HK1096032B - Solid dispersions comprising tacrolimus - Google Patents

Description

Solid dispersions containing tacrolimus

The present invention relates to solid dispersions containing tacrolimus or analogues thereof and having improved bioavailability, more particularly solid solutions or dispersions of tacrolimus in a hydrophilic vehicle; a pharmaceutical composition comprising a solid solution or solid dispersion; and dosage forms comprising solid solutions or solid dispersions.

Background

Tacrolimus, also known as FK-506 or FR-900506, having a chemical bond with C₄₄H₆₉NO₁₂The corresponding chemical tricyclic structure shown below:

tacrolimus exists in the form of white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and readily soluble in methanol and chloroform.

Tacrolimus is prepared as described in EP-A-0184162, whereas tacrolimus analogues are described in, for example, EP-A-0444659 and US 6,387,918 (both incorporated herein by reference).

Tacrolimus is a macrolide compound having useful immunosuppressive activity, antimicrobial activity, and other pharmacological activities, and is valuable for the treatment or prevention of rejection in organ or tissue transplantation, graft-versus-host disease, autoimmune disease, and infectious disease. Tacrolimus prolongs host and graft survival in animal transplant models of liver, kidney, heart, bone marrow and small intestine and pancreas, lung and trachea, skin, cornea, and extremities.

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

Tacrolimus inhibits T lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to the intracellular protein FKBP-12. Then, a complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is formed, and the phosphatase activity of calcineurin is inhibited. This result prevents dephosphorylation and translocation of the nuclear factor of activated T cells, which is thought to be the nuclear component that initiates transcription of genes for lymphokine formation. The net result is that T lymphocyte activation is inhibited, i.e., immunosuppressed.

Tacrolimus is widely metabolized by the CYP3a4 isoenzyme in the intestinal wall and liver. Thus, drugs affecting this isoenzyme may affect tacrolimus absorption and subsequent clearance of systemically absorbed tacrolimus. CYP3a4 inhibitors may increase tacrolimus levels, while CYP3a4 inducers may increase tacrolimus metabolism and decrease tacrolimus levels. Thus, tacrolimus may be administered with one or more CYP3a4 inhibitors to improve overall bioavailability.

Tacrolimus is typically administered orally and is thus absorbed from the gastrointestinal tract. Absorption was observed to be negatively affected by simultaneous food intake. Thus, the rate and extent of tacrolimus absorption is greatest under fasting conditions.

In general, it is known that absorption and bioavailability of therapeutically active substances when administered orally can be influenced by a variety of factors. These factors include the presence of food in the gastrointestinal tract, usually with the gastric residence time of the drug significantly longer than in the fasted state. A drug substance is said to exhibit a food effect if its bioavailability is affected more than to some extent by the presence of food in the gastrointestinal tract. The food effect is important because absorption and thus plasma levels can become highly variable depending on food intake. Absorption of the drug into the bloodstream can thus be adversely affected, exposing the patient to the risk of insufficient absorption of the drug for treatment of the condition for which the drug is administered. On the other hand, the very high peak concentrations seen under fasting conditions may sometimes be prone to induce significant nephrotoxic or neurotoxic side effects, as well as gastrointestinal side effects, etc.

The gastrointestinal absorption after oral administration of tacrolimus is rapid, with an average time-peak concentration (t)_max) Is about 1-2 hours after administration to a healthy subject or a kidney or liver transplant patient, but is incomplete and variable. Bioavailability after oral administration can often be as low as up to about 20%.

Side effects frequently observed are vomiting and nausea, but side effects such as tremor, headache, hypertension, renal dysfunction, hyperkalemia, hypomagnesemia, hyperglycemia, insomnia, diarrhea, constipation, abdominal pain, renal toxicity, and neurointoxication are also observed.

For oral administration, tacrolimus is currently formulated and sold as soft gelatin capsules containing 0.5, 1, or 5mg of anhydrous tacrolimus, under the trade name tacrolimusAndin patients, the recommended initial oral dose is about 0.1-0.2 mg/kg/day. The dose is intended to achieve a defined trough plasma level of about 5 to about 20 ng/ml.Is meant to be used in receiving a heterologous liver or kidney shiftOrgan rejection is prevented in patients with plants.

There remains a need for new pharmaceutical compositions and/or dosage forms containing tacrolimus and having improved bioavailability. The improved bioavailability may allow a patient to reduce the number of dosage units to take, for example, to one dose per day, and may also alleviate or eliminate the need for food to be taken simultaneously with the dosage form, thereby allowing the patient more freedom in taking the drug. In addition, it is envisaged that fluctuations in the plasma concentration versus time profile can be significantly reduced. In addition, the increase in bioavailability may also result in being more repeatable (i.e., not as reproducible as possible)Variable) release profile.

Summary of The Invention

The inventors have found that the bioavailability of tacrolimus can be significantly improved by dispersing or dissolving tacrolimus in a hydrophilic or water-miscible vehicle in an amount sufficient to prepare a useful pharmaceutical dosage form. Tacrolimus is known to have very low solubility in water, but the present invention provides pharmaceutical compositions and formulations that exhibit very rapid in vitro release characteristics, i.e., immediate release compositions that are expected to have significantly improved in vivo bioavailability in patients in need thereof.

Thus, in a first aspect, the present invention relates to a solid dispersion comprising an active ingredient selected from tacrolimus and analogues thereof dispersed or dissolved in a hydrophilic or water-miscible vehicle, wherein the melting point of the vehicle is at least 20 ℃ and the concentration of the active ingredient is from about 0.01 w/w% up to about 15 w/w% to form a solid dispersion or solid solution at ambient temperature. It is believed that such a dispersion is capable of releasing tacrolimus in an amount of at least 50 w/w% in about 30 minutes in any dissolution test carried out in accordance with the united states pharmacopeia using an aqueous dissolution medium.

In another aspect, the present invention relates to a pharmaceutical composition comprising a solid dispersion and/or solid solution of tacrolimus and one or more pharmaceutically acceptable excipients, which may be a filler, a disintegrant, a binder, or a lubricant. In yet another aspect, the invention relates to a dosage form, such as a solid oral unit dosage form, comprising a solid dispersion and/or solid solution of tacrolimus, a pharmaceutically acceptable excipient, and optionally a pharmaceutically acceptable additive, which may be, for example, a flavoring agent, a coloring agent, a taste-masking agent, a pH adjusting agent, a buffering agent, a preservative, a stabilizing agent, an antioxidant, a wetting agent, a humidity adjusting agent, a surfactant, a suspending agent, an absorption enhancer, and a release modifying agent (release modifying agent). In particular, the present invention relates to dosage forms comprising tacrolimus and a release modifier, especially dosage forms having delayed release, such as enteric coated solid oral unit dosage forms. The delayed release of tacrolimus at the distal duodenum may alleviate drug-related gastrointestinal related side effects and a higher degree of metabolism proximal to the gastrointestinal tract (CYP 3a4 mediated metabolism). Thanks to the novel solid dispersions and/or solid solutions according to the invention, this can be achieved without loss of systemic bioavailability.

Detailed Description

Definition of

As used herein, the term "active ingredient" or "active pharmaceutical ingredient" refers to any ingredient intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human or other animal body. The term includes ingredients that may undergo chemical changes in the manufacture of a pharmaceutical product and that are present in the pharmaceutical product in a modified form intended to provide a particular activity or effect.

In this context, the term "hydrophilic" describes substances "like water", i.e. hydrophilic molecules or hydrophilic parts of molecules are those that are generally electrically polarized and capable of forming hydrogen bonds with water molecules, making them more soluble in water than in oils or other "non-polar" solvents.

Herein, the term "amphiphilic" describes a molecule (as a surfactant) in which a polar water-solubilizing group is attached to a water-insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other end is hydrophobic (non-polar).

As used herein, the term "vehicle" refers to any solvent or carrier fluid in a pharmaceutical product that has no pharmacological effect. For example, water is a vehicle for xilocaine, while propylene glycol is a vehicle for many antibiotics.

As used herein, the term "solid dispersion" refers to a drug or active ingredient or substance dispersed at a particulate level in a solid inert vehicle, carrier, diluent, or matrix, i.e., often a fine particulate dispersion.

As used herein, the term "solid solution" refers to a drug or active ingredient or substance that is dissolved at the molecular level in a solid inert vehicle, carrier, diluent, or matrix.

As used herein, the term "analog" refers to a chemical compound that is structurally similar to another compound.

The term "drug" refers to a compound that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals.

As used herein, the term "dosage form" refers to a form in which a drug is delivered to a patient. It may be in parenteral form, topical form, tablet, oral (liquid or dissolved powder), suppository, inhalant, transdermal form, etc.

As used herein, the term "bioavailability" refers to the degree to which a drug or other substance is available to a target tissue after administration.

As used herein, the term "bioequivalency" refers to the scientific basis of comparison of brandless and branded drugs to each other. For exampleDrugs are bioequivalent if they enter the circulation at the same rate after administration at similar doses under similar conditions. A common parameter for bioequivalence studies is t_max、c_max、AU_C-0-infinity、AUC_0-t. Other relevant parameters are W₅₀、W₇₅And/or MRT. Thus, at least one of these parameters may be used in determining whether bioequivalence exists. In addition, in this context, if the numerical value of the parameter used is that used in the testOr similar commercially available tacrolimus-containing products, in the range of 80-125% of the values of the parameters, the two compositions are considered bioequivalent.

Herein, "t" is_max"means that the maximum plasma concentration (c) is reached after administration_max) The time of (d); AUC_0-infinityRefers to the area under the plasma concentration versus time curve from 0 to infinity; AUC_0-tRefers to the area under the plasma concentration versus time curve from 0 to t; w₅₀Means that the plasma concentration reaches C_max50% or more of the time; w₇₅Means that the plasma concentration reaches C_max75% or more of the time; and MRT refers to the mean residence time of tacrolimus (and/or its analogs).

As used herein, the term "pharmaceutical" refers to a compound used to treat a disease, injury, or pain. Drugs should be classified as "prophylactic" (i.e., areas of maintaining health) and "therapeutic" (i.e., areas of restoring health).

As used herein, the term "delayed release" refers to the release profile of a drug from a pharmaceutical composition or formulation, which has a constant C relative to the immediate release profile_maxThere is only a time delay from administration to release of the drug. Thus, t_maxIs delayed, and t_1/2Usually unchanged.

As used herein, the term "erosion" refers to the gradual disintegration of the surface of a material or structure, such as a tablet or tablet coating.

Solid dispersions and/or solid solutions of tacrolimus

The solid dispersion of the present invention contains an active ingredient selected from tacrolimus and analogs thereof, said ingredient being dispersed or dissolved in a hydrophilic or water-miscible vehicle having a melting point (freezing or pouring point) of at least 20 ℃ in a concentration of between about 0.01 w/w% and about 15 w/w%, and said dispersion forming a solid dispersion or solid solution at ambient temperature (room temperature).

The active ingredient is preferably tacrolimus or any analogue or derivative thereof having a pharmacological or therapeutic activity at least comparable to tacrolimus (FK-506 or FR-900506). Within the scope of the present invention, however, tacrolimus may be in any physical form, be it crystalline, amorphous powder, any possible polymorph (polymorph), any possible solvate including hydrate, anhydrate, complex, and the like. Also included are any analogs, derivatives, or active metabolites of tacrolimus as well as their pharmaceutically acceptable salts, solvates, complexes, and prodrugs.

The concentration of the active ingredient in the hydrophilic or water-miscible vehicle 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%, in particular at most 2 w/w%; and/or at least about 0.05 w/w%, preferably at least about 0.1 w/w%, more preferably at least about 0.5 w/w%, especially at least about 0.7 w/w%, especially at least about 1 w/w%.

Physically, the combination of the active ingredient with the vehicle may form a solid dispersion, i.e. the active ingredient is dispersed in the vehicle in particulate form, or may form a solid solution, i.e. the active ingredient is dissolved in the vehicle at the molecular level. The active ingredient and vehicle may also form a solid dispersion in which a portion of the active ingredient is dissolved at the molecular level. Various techniques may be used to determine the physical state of the dispersion and/or solution, such as Hot stage microscopy (Hot stage microscopy) (HSM), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), optionally in combination with energy dispersive X-ray (EDX), and X-ray powder diffraction. In a preferred embodiment, the active ingredient is completely dissolved in the vehicle to form a solid solution at ambient temperature.

An increase in bioavailability, i.e. the area under the curve (AUC), will generally reduce the internal (intra-) and inter (inter-) variability with respect to drug substance absorption). This is especially true whenever bioavailability is low or impaired due to poor water solubility. It is envisaged that the compositions according to the invention will provide numerical ratiosAnd significantly lower AUC data for similar products.

As mentioned above, an essential feature of the present invention is the possibility to obtain an increase in bioavailability by oral administration of the composition of the invention. Generally, the low bioavailability of a drug substance after oral administration is an obstacle to designing controlled or modified release compositions of drug substances due to the fact that effective drug levels are hardly obtainable over a prolonged period of time. However, with the technology of the present invention it is possible to obtain significantly improved bioavailability, making it possible to design e.g. delayed release compositions.

When the composition comprising the dispersion or solution is tested in a dissolution test according to the united states pharmacopeia using an aqueous dissolution medium, the solid dispersion of the present invention exhibits a very rapid immediate release of tacrolimus and at least 50 w/w% of the active pharmaceutical ingredient is released within about 30 minutes, preferably within 20 minutes, more preferably within 15 minutes; such as at least 75 w/w% of the active pharmaceutical ingredient, is released within about 40 minutes, or more preferably at least 90 w/w% of the active pharmaceutical ingredient is released within about 60 minutes, preferably within 45 minutes. For example, testing may be performed according to any method and any specification cited in the United states Pharmacopeia. Thus, dissolution testing can be performed in an aqueous dissolution medium at a neutral or near neutral pH, e.g., pH6.8, or any acidic pH that mimics the pH conditions of the gastrointestinal tract. However, variations in the specific methods employed and the components contained in the dissolution medium, etc., are within the scope of the invention. The skilled person will know how to perform suitable dissolution tests, e.g. following the guidelines of the us pharmacopoeia, european pharmacopoeia etc. Suitable conditions for the in vitro dissolution test are the United states Pharmacopeia dissolution test method (paddle method) and pH7.5 buffer containing 2.5% SDS and 1g/ml pancreatin as dissolution medium.

In other embodiments, the in vitro dissolution test achieves the following:

i) at least about 50 w/w% of the total amount of tacrolimus or analog thereof is released within about 10 hours, e.g., within about 8 hours, within about 6 hours, within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hour, within about 45 minutes, within about 30 minutes, or within about 15 minutes, when tested in an in vitro dissolution test using a dissolution medium comprising a buffer at ph 7.5;

ii) at least about 50 w/w% of the total amount of tacrolimus or analog thereof is released within about 1.5 hours, e.g., within about 1 hour, within about 0.75 hours, within about 0.5 hours, or within about 20 minutes, when tested in an in vitro dissolution test using a dissolution medium comprising a buffer at ph 7.5;

iii) at least about 55 w/w% such as about 60 w/w% or more, about 65 w/w% or more, about 70 w/w% or more, about 75 w/w% or more, or about 80 w/w% or more of the total amount of tacrolimus or analog thereof is released within about 15 hours such as within about 12 hours, within about 10 hours, within 8 hours, or within about 6 hours, when tested in an in vitro dissolution test using a dissolution medium comprising a buffer at pH 7.5;

iv) at least about 55 w/w% of the total amount of tacrolimus or analog thereof is released within about 5 hours, e.g., within about 4 hours, within about 3 hours, within about 2 hours, within about 1 hour, or within about 30 minutes, when tested in an in vitro dissolution test using a dissolution medium comprising a buffer at ph 7.5; and/or

v) at least about 20w/w such as at least about 25 w/w%, at least about 30 w/w%, at least about 35 w/w%, or at least about 40 w/w% of the total amount of tacrolimus or analog thereof is released within the first 3 hours such as within the first 2 hours, or within the first 1 hour, when tested in an in vitro dissolution test using a dissolution medium comprising a buffer at ph 7.5.

In other embodiments of the invention, the in vitro dissolution test performed under acidic conditions achieves the following:

i) at most about 30 w/w% such as at most about 25 w/w%, at most about 20 w/w%, at most about 15 w/w%, or at most about 10 w/w% of tacrolimus or an analog thereof is released within 2 hours in an in vitro dissolution test employing a dissolution medium having 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 at most about 7.5 w/w%, at most about 5 w/w%, or at most about 2.5 w/w% of tacrolimus or an analogue thereof is released within 2 hours in an in vitro dissolution test employing a dissolution medium having 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 at most about 50 w/w%, at most about 40 w/w%, or at most about 30 w/w% of tacrolimus or analogues thereof is released within 15 hours, such as within about 12 hours, when tested in an in vitro dissolution test employing a dissolution medium having a pH of at most about 4.5, such as 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 at most about 30 w/w%, at most about 25 w/w%, or at most about 20 w/w% of tacrolimus or an analogue thereof is released within 6 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at most about 4.5 such as 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 at most about 25 w/w%, at most about 20 w/w%, or at most about 15 w/w% of tacrolimus or an analogue thereof is released within 4 hours when tested in an in vitro dissolution test employing a dissolution medium having a pH of at most about 4.5 such as at most about 4.0, at most about 3.5, at most about 3, at most about 2, or at most about 1.5.

The melting point (freezing or pouring point) of the hydrophilic or water-miscible vehicles used according to the invention is preferably at least 20 ℃, more preferably at least 30 ℃, more preferably at least 40 ℃, more preferably at least 50 ℃, more preferably at least 52 ℃, more preferably at least 55 ℃, more preferably at least 59 ℃, especially at least 61 ℃, especially at least 65 ℃.

Examples of useful hydrophilic or water-miscible vehicles for use according to the invention are selected from the group consisting of: polyethylene glycol, polyoxyethylene oxide (polyoxothylene oxide), poloxamer, polyoxyethylene stearate, poly-epsilon-caprolactone, polyglycolyzed glyceride (polyglycolyzed glyceride) such asAnd mixtures thereof.

It is also contemplated that certain amphiphilic vehicles may be useful in the present invention, including vehicles disclosed herein that may also be amphiphilic in addition to being water miscible.

In a preferred embodiment of the invention, the vehicle is polyethylene glycol (PEG), in particular PEG having an average molecular weight of at least 1500, preferably at least 3000, more preferably at least 4000, especially at least 6000. The polyethylene glycol may advantageously be mixed with one or more other hydrophilic or water-miscible vehicles, such as poloxamers, preferably in a ratio (weight/weight) of 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 7: 3 mixture of PEG 6000 and Poloxamer 188.

For polyethylene glycol (PEG), the melting point (freezing or pour point) increases with increasing average molecular weight. For example, PEG 400 is in the range of 4-8 deg.C, PEG 600 is in the range of 20-25 deg.C, PEG 1500 is in the range of 44-48 deg.C, PEG 2000 is at about 52 deg.C, PEG 4000 is at about 59 deg.C, PEG 6000 is at about 65 deg.C, and PEG 8000 is at about 61 deg.C.

Useful poloxamers (also known as polyoxypropylene-polyoxyethylene block copolymers) are, for example, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407, or other block copolymers of ethylene oxide and propylene oxide, such asAnd/orAnd (4) series. Is suitably aThe series of block copolymers includes polymers having a molecular weight of about 3,000 or more, such as about 4,000 to about 20,000 and/or a viscosity (Brookfield) of about 200 to about 4,000cps, such as about 250 to about 3,000 cps. Suitable examples includeF38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, P127, 10R8, 17R8, 25R5, 25R8, and the like. Is suitably aA series of block copolymers includes polymers having a molecular weight of about 8,000 or more, such as from about 9,000 to about 35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000cps, such as from about 600 to about 40,000. The viscosities given above were determined at 60 ℃ (for materials that are pasty at room temperature) and 77 ℃ (for materials that are solid at room temperature).

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

Other useful hydrophilic or water-miscible vehicles may be polyvinylpyrrolidone, polyethylene-polyvinyl acetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic acid polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E), cellulose derivatives including Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, pectin, cyclodextrin, galactomannan, alginate, carrageenan, xanthan gum, and mixtures thereof.

"polyglycolyzed glycerides" refers to mixtures of mono-, di-and triglycerides of glycerol and mono-and diesters of polyethylene glycol (PEG), preferably with a molecular weight of 200-; examples of such mixtures areThe compositions are inert semi-solid waxy materials, amphiphilic in nature, and available in different physical characteristics. They are surfactants in nature and are dispersed or dissolved in an aqueous medium to form micelles, microspheres, or vesicles. They are identified by melting point/HLB values. Melting points are expressed in degrees celsius, while HLB (hydrophilic-lipophilic balance) is a numerical scale extending from 0 to about 20. Lower HLB values indicate more lipophilic and hydrophobic substances, while higher HLB values indicate more hydrophilic and lipophobic substances. The affinity of a compound for water or oily substances is determined and its HLB value is determined experimentally. With different levels being selectableOne or a mixture of excipients to achieve the desired characteristics of melting point and/or HLB value. They are long chains (C)₁₂-C₁₈) Mono-, di-and/or triglycerides of fatty acids with long chains (C)₁₂-C₁₈) Mixtures of PEG (mono and/or di) esters of fatty acids, and may contain free PEG.The compositions are generally described as glycerin fatty acid esters and PEG esters, or polyglycolyzed glycerides.The compositions are characterized by a broad melting point range, from about 33 ℃ to about 64 ℃, most commonly from about 35 ℃ to about 55 ℃, and a wide variety of HLB values, from about 1 to about 14, most commonly from about 7 to about 14. For example,50/13 indicating this levelThe melting point is about 50 ℃ and the HLB value is about 13.

Pharmaceutical composition

The pharmaceutical compositions of the present invention comprise a solid dispersion or solid solution of the present invention and one or more pharmaceutically acceptable excipients, for example one or more excipients that may act as fillers, disintegrants, binders, and/or lubricants.

Preferably, the pharmaceutical composition of the invention is in particulate form, e.g. in powder form. Preferably, the resulting particulate material is a free-flowing powder and is therefore readily processed into, for example, solid dosage forms such as tablets, capsules, or sachets. In general, the properties of the particulate material are suitable for the manufacture of tablets by direct compression without the addition of large amounts of other additives. A suitable test method for testing the flowability of the particulate material is the method described in the european pharmacopoeia, which measures the flow rate of the material through a funnel having an orifice (orifice) of 10.0mm diameter.

The geometric weighted mean diameter d of the particles_gwCan beAbout 10 μm to about 2000. mu.m, preferably about 20 μm to about 2000. mu.m, more preferably about 30 μm to about 2000. mu.m, more preferably about 50 μm to about 2000. mu.m, more preferably about 60 μm to about 2000. mu.m, more preferably about 75 μm to about 2000. mu.m, more preferably about 100 μm to about 1500. mu.m, more preferably about 100 μm to about 1000. mu.m, more preferably about 100 μm to about 700. mu.m, more preferably about 50 μm to about 400. mu.m, more preferably about 50 μm to about 350. mu.m, more preferably about 50 μm to about 300. mu.m, particularly about 50 μm to about 250. mu.m, and especially about 100 μm to about 300. mu.m. In a preferred embodiment of the invention, the particles have a geometrically weighted mean diameter d_gwIs about 50 μm to about 300 μm.

Examples of suitable excipients for use in the compositions or solid dosage forms according to the invention include fillers, diluents, disintegrants, binders, lubricants and the like or mixtures thereof. Because the compositions or solid dosage forms according to the present invention may be used for different purposes, the choice of excipients generally takes these different uses into account. Other pharmaceutically acceptable excipients which are suitable are, for example, acidifying agents, alkalinizing agents, preservatives, antioxidants, buffers, chelating agents, colorants, complexing agents, emulsifying and/or solubilizing agents, flavoring agents (flavors) and perfuming agents (perfume), humectants, sweeteners, wetting agents etc.

Examples of suitable fillers, diluents, and/or binders include lactose (e.g., spray-dried lactose, alpha-lactose, beta-lactose,of various gradesOr) Microcrystalline cellulose (of various grades)Or) Hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g., Methocel E, F, and K from Shin-Etsu Co., Ltd. and Methosose SH such as Methocel E and Methosose 60 SH grades of 4,000cps, Methocel F and Methosose 65 SH grades of 4,000cps, 15,000, and Methocel K grades of 100,000cps, and Methocel 90SH grades of 4,000, 15,000, 39,000, and 100,000), methylcellulose polymers (e.g., Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin, maltose, dextrin or modified starches (including potato starch, calcium phosphate starch (e.g., calcium phosphate), starch (calcium phosphate), and calcium phosphate starch (calcium phosphate), e.g., calcium phosphate), starch (calcium phosphate), starch, calcium phosphate, and calcium phosphate, and calcium phosphate, Dibasic calcium phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen, and the like.

Specific examples of diluents are, for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar and the like.

Specific examples of disintegrating agents are e.g. alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, cross-linked polyvinylpyrrolidone, polacrilin potassium, sodium starch glycolate, starchPowders, pregelatinized starches, carboxymethyl starches (e.g. starch gum)And) And the like.

Specific examples of the binder are, for example, acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, pectin, PEG, polyvinylpyrrolidone, pregelatinized starch, and the like.

Glidants and lubricants may also be included in the composition. 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 oil, corn starch, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate, sodium acetate, and the like.

Other excipients which may be included in the compositions or solid dosage forms of the invention are, for example, flavoring agents, colorants, taste-masking agents, pH-adjusting agents, buffers, preservatives, stabilizers, antioxidants, wetting agents, moisture-regulating agents, surfactants, suspending agents, absorption enhancers, release modifiers, and the like.

Other additives in the composition or solid dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulphite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium thiosulphate, sulphur dioxide, tocopherol, tocopheryl acetate, tocopherol hemisuccinate, TPGS, or other tocopherol derivatives, etc. The carrier composition may also comprise, for example, a stabilizer. The concentration of the antioxidant and/or stabilizer in the carrier composition is generally from about 0.1 w/w% to about 5 w/w%.

The pharmaceutical composition or solid dosage form according to the invention may also comprise one or more surfactants or substances with surface-active properties. It is envisaged that these materials involve wetting of the slightly soluble active material, thereby helping to improve the dissolution profile of the active material. Suitable excipients for use in the compositions or solid dosage forms according to the invention are surfactants, such as amphiphilic surfactants, as disclosed in WO 00/50007 in the name of Lipocine.

Examples of suitable substances which can be used as surfactants and/or even vehicles are:

i) polyethoxylated fatty acids, such as the fatty acid mono-or diesters of polyethylene glycol or mixtures thereof, such as the mono-or diesters of polyethylene glycol with lauric, oleic, stearic, myristic, ricinoleic acid, and polyethylene glycols can be selected from: PEG 4, PEG5, PEG 6, PEG 7, PEG8, PEG 9, PEG10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG32, PEG 40, PEG 45, PEG50, PEG 55, PEG100, PEG 200, PEG 400, PEG 600, PEG 800, PEG1000, PEG 2000, PEG 3000, PEG 4000, PEG5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG1000, PEG10,000, PEG 15,000, PEG 20,000, PEG 35,000;

ii) polyethylene glycol glycerol fatty acid esters, i.e. esters similar to those described above but present in the form of glycerol esters of the respective fatty acids;

iii) esters of glycerol, propylene glycol, ethylene glycol, PEG, or sorbitol with, for example, vegetable oils such as, for example, hydrogenated castor oil, almond oil, palm kernel oil, castor oil, almond oil, olive oil, peanut oil, hydrogenated palm kernel oil, and the like;

iv) polyglycerolated fatty acids (polyglycerolated fatty acids) such as, for example, polyglycerolated stearate, polyglycerolated oleate, polyglycerolated ricinoleate, polyglycerolated linoleate;

v) propylene glycol fatty acid esters such as propylene glycol monolaurate, propylene glycol ricinoleate, and the like;

vi) glycerol mono-and diesters, such as, for example, glycerol monooleate, glycerol dioleate, glycerol mono-and/or dioleate, glycerol octanoate, glycerol decanoate, etc.;

vii) sterols and sterol derivatives;

viii) Polyethyleneglycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters), e.g. esters and various of the molecular weights of PEG described aboveSeries;

ix) polyethylene glycol alkyl ethers such as PEG oleyl ether and PEG lauryl ether;

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

xi) polyethylene glycol alkylphenols, such as for example

X or N series;

xii) polyoxyethylene-polyoxypropylene block copolymers, e.g.A series of,A series of,And the like. These polymers are collectively referred to as "poloxamers," and relevant examples herein are poloxamers 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407;

xiii) sorbitan fatty acid esters, such asSeries orSeries, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, and the like;

xiv) lower alcohol fatty acid esters such as, for example, oleate, isopropyl myristate, isopropyl palmitate, and the like;

xv) ionic surfactants including cationic, anionic, and zwitterionic surfactants such as fatty acid salts, bile salts, phospholipids, phosphate esters, carboxylate salts, sulfate salts, and sulfonate salts, and the like.

When a surfactant or a mixture thereof is present in the composition or solid dosage form of the invention, the concentration of the surfactant is typically in the range of about 0.1 to 80 w/w%, such as about 0.1 to about 20 w/w%, about 0.1 to about 15 w/w%, about 0.5 to about 10 w/w%, or about 0.10 to about 80 w/w%, such as about 10 to about 70 w/w%, about 20 to about 60 w/w%, or about 30 to about 50 w/w%.

In a particular aspect of the invention, at least one of the one or more pharmaceutically acceptable excipients is selected from the group consisting of: silicic acid or derivatives or salts thereof, including silicates, silica, and polymers thereof; magnesium aluminosilicates and/or magnesium aluminosilicates, bentonite, kaolin, magnesium trisilicate, montmorillonite, and/or saponite (saponite).

These materials are particularly useful as sorbates for oils or oily substances in pharmaceuticals, cosmetics, and/or food products. In a particular embodiment, this material is used as a sorbate for oils or oily substances in pharmaceutical products. Such materials capable of functioning as a sorbate for oil or oily substances are also referred to as "oil sorbate". In addition, the term "sorption" is used herein to refer to both "absorption" and "adsorption". It is to be understood that whenever one of the terms is used, it is intended to cover absorption as well as adsorption phenomena.

In particular, the pharmaceutically acceptable excipient may comprise silicic acid or a derivative or salt thereof, such as silica or a polymer thereof, as a pharmaceutically acceptable excipient. The silica may be a lubricant or may be an oil-attracting substance depending on the mass employed. The quality of satisfying the latter function seems to be of utmost importance.

In one embodiment, the composition or solid dosage form according to the invention comprises a pharmaceutically acceptable excipient having a pharmaceutically acceptable carrier chain with300 (available from Degussa, frankfurt, germany) of comparable characteristics. As can be seen from the examples herein, very suitable materials are300 (including having and)300 of similar or equivalent characteristics).

The use of an oil sorbate in the composition or dosage form according to the present invention is very advantageous for the preparation of pharmaceutical, cosmetic, nutraceutical, and/or food compositions comprising oil or oily substances. One of the benefits is that it is possible to incorporate relatively large amounts of oil and oily substances and the material remains solid. Thus, by using the oil-absorbing material according to the present invention, it is possible to prepare a solid composition containing a relatively large amount of oil or oily substance. In the pharmaceutical field, it would be advantageous to be able to incorporate relatively large amounts of oil or oily-like substances into solid compositions, especially where the active substance does not have suitable properties with respect to water solubility (e.g. poor water solubility), stability in aqueous media (i.e. degradation occurs in aqueous media), oral bioavailability (e.g. low bioavailability), etc., or where it is desirable to modify the release of the active substance from the composition to obtain controlled, delayed, sustained, and/or pulsed delivery of the active substance. Thus, in one embodiment, an oil attractor is used in the preparation of the pharmaceutical composition.

The oil sorbate employed in processing the solid composition typically sorbs about 5 w/w% or more, such as 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 of the oil or oily substance, and still be a solid material.

In one aspect, the present invention relates to a pharmaceutical composition in particulate form comprising tacrolimus and/or an analog thereof and one or more pharmaceutically acceptable excipients, wherein the composition exhibits an AUC @/when orally administered to a mammal in need thereofThe value is at least about 1.3, and the AUC values are determined under similar conditions.

As can be seen from the examples herein, the bioavailability achieved after administration of the composition according to the invention is significantly improved. Thus, in a specific embodiment, the AUC @Values are at least about 1.5, e.g., about 1.75 or greater, about 1.8 or greater, about 1.9 or greater, about 2.0 or greater, about 2.5 or greater, about 2.75 or greater, about 3.0 or greater, about 3.25 or greater, about 3.5 or greater, about 3.75 or greater, about 4.0 or greater, about 4.25 or greater, about 4.5 or greater, about 4.75 or greater, or about 5.0 or greater, AUC values being determined under similar conditions.

After oral administration of the pharmaceutical composition according to the invention, it is envisaged that the plasma concentration versus time profile shows a long period of time in which the plasma concentration is maintained within the therapeutic window (i.e. the plasma concentration produces a therapeutic effect) without producing serious undesired side effects. Thus, a decrease in peak concentration is observed. Accordingly, the present invention relates to a pharmaceutical composition in particulate form comprising tacrolimus and one or more pharmaceutically acceptable excipients, wherein the composition exhibits a C when orally administered to a mammal in need thereof_maxAt most isTablet C_maxAbout 80%, such as up to about 75%, up to about 70%, up to about 65%, up to about 60%, up to about 55%, up to about 50%, up to about 45%, or up to about 40%.

However, a decrease in peak concentration may not result in a decrease in therapeutic effect as long as the plasma concentration of tacrolimus is maintained within the therapeutic window. Accordingly, the present invention also relates to pharmaceutical compositions wherein W is₅₀At least about 2 hours, such as at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.

Furthermore, C of the composition according to the invention_diff＝C_max-C_t(t-12 hours) ratio under the same conditionsLow. If it will beC of (A)_diffSet to 100, C for the composition according to the invention_diffPreferably 90 or less, 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 55Or less, about 50 or less, about 45 or less, or about 40 or less.

It is envisaged that the requirement for concurrent feeding in order to ensure adequate uptake of tacrolimus is significantly reduced or even completely eliminated when administering the pharmaceutical composition or dosage form of the present invention.

Thus, the pharmaceutical compositions of the present invention significantly improve the bioavailability of tacrolimus, which may reduce the number of dosage units administered daily and alleviate or eliminate the need to take the drug while feeding, which provides more freedom to the recipient of the pharmaceutical composition, which in turn may significantly improve patient acceptance and/or compliance. In addition, the composition significantly reduces side effects, especially those associated with high peak concentrations (e.g., renal and neurological toxicity, diarrhea, constipation, abdominal pain, nausea, etc.), and prolongs the release of tacrolimus, resulting in better therapeutic efficacy.

One of the major challenges with respect to formulating tacrolimus compositions is avoiding adverse food effects. Generally speaking, tacrolimus is absorbed much better when administered orally without food. Thus, a great difference in bioavailability was seen with or without food. This dependence makes it difficult to give an accurate indication of how large a dose should be administered, and additionally requires the patient to be informed of the dosing regimen. The present invention seeks to provide compositions with reduced adverse food effects. Thus, the present invention provides compositions that do not exhibit significant adverse food effects following administration of the compositions to a mammal in need of such treatment, as evidenced by AUC_{Eating food}/AUC_FastingThe value is at least about 0.85 and at the lower 90% confidence limit is at least 0.75.

More specifically, the AUC of the pharmaceutical composition according to the invention_{Eating food}/AUC_FastingThe value is about 0.9 or greater, such as about 0.95 or greater, about 0.97 or greater, or about 1 or greater, such as up to about 1.1 or up to about 1.2.

In addition to tacrolimus, the compositions of the present invention may contain another therapeutically, prophylactically, and/or diagnostically active substance. In particular, combinations of tacrolimus with at least one of the following active substances are contemplated: substances used in connection with organ transplantation, such as steroids, calcineurin inhibitors, and/or antiproliferative agents, are indicated. Specific examples include prednisone, prednisolone, methylprednisolone, cyclosporine, mycophenolate mofetil, azathioprine, sirolimus, everolimus, mycophenolate sodium, and FTY720 (developed by pharmaceutical company Novartis).

Dosage forms

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

The pharmaceutical composition according to the present invention is in the form of microparticles and can be used in this form. However, in many cases it will be more convenient to provide the composition in the form of particles, pellets, microspheres, nanoparticles, and the like, or in the form of a solid dosage form (including tablets, capsules, sachets, and the like).

The solid dosage form according to the invention may be a single unit dosage form, or it may comprise a plurality of individual units (e.g. pellets, beads and/or granules) in a polydepot dosage form.

The dosage form may also contain pharmaceutically acceptable additives such as flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, humidity adjusting agents, surfactants, suspending agents, absorption enhancing agents, and release modifying agents.

In a preferred embodiment, the dosage form comprises silicic acid or derivatives or salts thereof, including silicates, silicon dioxide, and polymers thereof; and/or magnesium aluminosilicates and/or magnesium n-aluminosilicates, bentonite, kaolin, magnesium trisilicate, montmorillonite, and/or saponite. A particularly useful excipient that may be included in the dosage form is a mixture of300 (available from Degussa, frankfurt, germany) of comparable characteristics.

The solid dosage form according to the present invention comprises a pharmaceutical composition in particulate form as described above. The details and details disclosed in this main aspect of the invention apply mutatis mutandis to the other aspects of the invention. Accordingly, the characteristics described and/or claimed herein with respect to the particulate form of the pharmaceutical composition in terms of improved bioavailability, altered bioavailability parameters, reduced adverse food effects, and release of tacrolimus and/or its analogs are also similar for the solid dosage forms according to the present invention.

Typically, the concentration of the pharmaceutical composition in particulate form is in the range of about 5-100 w/w% of the dosage form, such as about 10% -about 90 w/w%, about 15% -about 85 w/w%, about 20% -about 80 w/w%, about 25% -about 80 w/w%, about 30% -about 80 w/w%, about 35% -about 80 w/w%, about 40% -about 75 w/w%, about 45% -about 75 w/w%, or about 50% -about 70 w/w%. In one embodiment of the invention, the concentration of the pharmaceutical composition in particulate form is 50 w/w% or more of the dosage form.

Solid dosage forms according to the present invention are obtained by processing particulate materials according to the present invention using techniques well known to those skilled in the art. Typically, it also involves the addition of one or more pharmaceutically acceptable excipients as described herein.

The composition or solid dosage form according to the invention may be designed to release tacrolimus and/or its analogues in any suitable manner, as long as the bioavailability is increased. Thus, the active substance can be released relatively rapidly, thereby enhancing the onset of action (on-set); the active substance can be released with zero or first order kinetics; or the active substance may be released in a modified manner to obtain a predetermined release pattern. All of these ways are considered to be controlled ways. Conventional formulations are also within the scope of the present invention.

For theThe recommended dosage range is 0.1-0.2 mg/kg/day, administered twice a day, once every 12 hours. More importantly, blood levels must be monitored. Typical levels for 1-3 months are 7-20ng/ml, while levels for 4-12 months should be 5-15 ng/ml. This is a guide value only and may vary depending on the transplant type and race.

The following data were observed in renal transplant patients:

the expected recommended dosage for the product of the invention will be from 0.02 mg/kg/day to 0.15 mg/kg/day, taken once a day.

Enteric coating-delayed Release

It has been found that the efficacy of oral tacrolimus treatment can be greatly improved by appropriate design of the release profile of tacrolimus. On the one hand, larger doses of tacrolimus are required to avoid graft rejection; on the other hand, side effects are often too pronounced, even at therapeutically relevant levels. Thus, side effects such as acute nausea, vomiting, renal toxicity, and neurotoxicity are directly linked to high peak plasma concentrations. This association was demonstrated in dogs. In cases where lower doses are used to avoid high peak levels, dose-dependent side effects almost cease to occur at some threshold level, and if they do, to a much lesser extent. However, due to the reduction in dosage (and no increase in bioavailability), therapeutically effective levels are maintained for only a short period of time. The present invention addresses this problem by providing pharmaceutical compositions or dosage forms containing tacrolimus, wherein the release of tacrolimus is designed to avoid high peak concentrations while at the same time the composition is designed such that the overall bioavailability is maintained or improved compared to commercially available dosage forms containing tacrolimus. Furthermore, by delaying the release of tacrolimus and simultaneously providing a composition wherein at least part of the tacrolimus is in dissolved form, it is possible to obtain a significant absorption at the distal end of the gastrointestinal tract.

Thus, the dosage form of the present invention may further comprise one or more release modifiers selected from the group consisting of: water-miscible polymers, water-insoluble polymers, oils and oily substances.

The water insoluble polymer may be ethyl cellulose, cellulose acetate, cellulose nitrate, and mixtures thereof. The water-miscible polymer may also be a cellulose derivative selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, poloxamers, polyoxyethylene stearate, polyepsilon caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-PVA), polymethacrylic acid polymers and polyvinyl alcohol (PVA), polyethylene oxide (PEO) and mixtures thereof. Examples of particularly useful polymethacrylic acid polymers areRS、RL、NE, andE。

the oil or oily substance may be both hydrophilic and hydrophobic.

The hydrophilic oil or oily substance may be a polyether glycol such as polypropylene glycol; polyoxyethylene; polyoxypropylene; a poloxamer; polyglycolyzed glycerides, e.g.For example50/13、44/14、50/10、62/05 and mixtures thereof.

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

The oil or oil-like substance may also be a sorbitan ester, such as sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate, or mixtures thereof.

The oil or oil-like substance may of course comprise a mixture of different oils or oil-like substances, for example a mixture of hydrophilic and/or hydrophobic substances.

Other suitable oils or oily-like substances may be solvents or semi-solid excipients, such as for example propylene glycol, polyglycolyzed glycerides, including Gelucire 44/14, complex fatty substances of vegetable origin, including cocoa butter, carnauba wax, vegetable oils, such as 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, grapeseed oil and the like, 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 fatty substances of animal origin, including beeswax, lanolin, fatty alcohols, including cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearic fatty alcohol (stearic fatty alcohol), esters, including glyceryl stearate, ethylene glycol stearate, ethyl oleate, Isopropyl myristate, liquid interesterified (interesterified) semisynthetic glycerides including Miglycol 810/812, amides or fatty acid alkanolamides (alcolamides) including stearamidoethanol, diethanolamides of fatty coconut acids, acetates of mono and diglycerides, citrates of mono and diglycerides, lactates of mono and diglycerides, monoglycerides of glycerol, mono and diglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propylene glycol esters of fatty acids, sorbitan monostearate, sorbitan tristearate, sodium stearoyl lactylate, calcium stearoyl lactylate, diacetyl tartaric acid esters of mono and diglycerides and the like.

In order to improve the bioavailability of the active ingredient by delivery into the gastrointestinal tract, it is necessary to delay the release of the active ingredient, i.e. the release occurs mainly after passage through the stomach. For example, the dosage form of the invention may be designed such that, after oral administration to a mammal in need thereof, at most about 10 w/w%, preferably at most about 7.5 w/w%, more preferably at most about 5 w/w%, especially at most about 2 w/w% of the total amount of active ingredient is released within the first 3 hours, preferably within 2 hours, more preferably within 1 hour, in particular within about 30 minutes after administration.

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

Delayed release occurs primarily through certain types of enteric coatings. Although the semipermeable coating exhibits some sort of delayed release, it may not be able to "delay" the release very sufficiently. In addition, it requires a certain amount of time to release the contents. The coatings sought for the present invention are pH dependent coatings. This type of coating is very resistant to drug release until a certain pH is reached. With a small increase in pH, i.e., about 0.2-0.4, the membrane properties change, thereby becoming permeable.

Thus, the solid dosage form of the present invention may exhibit delayed release of the active ingredient by means of an enteric coating using a water-miscible polymer having pH-dependent water solubility. Examples of pH-sensitive polymers (less soluble and impermeable at the pH of the stomach, but more soluble and permeable at the pH of the small intestine and colon) include, but are not limited to, polyacrylamide; phthalate derivatives, such as acidic phthalates of carbohydrates, including amylose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate (HMPCP), methyl cellulose phthalate, methyl cellulose acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acidic phthalates; phthalates of other compounds, including polyvinyl acetate phthalate (PVAP); other cellulose derivatives, including hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose, vinegarAcid trimellitic acid cellulose; an alginate; carbomer; polyacrylic acid derivatives, such as acrylic acid and acrylate copolymers, polymethacrylic acid and esters thereof, polyacrylic acid methacrylic acid copolymers, methacrylic acid copolymers (e.g. acrylic acid and acrylic acid ester copolymers, polyacrylic acid methacrylic acid copolymers, polyacrylic acidAnd) (ii) a Styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl alcohol acetate phthalate copolymer, styrene and maleic acid copolymer; shellac, glycollic acid starch; polacrylin; copolymers of vinyl acetate and crotonic acid; and mixtures thereof. pH-sensitive polymers of particular interest include shellac; phthalate derivatives, in particular cellulose acetate phthalate, polyvinyl alcohol acetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, in particular polymethyl methacrylate mixed with acrylic acid and acrylate copolymers; and copolymers of vinyl acetate and crotonic acid.

A first delayed release embodiment according to the present invention is a "pH-dependent coated dosage form", such as a tablet or capsule. In the case of a tablet, which comprises a core containing tacrolimus (e.g. in solid solution and/or solid dispersion as a multiparticulate product), a controlled release matrix (e.g. HPMC), a disintegrant, a lubricant, and one or more pharmaceutical carriers, such core is coated with a material, preferably a polymer which is substantially insoluble and impermeable at the pH of the stomach but more soluble and permeable at the pH of the small intestine. Preferably, the coating polymer is substantially insoluble and impermeable at pH < 5.0 and soluble in water at pH > 5.0. The core may be coated with a sufficient amount of polymer to ensure that substantially no release of tacrolimus from the dosage form occurs until the dosage form exits the stomach to reside in the small intestine for about 15 minutes or more, preferably about 30 minutes or more, to ensure minimal release of tacrolimus in the duodenum. Mixtures of pH sensitive polymers with water insoluble polymers may also be employed. The tablet is coated with an amount of polymer which is about 10% to about 80% by weight of the tacrolimus-containing core. Preferably, the tablet is coated with an amount of polymer which is from about 15% to about 50% by weight of the tacrolimus core.

pH sensitive polymers that are extremely insoluble and impermeable at the pH of the stomach but more soluble and permeable at the pH of the small intestine and colon include polyacrylamide, phthalate derivatives such as acidic phthalate esters of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinylalcohol acetate phthalate, polyvinylacetate phthalate, sodium acetate phthalate, starch acidic phthalate, styrene-maleic dibutyl phthalate copolymer, styrene-maleic polyvinylalcohol acetate phthalate copolymer, sodium acetate phthalate, starch acidic phthalate, styrene-maleic dibutyl phthalate copolymer, sodium acetate phthalate, sodium starch acidic phthalate, sodium acetate phthalate, sodium maleate, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylate copolymers, polymethacrylic acid and its esters, polyacrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

Preferred pH-sensitive polymers include shellac; phthalate derivatives, in particular cellulose acetate phthalate, polyvinyl alcohol acetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, in particular polymethyl methacrylate mixed with acrylic acid and acrylate copolymers; and copolymers of vinyl acetate and crotonic acid. By selecting from among coatingsAndthe relative amount of the coating and the thickness of the coating can control the delay time after leaving the stomach before the tacrolimus is released from the "pH dependent coated tablet" dosage form.The membrane is dissolved above ph6.0,the membrane of (a) dissolves at a pH above 7.0, while the mixture dissolves at an intermediate pH. Since the pH of the duodenum is approximately 6.0 and the pH of the colon is approximately 7.0, the pH of the colon is approximatelyAndthe coating consisting of the mixture provides tacrolimus protection against the duodenum. If it is desired to delay the release of tacrolimus until the tacrolimus-containing "pH-dependent coated tablet" reaches the colon, it may be useful to useAs coating materials, as exemplified by Dew et al, br.j.clin.pharmac.14: 405 and 408, 1982. In order to delay the release of tacrolimus until about 15 minutes or more, preferably 30 minutes or more after the dosage form leaves the stomach, it is preferred that the coating comprises from about 9: 1 to 1: 9/More preferably about 9: 1 to 1: 4/The weight of the coating may be from about 3% to about 70% of the uncoated tablet core. Superior foodPreferably, the weight of the coating is from about 5% to about 50% of the core.

If, for example, zeatin (Zein) or a glycerol mono/di-ester mixture is used as coating material, the release of the active substance from the composition with a delayed-release coating can also be an enzymatic reaction.

Manufacture of the compositions and dosage forms of the invention

The present invention also provides a process for preparing the solid dispersion and/or solid solution of the invention, comprising the steps of: tacrolimus or its analogs are dispersed and/or dissolved in a hydrophilic or water-miscible vehicle to obtain a solid dispersion and/or solid solution at ambient temperature.

The pharmaceutical compositions of the present invention may be prepared by any convenient method, such as granulation, mixing, spray drying, and the like. An example of a useful method is the controlled agglomeration method disclosed in WO 03/004001, i.e. a method enabling controlled particle size growth. The method involves spraying a first composition comprising an active ingredient and a molten vehicle onto a second solid carrier. Typically, the melting point of the meltable vehicle is at least 5 ℃, but is preferably below the melting point of tacrolimus. The melting point of the vehicle may be in the range 10 ℃ to 150 ℃.

One of the benefits of using the controlled agglomeration method disclosed in WO 03/004001 is that it is possible to apply relatively large amounts of melt to the particulate material without undesirable growth in particle size.

For example, solid dispersions may also be obtained by employing an organic solvent or by dispersing or dissolving the active substance in another suitable medium (e.g. an oil or oily substance in liquid form at room or elevated temperature).

Solvent methods solid dispersions are prepared by dissolving a physical mixture of the active substance (e.g., drug substance) and the vehicle or carrier in a common organic solvent, followed by evaporation of the solvent. The vehicle carrier may be a hydrophilic polymer. Suitable organic solvents include pharmaceutically acceptable solvents in which the active substance is soluble, such as methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetone, or mixtures thereof.

Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearate, polyepsilon caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-PVA) (Kollidon VA64), polymethacrylic acid polymers (Eudragit RS, Eudragit RL, Eudragit NE, and Eudragit E), and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, and polyethylene oxide (PEO).

Polymers containing acidic functional groups may be suitable for solid dispersions that release the active substance in the preferred pH range to provide acceptable levels of absorption in the intestine. These polymers may be one or more polymers selected from the group consisting of: hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl alcohol acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), alginates, carbomers, carboxymethylcellulose, methacrylic acid copolymers (Eudragit L and Eudragit S), shellac, Cellulose Acetate Phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, and cellulose acetate trimellitate.

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

The solid dispersion is preferably formed by spray drying techniques, controlled agglomeration, lyophilization, or coating of the carrier particles, or any other solvent removal process. The dried product contains the active in the form of a solid dispersion, including molecular dispersions and solid solutions.

As an alternative to using an organic solvent, the drug and polymer may be co-milled or extruded at elevated temperatures (melt extrusion).

The pharmaceutical composition comprising tacrolimus may in principle be prepared using any suitable procedure known in the art for the preparation of pharmaceutical compositions wherein at least part of the tacrolimus is in the form of a solid dispersion or solid solution.

In addition to using an organic solvent based process, solid dispersions or solid solutions of tacrolimus and/or analogs thereof may be obtained by dispersing and/or dissolving tacrolimus in the carrier composition used in the controlled agglomeration process. Stabilizers and the like may be added to ensure stability of the solid dispersion/solid solution.

Use of

The solid dispersion and/or solid solution of the present invention or the pharmaceutical composition of the present invention may be used to prepare a solid oral dosage form, such as a tablet, capsule, or sachet; or for the preparation of particles, pellets, microspheres, or nanoparticles.

Preferably, the solid dispersion or solid solution is used to prepare an immediate release solid dosage form or a delayed release solid dosage form.

Other uses of the solid dispersions or solid solutions of the present invention are in the preparation of topical dosage forms.

Another advantage of the compositions of the present invention is that it is possible to obtain an effective therapeutic response at lower doses than conventional oral treatments. Thus, the solid dosage forms of the present invention are contemplated asOr up to about 85 w/w% of the dose of tacrolimus administered similar to commercially available tacrolimus-containing products, e.g., up to about 80 w/w%, up to about 75 w/w%, up to about 70 w/w%, up to about 65 w/w%, up to about 60 w/w%, up to about 55 w/w%, or up to about 50 w/w% of the dose of tacrolimus versus allAfter oral administration to a mammal in need thereof, on a substrateOr similar commercially available tacrolimus-containing products are bioequivalent.

Any tacrolimus-containing dosage form, composition, dispersion or solution of the present invention may improve the treatment of conditions responsive to tacrolimus treatment.

Tacrolimus is indicated (or suggested) for use in the treatment of, for example, the following diseases: rejection of organ or tissue transplants such as heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limbs, muscle, nerve, intervertebral disc, trachea, myoblasts, cartilage, etc.; graft versus host response after bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes; infections caused by pathogenic microorganisms (e.g., Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.); cutaneous manifestations of inflammatory or hyperproliferative skin diseases or immunologically-mediated diseases (e.g., psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vascultidines, erythema, cutaneous eosinophilia, lupus erythematosus, acne, and alopecia areata); autoimmune diseases of the eye (e.g., keratoconjunctivitis, vernal conjunctivitis, uveitis associated with behcet's disease, keratitis, herpetic keratitis, conal keratitis, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus (premphigus), morenulcer, scleritis, graves' eye disease, voacanthus-castanea syndrome, keratoconjunctivitis sicca (dry eye disease), small blisters, iridocyclitis, sarcoidosis, endocrine eye disease, etc.); reversible obstructive airways diseases [ asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or intractable asthma (e.g., late asthma and airway hyperresponsiveness) bronchitis and the like; mucosal or vascular inflammation (e.g., gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal injury associated with thermal burns, leukotriene B4-mediated diseases); intestinal inflammation/allergy (e.g., coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, crohn's disease, and ulcerative colitis); food-related allergic diseases with symptomatic manifestations away from the gastrointestinal tract (e.g. migraine, rhinitis, and eczema); renal diseases (e.g., interstitial nephritis, goodpasture's syndrome, hemolytic uremic syndrome, and diabetic nephropathy); neurological diseases (e.g., polymyositis, guillain-barre syndrome, meniere's disease, polyneuritis, mononeuritis, cerebral infarction, alzheimer's disease, parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and radiculopathy); ischemic disorders (e.g., craniocerebral injury, cerebral hemorrhage (e.g., subarachnoid hemorrhage, intracerebral hemorrhage), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, Transient Ischemic Attack (TIA), hypertensive encephalopathy, cerebral infarction); endocrine diseases (e.g., hyperthyroidism and Barcelia); hematological disorders (e.g., monocytic aplasia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and failure to erythropoiesis); bone diseases (e.g., osteoporosis); respiratory diseases (e.g., sarcoidosis, pulmonary fibrosis, and idiopathic interstitial pneumonia); skin diseases (e.g., dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photosensitivity, and cutaneous T-cell lymphoma); circulatory diseases (e.g., arteriosclerosis, atherosclerosis, aortolitis syndrome, polyarteritis nodosa, and cardiomyopathy); collagen diseases (e.g., scleroderma, wegener's necrotic granuloma, and sjogren's syndrome); obesity; eosinophilic fasciitis; periodontal disease (e.g., damage to the gingiva, periodontal ligament, alveolar bone, or cementum); nephrotic syndrome (e.g., glomerulonephritis); male pattern alopecia, senile alopecia; muscular dystrophy; pyoderma and sezary syndrome; disorders associated with chromosomal abnormalities (e.g., down syndrome); addison's disease; diseases mediated by reactive oxygen species (e.g., organ damage (e.g., ischemic circulatory disorders of organs (e.g., heart, liver, kidney, digestive tract, etc.) associated with preservation, transplantation, or ischemic diseases (e.g., thrombosis, cardiac infarction, etc.)), bowel diseases (e.g., endotoxic shock, pseudomembranous colitis, and drug-or radiation-induced colitis), renal diseases (e.g., ischemic acute renal insufficiency, chronic renal failure), pulmonary diseases (e.g., poisoning by pulmonary oxygen or drugs (e.g., paracort, bleomycin, etc.), lung cancers, and emphysema), ocular diseases (e.g., cataract, iron-storage disease (sideroptosis), retinitis, pigmentosa (pimenta), age spots, vitreous scarring, keratosis), dermatitis (e.g., erythema multiforme, linear immunoglobulin A bullous dermatitis, cemetermatatis), and other diseases (e.g., gingivitis), Periodontitis, sepsis, pancreatitis, and diseases caused by environmental pollution (e.g., air pollution), aging, carcinogens, metastasis, and baropathy) ]; diseases caused by histamine release or leukotriene C4 release; coronary restenosis following angioplasty and prevention of post-operative adhesions; autoimmune diseases and inflammatory conditions (e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male infertility, juvenile onset diabetes, pemphigus vulgaris, pemphigoid, sympathetic ophthalmia, lens uveitis, idiopathic leukopenia, chronic active hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g., osteoarthritis), or polychondritis); human Immunodeficiency Virus (HIV) infection, AIDS; allergic conjunctivitis; hypertrophic scar and keloid caused by trauma, burn, or surgery.

In addition, tricyclic macrolides such as, for example, tacrolimus have liver regenerating activity and/or activity to stimulate hepatocyte hypertrophy and hyperplasia. Accordingly, the pharmaceutical composition of the present invention can be used to enhance the effect of treating and/or preventing liver diseases [ e.g., immune diseases (e.g., chronic autoimmune liver diseases such as autoimmune liver diseases, primary biliary cirrhosis, or sclerosing cholangitis), partial hepatectomy, acute hepatic necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, or hypoxia), hepatitis b, non-a, non-b hepatitis, cirrhosis, and liver failure (e.g., fulminant hepatitis, late-onset hepatitis, and "liver-on-chronic" failure (acute liver failure of chronic liver diseases)) ].

In addition, due to the useful pharmacological activity of the tricyclic macrolide, the composition of the present invention can be used to improve the effect of preventing and/or treating various diseases, such as activity of improving the effect of chemotherapy, activity of mast cell virus infection, anti-inflammatory activity, inhibitory activity against peptidyl proline isomerase or rotamase, antimalarial activity, antitumor activity, and the like.

Materials and methods

Material

Tacrolimus (supplied by euretrade); batch number RD 03-111

Lactose monohydrate 200 mesh (from DMV)

The presence of a granulated silicon oxide results in,300(Degussa)

polyethylene glycol 6000 (polyethylene glycol 6000),e6000 (from BASF)

The preparation method comprises the following steps of (1) poloxamer 188,f-68 (from BASF)

The glycerol monostearate is obtained by mixing the raw materials,MD50 (from Danisco Cultor), european pharmacopeia grade; batch number 4010056276

Avicel PH200 (microcrystalline cellulose) (from FMC)

Lactose DCL 11 (from DMV)

Magnesium stearate

The cross-linked sodium carboxymethylcellulose is obtained by dissolving sodium carboxymethylcellulose in water,(from FMC)

30d.55 (from Degussa); batch number 1220314079

Triethyl citrate (from Merck); batch number RD 03-122

Antifoam emulsion (from Unikem)

Fine talc (micro talc)

Tablets, capsules, or granules can be enterically coated with various types of polymers such as hydroxypropyl methylcellulose acetate succinate (Aqoat), Cellulose Acetate Phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100/S, Eudragit 100/L.

Comparison of prior art tacrolimus formulations for in vivo studies:

hard gelatin capsules manufactured by Fujisawa Ireland Co., Ltd

Composition (I)	mg
		Tacrolimus, anhydrous	1.0
Gelatin	6.9
		Hydroxypropyl methylcellulose	1.0
Lactose monohydrate	24.7

Magnesium stearate	0.3
		Shellac	q.s.
Soybean agglutinin	q.s.
		Iron oxide red (E172)	q.s.
Titanium dioxide (E171)	q.s.
		Dimethicone (E900)	q.s.

Method of producing a composite material

Determination of weight change

The tablets prepared in the examples herein were tested for weight change according to the european pharmacopoeia. Determination of the average tablet hardness

Determination of the average tablet hardness

The tablets prepared in the examples herein were tested for tablet hardness using a Schleuniger type 6D device and in accordance with the general guidelines for that device.

Determination of disintegration time

The disintegration time of the tablets, i.e. the disintegration into granules or agglomerates, is measured according to the european pharmacopoeia.

Geometric weighted mean diameter d_gwMeasurement of (2)

The resulting particulate material (or starting material) was dispersed in air using laser diffraction and the geometric weight mean diameter was determined. The measurements were carried out at a dispersion pressure of 1 bar in a Sympatec Helos device which records the distribution of equivalent spherical diameters (equivalent spherial diameter). This distribution was fitted to a logarithmic normal volume-size distribution.

As used herein, "geometrically weighted average diameter" refers to the average diameter of a logarithmic normal volume-size distribution.

In vitro dissolution test

The following test methods were used for the compositions and dosage forms of the present invention.

Test 1:

in vitro dissolution test of the items related to delayed release (United states Pharmacopeia paddle method; rotation speed: 50 rpm; 37 ℃ C.; after 2 hours in an acidic medium, medium is exchanged for phosphate buffer at pH 6.8) according to United states Pharmacopeia method A.

And (3) testing 2:

in vitro dissolution test in an aqueous dissolution medium adjusted to pH4.5 (900ml of water containing 0.005% HPC (hydroxypropyl cellulose) adjusted to pH 4.5; 37 ℃; United states Pharmacopeia paddle method; rotation speed: 50 rpm).

In vivo studies in Beagle dogs

In vivo studies to determine bioavailability using Beagle dogs were conducted in order to compare the bioavailability of the compositions of the present invention to a commercially available tacrolimus product, i.e.The bioavailability of (a).

Experimental work was performed in Denmark using male Beagle dogs weighing 12-18kg per dog (starting body weight). The study was conducted in an open, non-randomized, crossover fashion. Dogs were preoperatively dosed with primperen injection (5mg/ml, antiemetic) and orally dosed with 0.5-4mg tacrolimus. The dogs were fasted for 10 hours prior to dosing (water ad libitum) and fed 5 hours after dosing (water ad libitum). Each dog was dosed with a specific dose of tacrolimus, regardless of the weight of the dog.

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

Using pharmacokinetic softwareThe measured whole blood concentration profile of tacrolimus was treated (Pharsight; California; USA) to calculate pharmacokinetic parameters. All data were dose adjusted.

The following examples are for the purpose of illustrating the invention and are not intended to limit the scope of the invention.

Pharmaceutical compositions and dosage forms of the invention are illustrated in examples 1-4, including the results of in vitro dissolution testing. The results (plasma concentrations) of the in vivo comparison studies conducted in Beagle dogs are listed in examples 5-6.

Example 1: immediate release tablet with improved bioavailability

The composition of the tablet is as follows:

	％	mg
			tacrolimus	0.50	1.00
Lactose 200 mesh	49.75	100.00
			PEG 6000	34.48	69.30
Poloxamer 188	14.78	29.70
			Magnesium stearate	0.50	1.01
Total up to	100.00	201.01

Tacrolimus was dissolved in polyethylene glycol 6000 and poloxamer 188(w/w ratio 70: 30) at 70 ℃. The solution was sprayed onto 250g of lactose in fluidized bed stream-1. The granulated product was sieved through a 0.7mm screen and mixed with magnesium stearate in a Turbula mixer for 0.5 minutes. The mixture was compressed into 8mm tablets (200mg tablets, compound cup) containing 1mg of active ingredient.

Average disintegration time: for 20 minutes. Hardness: 45N, respectively.

Example 2: immediate release tablet composition based on PEG 6000/poloxamer 188:

substance(s)	％	mg
			Tacrolimus	1.98	2.00
Lactose monohydrate, lactose 200 mesh	40.50	40.91
			PEG 6000	33.26	33.60
Poloxamer 188, Lutrol 68	14.40	14.40

Magnesium stearate	0.50	0.51
			Talc	4.50	4.55
Croscarmellose sodium, Ac-Di-Sol	5.00	5.05
				100.00	101.01

Tacrolimus is dissolved in PEG 6000 at temperatures above 80 ℃. Poloxamer 188 was added and the solution was heated to a temperature above 80 ℃. The solution was sprayed onto 200g of lactose monohydrate in a fluidized bed Phast FB100 using a feeding device Phast FS 1.7. The resulting granules were sieved with a Comill (No. 1397 mesh) at 4500rpm and mixed with croscarmellose sodium in a Turbula mixer for 3 minutes.

The magnesium stearate and talc were sieved through a 300 mesh screen and mixed in a Turbola mixer for 3 minutes. The granules were mixed with magnesium stearate talc (1: 9) in a Turbula mixer for 0.5 minutes.

The resulting mixture was compressed into 6mm tablets (100mg tablets, compound cup) containing 2mg of active ingredient.

Average disintegration time: for 7 minutes. Hardness: 65N.

The tablets were subjected to in vitro dissolution testing. Dissolution medium: 900ml of an aqueous medium containing 0.005% HPC (hydroxypropyl cellulose) adjusted to pH 4.5; usp paddle method; rotation speed: 50 rpm. The following dissolution characteristics were found:

time (minutes)	% release	Rs d％
			0	0	0
5	27.2	15.1
			10	49.1	10.9
20	80.7	8.0
			35	98.9	5.4
42	102.7	3.6
			52	104.9	2.0

Example 3: enteric coating of immediate Release tablet of example 2

The enteric coating was based on the acrylic polymer Eudragit L30D-55. Eudragit L30D is provided in the form of an aqueous latex suspension that forms a water insoluble film when water is evaporated off during the coating process. The polymer is insoluble at pH values below 5.0 and readily soluble at pH values above 6.0. Tablets prepared as described in example 2 were coated with the following film coating composition:

substance(s)	w/w ％
		Eudragit L30D-55	40
Water (W)	52
		Citric acid triethyl ester	1.8
Anti-foaming emulsion	0.2
		Talc (superfine)	6
Total up to	100

The amount of film polymer (Eudragit) applied is calculated based on mg of film polymer per cm2 of tablet surface. The thickness of the enteric coating was 80 μm. The determination of the film thickness used is based on the measurement of the tablet height increments with a digital micrometer. The film coating process was carried out in a Phast FB100 fluidized bed equipped with Wurster-like inserts, with an inlet air temperature of 50 deg.C, an inlet gas flow of 100 cbm/hr, a product temperature of 38 deg.C, and a feed rate of 15 g/min.

The coated tablets were hardened (cure) in an oven at 30 ℃ for 48 hours. Alternatively, the coated tablets can be hardened (cure) more efficiently at 40 ℃ for 24 hours.

The enteric coated tablets were tested for in vitro dissolution using two different dissolution media/test methods.

Using dissolution medium/test method: 900ml of an aqueous medium containing 0.005% HPC (hydroxypropylcellulose) adjusted to pH4.5 (United states Pharmacopeia paddle method; rotation speed: 50rpm) and found the following dissolution characteristics:

time (hours)	% release	Rs d％
			0	0	0
4	0.8	32.3
			8	0.4	61.1
15	11.0	17.3
			17	13.2	12.1

Using dissolution medium/test method: united states Pharmacopeia method A, a delayed release related item (United states Pharmacopeia paddle method; rotational speed: 50rpm), found the following dissolution characteristics:

time (minutes)	% release	Rs d％
			0	0	NA
120	0	NA
			155	84.8	12.8
165	102.9	NA
			175	101.0	3.5

Example 4

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

substance(s)	％	Mg
			Tacrolimus	2.09	2.10
Lactose monohydrate, 200 mesh	42.75	42.95
			PEG 6000	35.11	35.28
Poloxamer 188, Lutrol 68	15.05	15.12
			Magnesium stearate	0.50	0.50
Talc	4.50	4.52
				100.00	100.48

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

Example 5: in vivo testing of immediate release formulations in dogs

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

substance(s)	％	mg
			Tacrolimus	0.76	0.5
Lactose 200 mesh	49.14	32.43
			PEG 6000	34.73	22.92

Poloxamer 188	14.88	9.82
			Magnesium stearate	0.50	0.33
Total up to	100.00	66.00

66mg of granules were weighed into hard gelatin capsules.

As described above in methods, an in vivo study of 0.5mg of this formulation was conducted in Beagle dogs, relative to that described above in methods4X 1mg (run No. 1C56050), the results are as follows:

blood concentration (ng/ml) in dog No. F1182 after administration of the following dose:

relative bioavailability based on AUC (invention/Prograf): 293 percent.

Example 6: in vivo testing of immediate release formulations in dogs

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

substance(s)	％	mg
			Tacrolimus	1.86	0.50
Lactose monohydrate, lactose 200 mesh	43.56	11.72
			PEG 6000	31.21	8.40
Poloxamer 188, Lutrol 68	13.37	3.60
			Magnesium stearate	0.50	0.13

Talc	4.50	1.21
			Croscarmellose sodium, Ac-Di-Sol	5.00	1.35
	100.00	26.92

It was compressed into 4mm tablets (27mg tablets, compound cup) containing 0.5mg of active ingredient.

As described above in methods, an in vivo study of 0.5mg of this formulation was conducted in Beagle dogs, relative to that described above in methods0.5mg capsules (batch No. OC512OD), the results are as follows:

blood concentration (ng/ml) in dog No. 1 after administration of the following dose:

relative bioavailability based on AUC (invention/Prograf): 742%.

Claims (69)

1. A pharmaceutical composition comprising tacrolimus as active ingredient dispersed or dissolved in a hydrophilic or water-miscible vehicle comprising a mixture of polyethylene glycol and poloxamer in a weight ratio between 1: 3 and 10: 1, the vehicle having a melting point of at least 20 ℃ and wherein the active ingredient is present in a concentration between 0.01 and 15 w/w% so as to form a solid dispersion or solid solution at ambient temperature, together with one or more pharmaceutically acceptable excipientsThe composition further comprises a release modifier and exhibits a release profile of at least 1.3 when orally administered to a mammal in need thereof

2. The pharmaceutical composition according to claim 1, wherein the active ingredient is partially dissolved in the vehicle to form a mixture of solid dispersion and solid solution at ambient temperature.

3. The pharmaceutical composition according to claim 1, wherein the active ingredient is completely dissolved in the vehicle to form a solid solution at ambient temperature.

4. The pharmaceutical composition according to claim 1, wherein the hydrophilic or water-miscible vehicle has a melting point of at least 30 ℃.

5. The pharmaceutical composition according to claim 1, wherein the concentration of the active ingredient in the hydrophilic or water-miscible vehicle is at most 10 w/w%.

6. The pharmaceutical composition according to claim 1, wherein the concentration of the active ingredient in the hydrophilic or water-miscible vehicle is at least 0.05 w/w%.

7. The pharmaceutical composition according to claim 1, wherein the weight ratio of the polyethylene glycol and the poloxamer is between 1: 1 and 5: 1.

8. The pharmaceutical composition according to claim 1, wherein the weight ratio of the polyethylene glycol and the poloxamer is between 3: 2 and 4: 1.

9. The pharmaceutical composition according to claim 1, wherein the weight ratio of the polyethylene glycol and the poloxamer is between 2: 1 and 3: 1.

10. The pharmaceutical composition according to claim 1, wherein the weight ratio of polyethylene glycol to poloxamer is 7: 3.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the poloxamer is poloxamer 188.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the average molecular weight of the polyethylene glycol is 6000.

13. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of: fillers, disintegrants, binders and lubricants.

14. The pharmaceutical composition according to claim 1, in the form of granules.

15. The pharmaceutical composition according to claim 1, in the form of a powder.

16. The pharmaceutical composition according to claim 14, wherein the particles have a geometric weighted mean diameter d_gwIs 10 μm to 2000. mu.m.

17. The pharmaceutical composition according to claim 14, wherein the particles have a geometric weighted mean diameter d_gwIs 20 μm to 2000. mu.m.

18. The pharmaceutical composition according to claim 14, wherein the particles have a geometric weighted mean diameter d_gwIs 50 μm to 300. mu.m.

19. A dosage form comprising the pharmaceutical composition according to claim 1, which is a solid oral dosage form.

20. The dosage form according to claim 19, which is a unit dosage form.

21. The dosage form according to claim 19, further comprising a pharmaceutically acceptable additive selected from the group consisting of: flavors, colorants, taste masking agents, pH adjusters, buffers, preservatives, stabilizers, antioxidants, wetting agents, moisture regulators, surfactants, suspending agents, absorption enhancers, and release modifiers.

22. The dosage form according to claim 19, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of silicic acid or a salt, magnesium aluminosilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and saponite.

23. The dosage form according to claim 19, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of silicates, silicon dioxide and polymers thereof, and magnesium alumino-silicates.

24. The dosage form according to claim 19, wherein at least one pharmaceutically acceptable excipient is a silicic acid or salt.

25. The dosage form according to claim 19, wherein at least one pharmaceutically acceptable excipient is silicon dioxide or a polymer thereof.

26. A dosage form according to claim 24, wherein the silica product has a silica phase of the formula300 are of comparable nature.

27. The dosage form according to claim 21, wherein the release modifier is selected from the group consisting of water-miscible polymers, water-insoluble polymers, oils and oily substances.

28. The dosage form according to claim 27, wherein the water insoluble polymer is selected from the group consisting of: ethyl cellulose, cellulose acetate, cellulose nitrate and mixtures thereof.

29. A dosage form according to claim 27, wherein the oil or oily substance is selected from the group consisting of: hydrophilic and hydrophobic oils or oily substances.

30. The dosage form according to claim 29, wherein the oil or oily substance is hydrophilic and is selected from polyether glycols; polyoxyethylene; polyoxypropylene; a poloxamer; polyglycolyzed glycerides; and mixtures thereof.

31. A dosage form according to claim 30, wherein the oil or oily substance is selected from polypropylene glycol and

32. a dosage form according to claim 31, whereinSelected from the group consisting of:50/13、44/14、50/10、62/05 and mixtures thereof.

33. A dosage form according to claim 29, wherein said oil or oily substance is hydrophobic and is selected from the group consisting of straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils; higher fatty acids; a higher alcohol; a low melting wax; NVP polymers, PVP polymers, acrylic polymers; and mixtures thereof.

34. Dosage form according to claim 29, wherein the oil or oily substance is hydrophobic and is selected from cocoa butter, beef tallow, lard, polyether glycol esters, stearic acid, myristic acid, palmitic acid, cetyl alcohol, stearyl alcohol, glycerol monostearate, glycerol monooleate, hydrogenated fats, myristyl alcohol, stearyl alcohol, yellow beeswax, white beeswax, carnauba wax, castor wax, Japan wax and acetylated monoglycerides.

35. A dosage form according to claim 29, wherein the oil or oily substance is hydrophobic and is selected from substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides and substituted and/or unsubstituted triglycerides.

36. A dosage form according to claim 33, 34 or 35, wherein the oil or oily hydrophobic material has a melting point of at least 20 ℃.

37. The dosage form according to claim 27, wherein the water-miscible polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, poloxamers, polyoxyethylene stearates, polyepsilon caprolactone, polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA, polymethacrylic acid polymer, polyvinyl alcohol, polyethylene oxide and mixtures thereof.

38. The dosage form according to claim 37, wherein the polymethacrylic acid polymer is selected from the group consisting ofRS、RL、NE andE。

39. the dosage form according to claim 27, which uses a water-miscible polymer having pH-dependent solubility in water as an enteric coating.

40. The dosage form according to claim 39, wherein the water-miscible polymer is selected from the group consisting of polyacrylamides; an acidic phthalate of a carbohydrate; polyvinyl alcohol acetate phthalate; hydroxypropyl methylcellulose acetate succinate, carboxymethyl cellulose, cellulose acetate trimellitate; an alginate; carbomer; acrylic acid and acrylate copolymers, polymethacrylic acid and esters thereof, polyacrylic acid methacrylic acid copolymers, methacrylic acid copolymers; styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl alcohol acetate phthalate copolymer, styrene and maleic acid copolymer; shellac, glycollic acid starch; polycrystallin; copolymers of vinyl acetate and crotonic acid; and mixtures thereof.

41. The dosage form according to claim 39, wherein the water-miscible polymer is selected from the group consisting of amylose acetate phthalate, cellulose acetate terephthalate, isophthalic acetate phthalateCellulose, cellulose ether phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose acetate phthalate, polyvinyl alcohol acetate hydrogen phthalate, sodium acetate phthalate, starch acid phthalate,l andS。

42. the dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 10 w/w% of the total amount of active ingredient within the first 3 hours after administration.

43. A dosage form according to claim 39, which, upon oral administration to a mammal in need thereof, releases at most 7.5 w/w% of the total amount of active ingredient within the first 3 hours after administration.

44. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 5 w/w% of the total amount of active ingredient within the first 3 hours after administration.

45. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 2 w/w% of the total amount of active ingredient within the first 3 hours after administration.

46. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 10 w/w% of the total amount of active ingredient within the first 2 hours after administration.

47. A dosage form according to claim 39, which, upon oral administration to a mammal in need thereof, releases at most 7.5 w/w% of the total amount of active ingredient within the first 2 hours after administration.

48. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 5 w/w% of the total amount of active ingredient within the first 2 hours after administration.

49. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 2 w/w% of the total amount of active ingredient within the first 2 hours after administration.

50. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 10 w/w% of the total amount of active ingredient within the first 1 hour after administration.

51. A dosage form according to claim 39, which, upon oral administration to a mammal in need thereof, releases at most 7.5 w/w% of the total amount of active ingredient within the first 1 hour after administration.

52. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 5 w/w% of the total amount of active ingredient within the first 1 hour after administration.

53. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 2 w/w% of the total amount of active ingredient within the first 1 hour after administration.

54. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 10 w/w% of the total amount of active ingredient within the first 30 minutes after administration.

55. A dosage form according to claim 39, which, upon oral administration to a mammal in need thereof, releases at most 7.5 w/w% of the total amount of active ingredient within the first 30 minutes after administration.

56. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 5 w/w% of the total amount of active ingredient within the first 30 minutes after administration.

57. The dosage form according to claim 39, which upon oral administration to a mammal in need thereof releases at most 2 w/w% of the total amount of active ingredient within the first 30 minutes after administration.

58. The dosage form according to claim 19, wherein the dosage form is administered orally to a mammal in need thereof asOr similar to the dosage of tacrolimus administered in the form of commercially available tacrolimus-containing products, substantially corresponding to the dosage up to 85 w/w% of the dosage of tacrolimus administeredOr similar commercially available tacrolimus-containing products are bioequivalent.

59. The dosage form according to claim 19, wherein the dosage form releases at least 50 w/w% of the active ingredient within 24 hours upon oral administration to a mammal in need thereof.

60. The dosage form according to claim 19, wherein the dosage form releases at least 50 w/w% of the active ingredient within 20 hours upon oral administration to a mammal in need thereof.

61. The dosage form according to claim 19, wherein the dosage form releases at least 50 w/w% of the active ingredient within 18 hours upon oral administration to a mammal in need thereof.

62. The dosage form according to claim 19, wherein the dosage form releases at least 50 w/w% of the active ingredient within 15 hours upon oral administration to a mammal in need thereof.

63. The dosage form according to claim 19, wherein the dosage form releases at least 50 w/w% of the active ingredient within 12 hours upon oral administration to a mammal in need thereof.

64. Use of a pharmaceutical composition according to claim 1 for improving the oral bioavailability of tacrolimus.

65. Use of a pharmaceutical composition according to claim 1 for the preparation of a solid oral dosage form.

66. Use of the pharmaceutical composition according to claim 1 for the preparation of tablets, capsules or sachets.

67. Use of the pharmaceutical composition according to claim 1 for the preparation of granules, pellets or microspheres.

68. Use of a pharmaceutical composition according to claim 1 for the preparation of nanoparticles.

69. A process for preparing a pharmaceutical composition according to claim 1, comprising the steps of: tacrolimus or an analogue thereof having a therapeutic activity at least comparable to tacrolimus is dispersed and/or dissolved in a hydrophilic or water-miscible vehicle to obtain a solid dispersion and/or solid solution at ambient temperature.