oil or oily material.

[0108] In the present context, the term "oils and oily materials" is used in a very broad sense to include oils, waxes, semi-solid materials and materials that are typically used in the pharmaceutical industry as solvents (such as organic solvents) or cosolvents, and the term also includes therapeutically and / or prophylactically active substances that are in liquid form at ambient temperature; in addition, the term includes emulsions such as, for example, microemulsions and nanoemulsions, and suspensions. Oils and oily materials that can be absorbed will usually be liquids at ambient temperature or at elevated temperature (for practical reasons, the maximum temperature is around 250 ° C). They can be hydrophilic, lipophilic, hydrophobic and / or amphiphilic materials.

[0109] Oils and oily materials suitable for use in the present context are substances or materials whose melting point is at least about 0 ° C and at most about 250 ° C.

[0110] In certain embodiments of the invention, the oil or oily material has a melting point of about 5 ° C or higher, such as e.g. about 10 ° C or higher, about 15 ° C or higher, about 20 ° C or higher or about 25 ° C or higher.

[0111] In further embodiments of the invention, the oil or oily material has a melting point of at least about 25 ° C, such as e.g. at least about 30 ° C, at least about 35 ° C or at least about 40 ° C. For practical reasons, the melting point cannot usually be too high, so the oil or oily material usually has a melting point of at most about 300 ° C, such as e.g. at most about 250 ° C, at most about 200 ° C, at most about 150 ° C or at most about 100 ° C. If the melting point is higher, a relatively high temperature may e.g. lead to oxidation or other degradation of the active substance in those cases where e.g. a therapeutically and / or prophylactically active substance is included.

[0112] In the present context, the melting point is determined by DSC (differential scanning calorimetry). The melting point is determined as the temperature at which a linearly increasing DSC curve intersects the temperature axis.

[0113] Interesting oils and oily materials are generally substances that are used in the production of pharmaceuticals as so-called melt binders or solid solvents (in solid dosage form) or as co-solvents or pharmaceutical ingredients for topical use.

[0114] It may be hydrophilic, hydrophobic and / or have surface-active properties. In general, hydrophilic and / or hydrophobic oils or oily materials are suitable for use in the manufacture of a pharmaceutical composition containing a therapeutically and / or prophylactically active substance with relatively low water solubility and / or when the release of the active substance from the pharmaceutical composition is designed so that was immediate or unmodified. On the other hand, hydrophobic oils or oily materials are usually used in the production of modified release pharmaceutical compositions. The considerations outlined above are simplified to illustrate the general principles, but there are many cases where other combinations of oils or oily materials and other purposes are appropriate, and therefore the above examples should not in any way limit the invention.

[0115] A suitable hydrophilic oil or oily material is usually selected from the group consisting of: polyether glycols, such as, e.g., polyethylene glycols, polypropylene glycols;

polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof or can be selected from the group consisting of: xylitol, sorbitol, sodium potassium tartaric acid, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone methyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid , Gelucire 50/13, other types of Gelucire, such as e.g. Gelucire 44/14 etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Sucro-ester 11, Sucro-ester 15, maltose, mannitol and mixtures thereof.

[0116] A suitable hydrophobic oil or oily material may be selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils, such as, for example, cocoa butter, beef tallow, lard, polyether glycol esters; higher fatty acid such as e.g. stearic acid, myristic acid, palmitic acid; higher alcohols such as e.g. cetanol, stearyl alcohol; low melting waxes, such as glyceryl monostearate, glyceryl monooleate, hydrogenated tallow, myristyl alcohol, old alcohol, substituted and / or unsubstituted monoglycerides, substituted and / or unsubstituted diglycerides, substituted and / or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax, carnauba wax Japanese wax, acetylated monoglycerides; NVP polymers, PVP polymers, acrylic polymers and mixtures thereof.

[0117] In an interesting embodiment, the oil or oily-like material is polyethylene glycol with an average molecular weight in the range of from about 400 to about 35,000, such as e.g. from about 800 to about 35,000, from about 1000 to about 35,000, such as for example. polyethylene glycol 1000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6,000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000, polyethylene glycol 10,000, glycol 15,000 polyethylene glycol, 20,000 polyethylene glycol, or 35,000 polyethylene glycol. In certain situations, polyethylene glycol with a molecular weight of from about 35,000 to about 100,000 can be used.

[0118] In another interesting embodiment, the oil or oily-like material is polyethylene oxide with a molecular weight from about 2,000 to about 7,000,000, such as, e.g., from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000, such as from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 from about 400,000, or from about 100,000 to about 300,000. [0119] In a further embodiment, the oil or oily-like material is a poloxamer, such as e.g. Poloksamer 188, Poloksamer 237, Poloksamer 338 or Poloksamer 407 or other block copolymers of ethylene oxide and propylene oxide, such as from the Pluronic® and / or Tetronic® series.

Suitable block copolymers of the Pluronic® series include polymers with a molecular weight of about 3,000 or more, such as, e.g., from about 4,000 to about 20,000, and / or a Brookfield viscosity from about 200 to about 4,000 cP, such as e.g. from about 250 to about 3,000 cP. Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable block copolymers of the Tetronic® series include polymers with a molecular weight of about 8,000 or more, such as, for example, from about 9,000 to about 35,000 and / or Brookfield viscosities from about 500 to about 45,000 cP, such as from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances that are pastes at room temperature and at 77 ° C for substances that are solid at room temperature.

[0120] The oil or oily-like material may also be a sorbitan ester, such as, for example, sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monostearate, sesquiate sorbitan, sorbitan trioleate, sorbitan tristearate or mixtures thereof. [0121] The oil or oily-like material may of course contain a mixture of different oils or oily-like materials, such as, for example, a mixture of hydrophilic and / or hydrophobic materials.

[0122] Other suitable oils or oily materials may be solvents or semi-solid excipients such as polypropylene glycol, polyglycosylated glycerides, including Gelucire 44/14, materials of complex fats of vegetable origin, including cocoa oil, carnauba wax, vegetable oils, such like for example. almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil, olive oil, castor oil, palm kernel oil, peanut oil, rapeseed oil, grape seed oil etc., hydrogenated vegetable oils, such as . hydrogenated peanut oil, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; natural fat materials of animal origin, including beeswax, lanolin, fatty alcohols, including fatty cetyl, stearyl, lauric, myristic, palmitic, stearic alcohol; esters including glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; liquid esterified semi-synthetic glycerides, including Miglycol 810/812; fatty acid amides or alkanolamides, including ethanol stearamide, coconut fatty acid diethanolamide, acetic acid esters with mono and diglycerides, citric acid esters with mono and diglycerides, lactic acid esters with mono and diglycerides, mono and diglycerides, polyesters of glycerol fatty acids, polyglycerol polyricinolate, fatty acid propylene glycol esters, sorbitan monostearates, sorbitan tristearates, sodium stearyl lactate, calcium stearyl lactate, diacetyltartaric acid esters with mono and diglycerides etc.

[0123] Typically, the pharmaceutical composition or solid dosage form according to the invention contain a concentration of oil or oily material in the composition of about 5% w / w. or more, such as e.g. about 10% w / w or more, about 15% w / w or more, about 20% w / w or more, about 25% w / w or more, about 30% w / w or more, about 35% w / w or more, about 40% w / w or more, about 45% w / w or more, about 50 w / w or more, about 55% w / w or more, about 60% w / w or more, about 65% w / w or more, about 70% w / w or more, about 75% w / w or more, about 80% w / w or more, about 85% w / w or more, about 90% w / w or more or about 95% w / w or more.

[0124] The concentration of the oil or oily material in the composition or solid dosage form of the invention may range from about 20% to about 80% w / w, such as, e.g., from about 25% to about 75% w / w wt.

[0125] One advantage is the possibility of introducing a relatively large amount of oil and oily material and still having material that is solid. Thus, it is possible to prepare solid compositions with a relatively high oil or oily materials addition by using the oil-absorbing material according to the invention. In the pharmaceutical field, it is convenient to incorporate a relatively large amount of oil or oily material into the solid composition, especially in those situations where the active substance does not have adequate water solubility properties (e.g., has low water solubility), stability in an aqueous medium (i.e. degradation in the aqueous medium), oral bioavailability (i.e. has low bioavailability) etc., or in those situations where it is desired to modify the release of the active ingredient from the composition to achieve controlled, delayed, prolonged and / or pulsed delivery of the active ingredient.

[0126] A further advantage is that the resulting particulate material is a free-flowing powder and thus can be easily processed, e.g. into solid dosage forms, such as tablets, capsules or sachets. Typically, the particulate material has the right properties for producing tablets by direct compression without adding large amounts of other additives. A suitable test for testing the fluidity of a particulate material is the method described in Ph.Eur., Which measures the flow rate of material through a funnel with a 10.0 mm diameter outlet (orifice).

[0127] At least a portion of tacrolimus is present in the composition in the form of a solid solution, including molecular dispersion and solid dispersion. Usually 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, such as e.g. 95% or more or about 100% w / w Tacrolimus is present in the composition as a solid dispersion.

[0128] Solid dispersion can be obtained by various routes, e.g., using organic solvents, or by dispersing or dissolving the active ingredient in another suitable medium (e.g., oil or oily material that occurs as a liquid at room temperature or at elevated temperatures).

[0129] Solid dispersions (solvent method) can, for example, be prepared by dissolving a physical mixture of the active substance (e.g. drug substance) and carrier in a conventional organic solvent, followed by evaporation of the solvent. The carrier is often a hydrophilic polymer. Suitable organic solvents include an acceptable pharmaceutical solvent in which the active substance is soluble, such as methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone and mixtures thereof.

[0130] Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearates, poly &lt;-caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-poly (vinyl acetate) copolymer PVP-PVA (Kollidon VA64) polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose and polyethylene oxide (PEO).

[0131] For solid dispersions that release the active substance in a favorable pH range providing acceptable intestinal absorption, suitable acid-containing polymers may be suitable. Such a polymer can be one or more selected from the group consisting of hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, E-methacrylate copolymer, E-methacrylate cellulose (CAP), starch glycolate, polacryline, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.

[0132] 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 29:20. However, narrower ranges from about 3: 1 to about 1: 5 can be used, such as e.g. from about 1: 1 to about 1: 3.

[0133] The solid dispersion is preferably prepared by spray drying, controlled agglomeration, lyophilization or coating on carrier particles, or by any other solvent removal process. The dried product contains the active substance present in the form of a solid dispersion, including a molecular dispersion and a solid solution.

[0134] As an alternative to the use of organic solvents, the drug and polymer can be co-milled or extruded together at elevated temperatures (hot extrusion).

[0135] Pharmaceutical compositions containing tacrolimus at least partially in the form of a solid dispersion or solid solution can generally be prepared using any suitable procedure for preparing pharmaceutical compositions known in the art.

[0136] In addition to using the organic solvent based method, solid tacrolimus dispersion or solid solutions can 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 the stability of the solid dispersion / solution.

[0137] In a further aspect, the invention relates to a method of preparing a pharmaceutical composition according to the invention. In general, any suitable method in the pharmaceutical field can be used. However, to enable the incorporation of a relatively large amount of oil or oily material, the method described in WO 03/004001 has proved particularly useful. The method comprises spraying the first composition in liquid form, said composition comprising a first carrier or carrier fluid and having a melting point higher than 5 ° C, on a second composition comprising a second carrier or carrier material, said second composition being e.g. liquefied and has a melting point lower than the melting point of the first carrier or carrier fluid. The active substance may be present in the first carrier composition or carrier fluid and / or in the second carrier composition or carrier. However, in those cases where tacrolimus is present, at least in part, in the form of a solid dispersion, it is preferable to incorporate or dissolve tacrolimus in the first carrier composition or carrier fluid.

Solid Dosage Forms [0138] The pharmaceutical composition of the invention is in the form of particles and can be used as such. However, in many cases it is more convenient to provide the composition in the form of granules, pellets, microspheres, nanoparticles and the like, or in the form of solid dosage forms including tablets, capsules, sachets and the like. The solid dosage form of the invention may be a single unit dosage form, or it may be in the form of a multi-depot dosage form containing a plurality of individual units, such as, for example, pellets, beads and / or granules.

[0139] Typically, the pharmaceutical composition or solid dosage form of the invention is for oral, buccal or sublingual administration.

[0140] The invention also relates to the above-mentioned pharmaceutical form. Compositions / solid dosage forms which are intended to release tacrolimus and / or its analog in a fast, delayed or modified manner are within the scope of the invention. All these methods are considered controlled. Furthermore, pH dependent release is also included in the term "controlled method".

[0141] The solid dosage form according to the present invention comprises a particulate pharmaceutical composition as described above. The details and particulars disclosed in this main aspect of the invention relate mutatis mutandis to other aspects of the invention. Therefore, properties with respect to increasing bioavailability, changes in bioavailability parameters, reduction of undesirable food effect as well as release of tacrolimus and / or its analogue etc. the particulate pharmaceutical compositions described herein and / or claimed are analogous to the solid dosage form of the present invention.

[0142] Typically, the concentration of the particulate pharmaceutical composition ranges from about 5 to 100% w / w, such as, e.g., from about 10% to about 90% w / w, from about 15% to about 85% w / w, from about 20% to about 80% w / w, from about 25% to about 80% w / w, from about 30% to about 80% w / w, from about 35% to about 80% w / w, from about 40% to about 75% w / w, from about 45% to about 75% w / w. or from about 50% to about 70% w / w dosage form. For example, the concentration of the particulate pharmaceutical composition is 50% w / w. or more dosage forms.

[0143] The solid dosage form of the invention is obtained by processing the particulate material of the invention using techniques well known to the person skilled in the art. Typically, this further includes the addition of one or more of the pharmaceutically acceptable excipients listed herein.

[0144] The composition or solid dosage form of the invention may be designed to release tacrolimus and / or its analogs in any suitable manner, provided that bioavailability increases. Thus, the active substance can be released relatively quickly to achieve a faster onset of action, it can be released so that it exhibits zero or first order kinetics, or it can be released in a modified manner to achieve a specific course of release.

All such routes are considered controlled. Normal formulations are also within the scope of the present invention.

[0145] Recommended dose range for Prograf^® is 0.1 to 0.2 mg / kg / day when given every 12 hours in two divided doses. More importantly, blood levels must be monitored.

[0146] A typical level for 1-3 months is 7-20 ng / ml, and for 4-12 months the level should be 5-15 ng / ml. These are only indications and may vary depending on the type of transplant and ethnic issues.

[0147] The following data were determined for renal transplant patients:

<td></td><td colspan="2">Caucasian race n = 114</td><td colspan="2">Black breed n = 56</td>

<td>Time after transplantation</td><td>Dose^(mg^{/ k}g)</td><td>Minimum concentration (ng / ml)</td><td>Dose^(mg^{/ k}g⁾</td><td>Minimum concentration (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>6th month</td><td> 0,14</td><td> 11,8</td><td> 0,24</td><td> 11,5</td>

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

[0148] Contemplated recommended doses of the products of the present invention will be from 0.02 mg / kg / day to 0.15 mg / kg / day, with once daily dosing.

[0149] The composition or solid dosage form of the invention may also be coated with a film coating, enteric coating, modified release coating, protective coating, anti-stick coating, etc.

[0150] The solid dosage form according to the invention may also be coated to obtain suitable properties, eg regarding controlled release of the active ingredient. The coating can be applied to individual unit dosage forms (e.g. tablets, capsules) or applied to a multi-depot dosage form or individual units thereof.

[0151] Suitable coating materials are e.g. methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic polymers, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate, cellulose acetate, cellulose acetate, cellulose acetate, cellulose acetate, cellulose acetate carnauba, microcrystalline wax, glyceryl monostearate, zein.

[0152] A plasticizer or other ingredients may be added to the coating material. The same or other active ingredients can also be added to the coating material.

[0153] In preferred embodiments of the invention, solid dosage forms are designed to release tacrolimus and / or its analog in a controlled manner. In the present context, the term "controlled method" is intended to include all types of release that differ from the release obtained from conventional tablets. Thus, the term also includes so-called "controlled release", "modified release", "sustained release", "pulsed release", "prolonged release", "burst release", "slow release", "extended release" as well as "delayed release" and pH dependent release. However, a specific aspect of the invention relates to a delayed release composition or dosage form that is intended in this context to mean a composition or dosage form that releases a maximum of 10% w / w. active substance within the first 2 hours after administration and / or after starting the dissolution test using a dissolution medium with a pH of at most 3.

Modified release systems [0154] The first modified release system includes matrix systems in which tacrolimus is embedded or dispersed in a matrix of other material that serves to delay the release of tacrolimus into the aquatic environment (i.e. fluid in the lumen of the gastrointestinal tract). When tacrolimus is dispersed in this type of matrix, drug release occurs mainly from the surface of the matrix. Thus, the drug is released from the surface of the element that contains the matrix after it diffuses through the matrix or when the surface of the element is destroyed, exposing the drug. In some embodiments, both mechanisms can work simultaneously. Matrix systems can be large, i.e., tablet (about 1 cm) or small (&lt;0.3 cm). The system can be individual (e.g. bolus), can be divided due to the fact that it is composed of several subunits (for example, several capsules, which constitute a single dose), which are administered basically simultaneously or can contain many particles, also called multiparticles. The multiparticulate system can have numerous applications in formulation. For example, the multiparticulates can be used as a powder to fill the capsule shell or as such to mix with food to facilitate uptake.

A useful multiparticulate matrix system includes a plurality of tacrolimus-containing particles, each of which contains tacrolimus and / or an analogue thereof e.g. in the form of a solid solution / dispersion with one or more excipients selected to form a matrix capable of controlling the dissolution rate of tacrolimus in water center. Matrix materials are generally hydrophobic materials, such as waxes, some cellulose derivatives or other hydrophobic polymers. If desired, matrix materials can optionally be formulated with hydrophobic materials that can be used as binding or reinforcing agents. Matrix materials useful in the production of these dosage forms, such as ethyl cellulose, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, and the like, as well as synthetic polymers such as poly (vinyl chloride), poly (vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene and the like. Water-soluble or hydrophilic binders or release-modifying agents that can optionally be formulated into a matrix include hydrophilic polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, poly (N-vinyl-2-pyrrolidone) (PVP), poly (ethylene oxide) (PEO), polyvinyl alcohol (PVA), xanthan gum, carrageenan and other such natural and synthetic materials. In addition, materials that act 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.

[0156] The multiparticulate product can also be processed by controlled agglomeration. In this case, tacrolimus is dissolved or partially dissolved in a suitable hot melt carrier and sprayed onto carrier particles containing the matrix substance. Suitable hot melt carriers are already listed herein.

[0157] Alternatively, tacrolimus is dissolved in an organic solvent together with the matrix substance and spray dried or applied to carrier particles, see below. Solvents usually used in this process include acetone, ethanol, isopropanol, ethyl acetate and mixtures of two or more thereof.

[0158] Once prepared, the multiparticulates with tacrolimus can be mixed with compressible excipients such as lactose, microcrystalline cellulose, dicalcium phosphate and the like, and the mixture is compressed into a tablet. Suitable disintegrants, such as sodium starch glycolate or cross-linked poly (vinylpyrrolidone) are also used. Tablets made in this way disintegrate when placed in an aqueous medium (such as the gastrointestinal tract), thereby exposing the multiparticulate matrix that releases tacrolimus.

[0159] The matrix system may also be in the form of a tablet from a hydrophilic matrix containing tacrolimus and / or an analogue thereof (e.g. in the form of a solid dispersion) as a multiparticulate product and some hydrophilic polymer sufficient to provide adequate control over the dissolution of tacrolimus. Hydrophilic polymers useful for forming the matrix include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene oxide, polyvinyl alcohol, xanthan gum, carbomer, carrageenan and zooglan. HPMC is the preferred material. Other similar hydrophilic polymers can also be used. In use, the hydrophilic material is loosened in water and finally dissolves. Tacrolimus is released by both matrix diffusion and matrix erosion. The dissolution rate of tacrolimus from these hydrophilic matrix tablets can be controlled by the amount, molecular weight and gel strength of the hydrophilic polymer used. Generally, the use of more hydrophilic polymer reduces the dissolution rate, as does the use of a higher molecular weight polymer. The use of a lower molecular weight polymer usually increases the dissolution rate. The matrix tablet typically contains about 20 to 90% by weight of tacrolimus and about 80 to 10% by weight of polymer.

[0160] A preferred matrix tablet contains, by weight, about 30% to about 80% of a solid dispersion containing tacrolimus and / or an analogue thereof, about 15% to about 35% of a matrix forming substance (such as e.g. HPMC), 0% to about 35% lactose, 0% to about 20% microcrystalline cellulose and about 0.25% to about 2% of a lubricant (such as e.g. magnesium stearate).

[0161] Matrix systems as a class often exhibit discontinuous release of drug from the matrix. This effect may be a consequence of the diffusive mechanism of drug release, and modifications of the geometric structure of the dosage form can be used with the advantage of achieving greater continuity of drug release rate.

[0162] A second class of tacrolimus-releasing dosage forms in a controlled manner according to the invention include membrane-controlled and reservoir systems. In this class, the tacrolimus reservoir, e.g. in a solid solution / dispersion, is surrounded by a speed limiting film as a multiparticulate. Tacrolimus crosses the membrane by mass transport mechanisms well known in the art, including but not limited to membrane dissolution and subsequent membrane diffusion or diffusion through liquid-filled pores in the membrane. These individual dosage forms in a reservoir system may be large, as in the case of a tablet containing a single large reservoir, or multiparticulates, as in the case of capsules or multi-depot tablets containing a plurality of reservoir particles, each of which is separately coated with a film. The coating may be non-porous but permeable to tacrolimus (tacrolimus may, for example, diffuse directly through the membrane) or may be porous. As with other forms of this invention, the molecular transport mechanism is not considered critical.

[0163] Sustained release coatings known in the art can be used to form films, and in particular polymer coatings such as cellulose ester or ether, acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer can be used as a solution in an organic solvent or as an aqueous dispersion or latex. The coating process can be carried out using standard equipment such as a fluidized bed coater, Wurster coater or rotary fluid bed coater. [0164] When desired, the permeability of the coating can be adjusted by mixing two or more materials. Particularly useful processes for adjusting the porosity of the coating include the addition to a solution or dispersion (e.g. aqueous latex) of the film-forming polymer used is a predetermined amount of finely divided water-soluble material, such as sugars or salts or water-soluble polymers. When the dosage form is taken up into the aqueous medium of the digestive system, these water-soluble membrane additives escape from the membrane leaving pores that facilitate release of the drug. The coating film can also be modified by adding plasticizers, as is known in the art.

[0165] A particularly useful variation of the coating film application process involves dissolving the coating polymer in a mixture of solvents selected so that when the coating dries, the phase reversal occurs in the coating solution used, resulting in a film with a porous structure.

[0166] In general, no substrate is required to mechanically strengthen the film.

[0167] Membrane morphology is not critical provided that the permeability properties calculated herein are met. The membrane may be amorphous or crystalline. It can have any type of morphology produced in any particular process and can be, for example, an interphase polymerized film (which includes a thin speed-limiting layer on a porous substrate), a porous hydrophilic film, a porous hydrophobic film, a hydrogel film, an ion film and other such material, which has controlled permeability to tacrolimus.

[0168] The goal is to reduce the exposure of the upper gastrointestinal tract to high tacrolimus concentrations. Accordingly, suitable dosage forms include those that provide a specific delay before the controlled release of tacrolimus begins. An exemplary form may be illustrated by a tablet (or particulate material) comprising a tacrolimus-containing core coated with a first coating of a polymer material of the type useful for sustained release of tacrolimus and a second coating of the type useful for delaying release of drugs when the dosage form is swallowed. The first coating is applied to and surrounds the tablet or individual particles. A second coating is applied to and surrounds the first coating.

[0169] A tablet can be made by methods well known in the art and contains a therapeutically useful amount of tacrolimus and such excipients as are necessary to make the tablet by these methods.

[0170] The first coating may be a sustained release coating, as known in the art, and in particular a polymer coating to form a film as previously outlined for reservoir systems or it may be a controlled release matrix core that is coated a second time delayed release material.

[0171] Materials useful in making the second coating on the tablet include polymers known in the art as enteric coatings for delayed release of pharmaceuticals. The most common are pH sensitive materials such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate and acrylic copolymers such as Eudragit L-100 (Rohm Pharma) and related materials as described in more detail below under "Delay release. " The thickness of the delayed release coating is adjusted to give the desired delay properties. Generally, thicker coatings are more resistant to erosion and, consequently, give a longer and more effective delay. Preferred coatings range from about 30 μm thick to about 3 mm thick.

[0172] When using a hydrophobic matrix material, such as glyceryl monostearate, no delay coating is necessary. The tablet will not release tacrolimus until the enzymatic degradation area is reached, more specifically behind the duodenum. [0173] After swallowing, the double-coated tablet passes through the stomach, where the second coating prevents the release of tacrolimus under the most common acidic conditions. When the tablet passes from the stomach to the small intestine, where the pH is higher, the second coating breaks down or dissolves according to the physicochemical properties of the selected material. After disintegration or dissolution of the second coating, the first po37 prevents the immediate or rapid release of tacrolimus and modulates the release to prevent the formation of high peak concentrations, thus minimizing side effects.

[0174] Another example is a multiparticulate in which each particle is double-coated as described above for tablets, first with a polymer designed to obtain sustained release of tacrolimus, and then coated with a polymer designed to delay the onset of release in the gastrointestinal environment when the dosage form will be swallowed.

[0175] The release rate of tacrolimus from multiparticulates with a sustained release coating (i.e., multiparticulates prior to obtaining a delayed release coating) and methods of coating modification are also controlled by the factors previously described for multiparticulates with tacrolimus reservoir. [0176] The second film or coating for the double-coated multiparticulates is a delayed release coating that is applied to the first extended release coating as disclosed above for tablets and can be made from the same materials. It should be emphasized that the use of so-called "enteric" materials for the practical application of this form differs significantly from their use in the preparation of traditional enteric dosage forms. With traditional enteral forms, the goal is to delay drug release until the dosage form passes the stomach, followed by delivery of the dose to the duodenum. However, dosing of tacrolimus directly and completely into the duodenum may be undesirable because of the side effects to be minimized or avoided in this invention. Thus, if standard enteric polymers are to be used in practice in this form, it may be necessary to apply a significantly thicker layer than in traditional practice to delay drug release until the dosage form reaches the lower gastrointestinal tract. However, sustained or controlled delivery of tacrolimus after dissolution or disintegration of the delayed release coating can also be achieved, and thus the benefits of this form can be realized using the appropriate combination of delayed release properties and sustained release properties, and part of the delayed release may or may not necessarily correspond criteria of enteric agents in accordance with USP. The thickness of the delayed release coating is adjusted to give the desired delaying properties. Generally, thicker coatings are more resistant to erosion and, consequently, give a longer delay.

[0177] The first delayed release dosage form of the invention is a "pH-dependent coated dosage form", such as, e.g., a tablet or capsule. In the case of a tablet, it contains a tablet core containing tacrolimus, e.g. in a solid solution / solid dispersion as a multi-particle product, a controlled release matrix, e.g. with 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 at gastric pH, but which is more soluble and permeable at pH in the stomach small intestine. Preferably, the coating polymer is substantially insoluble and impermeable at pH &lt;5.0 and soluble in water at pH&gt; 5.0. The tablet core may be coated with an amount of polymer sufficient to ensure that there is essentially no release of tacrolimus from the dosage form until the dosage form leaves the stomach and remains in the small intestine for about 15 minutes or longer, preferably about 30 minutes or longer, which will ensure minimal release of tacrolimus in the duodenum. Mixtures of a pH sensitive polymer with a water insoluble polymer can also be used. The tablets are coated with the polymer in an amount from about 10% to about 80% by weight of the tacrolimus-containing tablet core. Preferred tablets are coated with an amount of polymer comprising about 15% to about 50% of the weight of the tacrolimus-containing tablet core.

[0178] pH sensitive polymers that are very insoluble and impermeable at gastric pH, but which are more soluble and permeable at pH in the small intestine and colon, include polyacrylamides, phthalate derivatives such as acid carbohydrate phthalates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose phthalate esters, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate phthalate phthalate, sodium cellulose acetate phthalate, acid starch phthalate, styrene-maleic acid copolymer-dibutyl copolymer, styrene-maleic acid-polyvinyl acetate phthalate copolymer, styrene-like copolymer and styrene copolymer acrylic and acrylic esters, poly methacrylic acid and its esters, poly (acrylic methacrylic acid) copolymers, shellac and copolymers of vinyl acetate and crotonic acid.

[0179] Preferred pH sensitive polymers include shellac; phthalate derivatives, in particular cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose phthalate; polyacrylic acid derivatives, especially polymethyl methacrylate mixed with copolymers of acrylic acid and acrylic esters; and copolymers of vinyl acetate and crotonic acid.

[0180] The delay time before tacrolimus release after the stomach leaves the dosage form in the form of a "coated pH dependent tablet" can be adjusted by selecting the relative amounts of Eudragit-L^® and Eudragit-S^® in the coating and by choosing the thickness of the coating. Membranes from Eudragit-L^® dissolve at pH above 6.0, membranes from Eudragit-S^® they dissolve at a pH above 7.0, and the mixtures dissolve at an intermediate pH. Because the duodenal pH is about 6.0 and the colon pH is about 7.0, coatings consisting of Eudragit-L mixtures^® and Eudragit-S® provide duodenal protection against tacrolimus. If it is desired to delay the release of tacrolimus until the "coated pH-dependent tablet" containing tacrolimus reaches the colon, Eudragit-S may be used as the coating material^®as described by Dew et al. (Br. J. Clin. Pharmac. 14 (1982) 405-408). To delay the release of tacrolimus by about 15 minutes or more, preferably 30 minutes or more after the stomach leaves the dosage form, preferred coatings contain from about 9: 1 to about 1: 9 EudragitL® / Eudragit-S®, more preferably from about 9 : 1 to about 1: 4 Eudragit-L® / Eudragit-S®. Each yarn may constitute 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 weight of the tablet core. Uses [0181] The solid pharmaceutical composition of the invention may be used to prepare a solid dosage form for oral administration, such as tablets, capsules or sachets, or for the production of granules, pellets, microspheres, nanoparticles.

[0182] Preferably, the pharmaceutical composition is used for the preparation of an immediate immediate-release solid dosage form or a delayed-release solid dosage form.

[0183] Another advantage of the compositions of the invention is the ability to achieve an effective therapeutic response at a lower dose compared to traditional oral treatment. Therefore, it is believed that the solid dosage form of the invention, administered orally to a mammal in need thereof, at a dose of at most about 85% w / w, such as e.g. at most 80% w / w, at most about 75%, at most about 70% w / w, at most about 65% w / w, at most about 60% w / w, at most about 55% w / w or at most about 50% w / w doses of tacrolumus administered in the form of Prograf^® or a similar tacrolimus-containing product, commercially available, is essentially bioequivalent to Prograf^® or a similar commercial product containing tacrolimus.

[0184] Each of the dosage forms and compositions of the invention containing tacrolimus may improve the treatment of conditions responsive to tacrolimus treatment. [0185] Tacrolimus is indicated (or suggested to be used) in the treatment of diseases such as e.g. rejection reactions for organ or tissue transplants such as heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc .; graft versus host reactions after bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc .; infections caused by pathogenic microorganisms (e.g. Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.); inflammatory or hyperproliferative skin diseases or cutaneous manifestations of the immune-mediated disease (e.g. psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermal separation, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne areata); autoimmune eye diseases (e.g. keratoconjunctivitis, spring conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conic keratitis, corneal epithelial dystrophy, corneal endosperm, ocular pemphigus, Mooren's ulcer, scleritis, Graves ophthalmopathy, Vogt syndrome -Koyanagi-Harada, dry keratoconjunctivitis (dry eye syndrome), pimple, iritis and ciliary body inflammation, sarcoidosis, ophthalmopathy on the background of endocrine disease, etc.); recurrent obstructive airway disease [asthma (e.g. bronchial asthma, allergic asthma, essential asthma, extrinsic asthma and pulmonary asthma), in particular chronic or persistent asthma (e.g. late asthma and airway hypersensitivity), bronchitis, etc .; inflammation of the mucous membranes or vessels (e.g. stomach ulcer, ischemic or thrombotic blood vessel damage, ischemic bowel disease, enteritis, gangrenous colitis, burn damage associated with burns, leukotriene B4 diseases); enteritis / intestinal allergy (e.g. celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis); food allergy diseases with symptoms occurring outside the gastrointestinal tract (e.g. migraine, rhinitis and eczema); kidney disease (e.g., interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome and diabetic nephropathy); nervous system diseases (e.g. dermatomyositis, Guillain-Barre syndrome, Menie41 disease, polyneuritis, single neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and radiculopathy); ischemic brain disease (e.g. head injury, cerebral haemorrhage (e.g. subarachnoid haemorrhage, intracerebral bleeding), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient cerebral ischemia (TIA), hypertensive encephalopathy, cerebral infarction); endocrine diseases (e.g. hyperthyroidism and Basedow's disease); blood diseases (e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerytroplasia); bone diseases (e.g. osteoporosis); respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis and idiopathic interstitial pneumonia); skin diseases (e.g. dermatomyositis, albinism of the skin, fish scale, photosensitivity and cutaneous T-cell lymphoma); cardiovascular diseases (e.g. arteriosclerosis, atherosclerosis, aortitis syndrome, nodular arteritis and myocarditis); collagoses (e.g. scleroderma, Wegener's granulomatosis and Sjogren's syndrome); fatness, eosinophilic fasciitis; periodontal disease (e.g. damage to the gums, periodontium, alveolar bone or tooth cement); nephrotic syndrome (e.g. glomerulonephritis); male pattern baldness, senile alopecia; muscular dystrophy; purulent dermatitis and Sezary syndrome; diseases associated with chromosomal disorders (e.g. Down syndrome); Addison's disease; active oxygen mediated diseases [e.g. organ damage (e.g. ischemic circulatory disorders (e.g. heart, liver, kidneys, gastrointestinal tract, etc.) associated with maintenance, transplantation or ischemic disease (e.g. thrombosis, heart attack, etc.); intestinal diseases (e.g. endotoxic shock, pseudomembranous colitis and drug-induced or radiation colitis); kidney disease (e.g. ischemic acute renal failure, chronic renal failure); lung diseases (e.g. oxygen or drug toxic lung damage (e.g. paracort, bleomycin, etc.), lung cancer and emphysema); eye diseases (e.g. cataracts, iron storage disease (ocular siderosis), retinitis, pigmentary degeneration, senile plaques, vitreous scarring, corneal burn with alkali); dermatitis (e.g., erythema multiforme, bullous dermatitis associated with linear immunoglobulin A, cement dermatitis); and other diseases (e.g. gingivitis, periodontitis, sepsis, pancreatitis and diseases caused by environmental pollution (e.g. air pollution), aging, carcinogens, cancer metastasis and ailments caused by atmospheric pressure reduction]]; diseases caused by the release of histamine or leukotriene C4; coronary artery restenosis after angioplasty and prevention of postoperative adhesions; autoimmune diseases and inflammation (e.g. primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male infertility, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympathetic ophthalmic or conjunctivitis, uveitis caused by the lens, idiopathic leukopenia, active chronic hepatitis, idiopathic hepatitis , chronic lupus erythematosus, autoimmune orchitis, arthritis (e.g. deforming arthritis) or multi-cartilaginitis); human immunodeficiency virus (HIV) infection, AIDS;

allergic conjunctivitis; hypertrophic scars and keloid caused by injury, burns or surgery.

[0186] In addition, tricyclic macrolides, such as, for example, tacrolimus, have liver regenerating and / or hepatocyte hyperplasia and hyperplasia stimulating effects. Therefore, the pharmaceutical composition of the invention is useful for increasing the effect of treatment and / or prevention of liver disease [e.g. immunogenic diseases (e.g. chronic autoimmune liver disease such as autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. toxin-induced necrosis, viral hepatitis, shock or anoxia), hepatitis B, non-A and non-hepatitis B, cirrhosis and liver failure (e.g. fulminant hepatitis, late onset hepatitis and exacerbated chronic liver failure (acute liver failure in the course of chronic liver disease)].

[0187] In addition, the composition of the invention is useful for increasing the effect of preventing and / or treating various diseases due to the useful pharmacological activity of tricyclic macrolides, such as the complementary activity of the chemotherapeutic effect, activity in cytomegalovirus infection, anti-inflammatory activity, inhibition of peptidyl prolyl isomerase activity or rotamases, anti-malarial activity, anti-tumor activity and so on.

Materials and methods Materials [0188]

Tacrolimus (supplied by Eurotrade); serial number RD 03-111 Lactose monohydrate 200 mesh (from DMV)

Granular Silicon Oxide, Aeroperl^® 300, (Degussa)

Polyethylene glycol 6000, Pluracol^® E6000 (with BASF)

Poloksamer 188, Pluronic^® F-68 (from BASF)

Glyceryl monostearate, Rylo^® MD50, (with Danisco Cultor), Ph. Eur .; Lot No. 4010056276

Avicel PH200 (microcrystalline cellulose) (with FMC)

DCL 11 lactose (from DMV)

Magnesium stearate

Croscarmellose sodium, Ac-Di-Sol^® (from FMC)

Eudragit^® L30D.55 (from Degussa);

Triethyl citrate (from Merck);

Anti-foaming emulsion (with Dodge)

Mikrotalk

HPMC applies to Metalose 90SH (type 2910, 2208) or Metolose 60SH (type 2910) from ShinEtsu, available in various degrees of polymerization (viscosity 3-100,000 cP).

[0189] Tablets, capsules and granules may be enteric coated with various types of polymers such as hydroxypropyl methylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropyl methylcellulose phthalate HPMCP or copolymers of methacrylic acid such as Eudrag, Eudrag 100, Eudrag, / L.

Comparative known tacrolimus preparation:

[0190] Hard gelatin capsules Prograf^©, manufactured by Fujisawa Ireland Ltd.

<td>Ingredients</td><td>mg</td>

<td>Tacrolimus, anhydrous</td><td> 1,0</td>

<td>Gelatin</td><td> 6,9</td>

<td>Hypromellose</td><td> 1,0</td>

<td>Lactose monohydrate</td><td> 24,7</td>

<td>Magnesium stearate</td><td> 0,3</td>

<td>Shellac</td><td>as much as needed</td>

<td>Soy Lecithin</td><td>as much as needed</td>

<td>Red iron oxide (E172)</td><td>as much as needed</td>

<td>Titanium dioxide (E171)</td><td>as much as needed</td>

Ingredients Dimetikon (E900) mg as much as needed

methods

Determination of mass variability [0191] The tablets prepared according to the examples were subjected to a mass variability test, carried out in accordance with Ph. Eur.

Determination of average tablet hardness [0192] The tablets prepared according to the examples were tested for tablet hardness using a Schleuniger Model 6D apparatus, carried out in accordance with the general apparatus instructions.

Determination of disintegration time [0193] The disintegration time of the tablet, i.e. the time to break down into particles or agglomerates, was determined according to Ph. Eur.

Determination of the weighted geometric mean diameter dgw [0194] The weighted geometric mean diameter was determined using a laser diffraction method by dispersing the obtained particulate material (or starting material) in the air. The measurement was made at a dispersing pressure of 1 bar in a Sympatec Helos device that records the distribution of an equivalent spherical diameter. This distribution adapts to the normal volume-size logarithm distribution.

[0195] As used herein, "geometric weighted average diameter" means the average diameter from the log of normal volume-size distribution.

In Vitro Dissolution Studies [0196] The following methods were used to test the compositions and dosage forms of the invention.

Test 1:

[0197] In vitro dissolution study according to USP Method A, delayed release articles (paddle method according to USP; rotation speed: 50 rpm; 37 ° C; after 2 hours in acidic medium, the medium was changed to pH phosphate buffer 6.8).

Test 2:

[0198] In vitro dissolution test in an aqueous dissolution medium with a pH set to 4.5 (900 ml water with 0.005% HPC (hydroxypropyl cellulose), pH set to 4.5; paddle method according to USP; rotation speed: 50 rpm for a minute).

[0199] Pharmaceutical compositions and dosage forms of the invention are illustrated in examples 1-7. The results of dissolution studies of the compositions and dosage forms in vitro can be found in Example 8.

EXAMPLE 1 [0200] Multi-depot capsule with modified release based on a swellable hydroxy colloidal hydroxypropyl cellulose matrix

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

<td>tacrolimus</td><td> 0,5</td><td> 1,00</td>

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

<td>200 mesh lactose</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>Sum</td><td> 100,00</td><td> 200,00</td>

[0201] Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (70:30 w / w ratio) at 70 ° C. The solution was sprayed on a mixture of 150 g lactose and 100 g HPMC in a Strea-1 fluidized bed. The granulated product was sieved through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

EXAMPLE 2 [0202] Tablet with modified release matrix based on a swellable hydrocolloid matrix from hydroxypropyl cellulose

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

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

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

<td>200 mesh lactose</td><td> 29,85</td><td> 60,00</td>

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

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

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

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

[0203] Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188 (w / w ratio 70:30) at 70 ° C. The solution was sprayed onto 250 g lactose in a Strea-1 fluidized bed. The obtained granulated product was sieved through a 0.7 mm sieve and mixed with HPMC and magnesium stearate for 0.5 minutes in a Turbula mixer.

[0204] The mixture was compressed into 8 mm tablets with 1 mg active ingredient (200 mg tablet) in the shape of a shell.

[0205] Average disintegration time: 20 minutes. Hardness: 45 N.

EXAMPLE 3

Enteric coating [0206] The capsules and tablets of Examples 1 and 2 were then coated with the following enteric coatings to obtain delayed release of the active substance after administration.

<td>Ingredients</td><td> %</td>

<td>Eudragit® L30D</td><td> 40</td>

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

<td>Triethyl acetyl citrate</td><td> 1,8</td>

<td>Anti-foaming emulsion</td><td> 0,2</td>

<td>Talc</td><td> 6</td>

<td>Sum</td><td> 100</td>

[0207] The coating suspension was prepared by mixing trimethyl acetyl citrate, anti-foaming emulsion and purified water in an Ultra Turrax apparatus at 9,500 rpm for 30 min. After 1 minute, talc was added. The mixture was passed through a No. 300 screen and mixed in a magnetic mixer. Eudragit was passed through a No. 300 screen and added to the mixture, which was stirred for 5 minutes.

[0208] The conditions of the coating process were as follows: inlet temperature 40 ° C, tempe₃ outlet pipe 31 ° C, air inlet 140 m per hour and coating time approximately 50 minutes (300 g coating material). About 400 g tablets or 200 g capsules were coated.

[0209] Film-coated tablets and capsules were cured for 48 hours at 30 ° C before dissolution testing.

EXAMPLE 4 [0210] Coated tablet with a core based on PEG 6000 / Poloksamer 188 and an enteric coating based on Eudragit L30D 55

Tablet core composition:

[0211]

<td>Substance</td><td> %</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>Talc</td><td> 4,50</td><td> 4,55</td>

<td>Croscarmellose sodium, Ac-di-sol</td><td> 5,00</td><td> 5,05</td>

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

[0212] A tablet core with tacrolimus was prepared by dissolving it in PEG 6000 at a temperature above 80 ° C. Poloxamer 188 was added and the solution was heated to above 80 ° C. The solution was sprayed in a Phast FS1.7 feeder onto 200 g lactose monohydrate in a fluid bed Phast FB100. The obtained granulate was sieved through a Comill 1397 screen, 4500 rpm and mixed with croscarmellose sodium for 3 minutes in a Turbula mixer.

[0213] Magnesium stearate and talc were sieved through a No. 300 screen and mixed in a mixer

Turbula for 3 minutes. The granules were mixed with magnesium stearate and talc (1: 9) for 0.5 minutes in a Turbula mixer.

[0214] The obtained mixture was compressed into 6 mm tablets with 2 mg active ingredient (100 mg tablet) in the shape of a shell.

[0215] Average disintegration time: 7 minutes. Hardness: 65 N.

Intestinal coating:

[0216] The enteric coating is based on Eudragit L30D-55 acrylic polymer. Eudragit L30D is supplied as an aqueous latex suspension forming an insoluble film upon evaporation of water during coating. The polymer is insoluble at pH below 5.0 and easily soluble at pH values ​​above 6.0. The film-forming composition is as follows:

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

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

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

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

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

<td>Anti-foaming emulsion</td><td> 0,2</td>

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

<td>Sum</td><td> 100</td>

[0217] The amount of film-forming polymer (Eudragit) used was based on the calculation of mg ₂ film-forming polymer per cm of tablet surface. The enteric coating thickness was 80 μm. Checking the film thickness applied was based on measuring the increase in tablet height using a digital micrometer. The film coating process was carried out in a fluid bed Phast FB100 equipped with a Wurster type insert. The process conditions were: air inlet temperature 50 ° C; inlet flow₃ air 100 m³ for an hour; Product temperature 38 ° C; Feed rate 15 g / min. [0218] After coating, the formation of the correct film requires curing of coated tablets ie 30 ° C for 48 hours in an incubator. Alternatively, coated tablets can be more efficiently cured at 40 ° C for 24 hours.

EXAMPLE 5 [0219] Tablet with PEG 6000 / Poloxamer controlled release based on HPMC matrix.

The composition of the tablet:

[0220]

<td>Substance</td><td> %</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>Talc</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>

[0221] Tacrolimus was dissolved in PEG 6000 at a temperature above 80 ° C. Poloxamer 188 was added and the solution heated to above 80 ° C. The solution was sprayed in a Phast FS1.7 feeder onto 200 g lactose monohydrate in a Phast FB100 fluidized bed.

The granulated product was sieved through a Comill 1397 screen, 4500 rpm and mixed with hydroxypropyl methylcellulose for 3 minutes in a Turbula mixer.

[0222] Magnesium stearate and talc were sieved through a 300 sieve 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.

[0223] The mixture was compressed into 8 mm tablets of 2 mg (165 mg tablet in the shape of a shell).

[0224] Average disintegration time: 2 hours and 34 minutes, Hardness: 50 N EXAMPLE 6 [0225] Controlled release tablet formulation based on an eroding matrix

HPMC, where HPMC is added as part of the intragranular phase. Melting granulation.

The composition of the tablet:

[0226]

<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>Sum</td><td> 245</td>

[0227] Tablet formulation was based on melt granulation in a Pellmix 1/8 high shear mixer. 16g of micronized tacrolimus was mixed with 640 g of 125 mesh lactose and 120 g of polyethylene glycol 6000, 48 g of poloxamer 188 and 640 g of Metolose SH 90 15,000 cP hydroxypropyl methylcellulose in the same high shear mixer.

The blender shell jacket was heated to 80 ° C and the mixture was heated at a rotor speed of 1000 rpm until the melting point of PEG and Poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm. The granulate was sieved through a No. 0.7 screen and cooled in a tray. The granules were mixed with 480 g Avicel PH200 for 3 minutes and during and after adding 16 g magnesium stearate for subsequent

0.5 minutes. The mixture was compressed into tablets in a Diaf TM20 single punch tabletting machine. Tablet diameter: 8 mm. Tablet shape: round, shell.

EXAMPLE 7 [0229] Formulation of an enteric coated tablet (melt granulation and enteric coated tablets)

The composition of the tablet:

[0230]

<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>Sum</td><td> 165</td>

[0231] Tablet formulation was based on melt granulation in a Pellmix 1/8 high shear mixer. 16 g micronized tacrolimus was mixed with 640 g lactose

125 mesh and 120 polyethylene glycol 6000, 48 g poloxamer 188 in a high shear mixer. The blender shell jacket was heated to 80 ° C and the mixture was heated at a rotor speed of 1000 rpm until the melting point of PEG and poloxamer. After melting, kneading was continued for 4 minutes at 800 rpm. The granulate was sieved through a No. 0.7 screen and cooled in a tray. Granules mixed with

480 g Avicel PH200 for 3 minutes and during and after adding 16 g magnesium stearate for another 0.5 minutes. The mixture was compressed into tablets in a Diaf TM20 single punch tabletting machine. Tablet diameter: 7 mm. Tablet shape: round, folded shell.

[0232] Coating of the tablets with an enteric coating was carried out according to the procedure described in Example 11.

EXAMPLE 8 [0233] In vitro solubility data [0234] The compositions and dosage forms according to the previous examples were subjected to in vitro dissolution studies using two different dissolution / test centers.

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

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

<td>Time (hours)</td><td>Example 1</td><td>Example 2</td><td>Example 4 - EC (relative standard deviation%)</td><td>Example 5 (relative standard deviation%)</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>

<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>

[0235] Dissolution profile for tablet cores of Example 4 in dissolution medium: 900 ml aqueous medium with 0.005% HPC (hydroxypropyl cellulose) adjusted to pH = 4.5. Paddle method according to USP. Rotation speed: 50 rpm:

<td>Time (minutes)</td><td>% release</td><td>relative standard deviation%</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>Time (minutes)</td><td>% release</td><td>relative standard deviation%</td>

<td> 20</td><td> 80,7</td><td> 8</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</td>

[0236] Dissolution profile for the enteric-coated tablets of example 4 in the dissolution medium according to Method A USP, delayed release particles. Paddle method according to USP. Rotation speed: 50 rpm:

<td>Time (minutes)</td><td>% release</td><td>relative standard deviation%</td>

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

<td> 120</td><td> 0</td><td>ON</td>

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

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

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