KR101714090B1 - Tacrolimus for improved treatment of transplant patients - Google Patents

Abstract

A sustained release oral dosage form for immunosuppressive treatment once daily in a patient in need thereof, preferably a kidney or liver transplant patient, comprising tacrolimus or a pharmaceutically active analogue thereof as an active substance. The dosage form releases the active substance over an extended period of time. It should also be noted that, despite the conventional rapid-release dosage form and the increased bioavailability as compared to recent controlled-release tacrolimus dosage forms, the dosage form has a significantly reduced maximum concentration, a significantly extended maximum concentration reaching time, Lt; RTI ID = 0.0 > pharmacokinetic < / RTI > parameters due to extended and constant in vivo release.

Description

[0001] TACROLIMUS FOR IMPROVED TREATMENT OF TRANSPLANT PATENTS [0002]

Related US Applications

This application claims priority to U.S. Provisional Application No. 61 / 079,015, filed July 8, 2008, which is hereby incorporated by reference in its entirety.

Field of invention

The present invention relates to a sustained release oral dosage form for use in immunosuppressive therapy once daily in a patient in need thereof, comprising tacrolimus or a pharmaceutically active analogue thereof as an active substance, Release the active substance over a period of time and provide higher bioavailability and improved pharmacokinetic profile in vivo compared to conventional dosage forms.

BACKGROUND OF THE INVENTION

Tacrolimus, also known as FK-506 or FR-900506, is the active ingredient of Prograf® Protopic® and Advagraf® approved by the European Medicines Evaluation Agency (EMEA) on April 23, Advagraf® During its development, the product was known as MR4. Details regarding Advagraf are contained in the European Public Assessment Reports (EPAR) on Licensed Drugs for Human Use, including the Scientific Discussion Paper published by EMEA after approval, and product information cited as reference in this application (label, 25/01 / 2008 Advagraf-HC-712-T-03). Prograf® was approved under NDA No. 050708 by the FDA in April 1994 for the prevention of organ rejection in patients receiving allogeneic liver transplants. Tacrolimus is also licensed under the same trade name in the European Union, Japan, Canada, Switzerland and several other countries. Tacrolimus was authorized for the prevention of organ rejection in patients receiving allogeneic liver, kidney or heart grafts. It is estimated that 72% of all recipients of kidney transplants and 89% of recipients of liver transplants receive tacrolimus.

Tacrolimus administered as a Prograf® capsule exhibits large inter-individual and intra-individual variability in absorption and metabolism. Because of this variability, the standard dose is not an accurate predictor of concentration. In clinical use, tacrolimus dose adjustments are often required to be based on monitoring the tacrolimus minimum blood concentration. Tacrolimus appears in the form of a white measuring or measuring powder. Tacrolimus is almost insoluble in water, well soluble in ethanol, and soluble in methanol and chloroform.

The preparation of tacrolimus is described in EP-A-0 184 162, and analogs of tacrolimus are disclosed, for example, in EP-A-0 444 659 and US Pat. No. 6,387,918, both of which are incorporated herein by reference.

Tacrolimus is a macrolide compound with useful immunosuppressive, antimicrobial and other pharmacological activities and is useful for the treatment or prevention of rejection by grafting of organs or tissues, graft versus host disease, autoimmune diseases and infectious diseases .

The exact mechanism of action is not known, but tacrolimus inhibits T-lymphocyte activation. Experimental evidence suggests that tacrolimus binds to the intracellular protein FKBP-12. Complexes of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin are then formed, and the phosphatase activity of calcineurin is inhibited. This effect can prevent dephosphorylation and dislocation of activated T-cell nuclear factor (a nuclear component that is thought to initiate gene transcription for the formation of lymphokines). The end result is inhibition of T-lymphocyte activation, i. E. Immunosuppression.

Tacrolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. The CYP3A4 isozyme is expressed or is present in all regions of the gastrointestinal tract, including the colon. Absorption was observed to be negatively affected by simultaneous ingestion of food. Thus, the rate and extent of tacrolimus absorption was greatest under fasting conditions.

Tacrolimus is known to cause GI side effects as well as significant side effects of nephrotoxicity or neurotoxicity.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and mutagenic, although the mean time to peak concentration (T _max ) is rapid to about 1-2 hours after administration to healthy subjects or kidney or liver transplant recipients. Bioavailability is usually as low as about 20% or less after oral administration.

Adverse effects such as tremor, headache, hypertension, kidney dysfunction, hyperkalemia, hypomagnesemia, hyperglycemia, insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity and neurotoxicity are also observed .

For oral administration, tacrolimus is formulated and marketed as a soft gelatin capsule originally containing 0.5, 1 or 5 mg equivalents of anhydrous tacrolimus and is marketed under the trade name Prograf®. The recommended initial oral dose is about 0.1 to 0.2 mg / kg / day of the patient. The dosage is aimed at a specific minimum plasma level of from about 5 to about 20 ng / ml. Prograf® is indicated for the prevention of organ rejection in patients receiving allogeneic liver or kidney transplants. Details regarding clinical pharmacology, pharmacokinetic and clinical studies are described in the NDA 50708 label, approved by the FDA on April 27, 2006, for Prograf®, which is incorporated herein by reference.

There is a need for a novel pharmaceutical composition and / or dosage form comprising tacrolimus exhibiting improved bioavailability and improved pharmacokinetic properties. Increased bioavailability combined with a sustained release dosage form can result in a reduction in the dosage unit taken by the patient without the risk of lack of clinical efficacy due to low doses during the last past administration interval, It is possible to make it possible. In addition, the fluctuation of the plasma concentration versus time profile can be significantly reduced. Furthermore, improved bioavailability can also result in a more reproducible (i.e., less mutagenic) release profile than Prograf®.

Sustained-release tacrolimus formulations are described in WO 99/49863 (Fujisawa Pharmaceutical Co.), and in particular, for formulations with a time to dissolve 63.2% tacrolimus (T63.2% value) of 0.7 to 15 hours, No. 6,440,458, US 6,576,259 and US 6,884,433. However, the formulations in which 63.2% are released within 42 minutes appear to be only slightly different from those of conventional fasted tacrolimus, where 68.4% are released within 30 minutes. It is clearly stated that if the T63.6 value of the formulation is greater than 15 hours, the release of the active ingredient will be delayed and the active ingredient will be removed from the body before the effective blood concentration is reached. A most preferred embodiment is a sustained release dosage form having a T63.6 value of 2-5 hours. The formulations prepared according to the examples of this application all have a T63.6% value of 1.9 (for the fastest releasing formulations) to 8.2 hours (for the slowest releasing formulations). Furthermore, tacrolimus is said to be excellently absorbed in sustained release formulations and to inhibit variations in absorbability. In the examples of the reference above, improved bioavailability is obtained for all tested formulations. The T63.6% values disclosed for these formulations are 3.0, 3.3, 2.0, and 2.5, respectively.

The inventors of the present application also tested different formulations of tacrolimus in patent application WO 2005/020993 in beagle dogs and mini-pigs, but both fast-release tablets (Example 18) and sustained-release tablets (Example 19) Which can lead to improved bioavailability. This indicates that improved bioavailability may be associated with inclusion of tacrolimus in dissolved form in dosage forms, which also appears in WO 2005/020994 by the same inventors relating to solid dispersions containing tacrolimus. Fujisawa Pharmaceutical Co., Ltd., which was referred to above and developed Prograf®. As described in Example 31 of WO99 / 49863, currently owned by Astellas, the immediate-release conventional product Prograf® contains tacrolimus in a physical mixture of HPMC, lactose, croscarmellose sodium.

One major problem with controlled or sustained dosage forms is the difficulty in obtaining sufficient absorption in the lower portion of the gastrointestinal tract because the oral dosage form entering the colon can be easily excreted before significant release occurs. Release is generally reduced due to lack of fluid and physical interaction of the dosage form with increasing solids content of the colon. Also, the absorption surface is several times smaller than the small surface of the small intestine, and this factor increases the time for which the released active substance is subject to possible degradation and capture in solids present in the colon.

It is generally accepted that overexciting the release, even though it is a substance that is expected to be well permeable in the colon, can seriously affect bioavailability. If the material is a substrate for CYP3A4, the advantage of lower concentrations of the metabolic enzyme in the lower GI can be expected from a bioavailability perspective. On the other hand, within the lower GI tract containing the colon, the relatively higher concentration of P-glycoprotein in the transport system usually counteracts the effect of low concentrations of the CYP3A4 enzyme, Because it is transported to the intestinal lumen. Tacrolimus is a known substrate for both the above mechanism, CYP3A4 metabolism and P-glycoprotein transport system. Thus, increased bioavailability can not be associated with the expansion of the release in a simple linear fashion. Release can be carefully adjusted so that some counteracting factors are equal. These factors include a lower absorption area, lower fluid content, higher solids content, bacterial degradation, greater effect from the P-glycoprotein transport system, lower motility, mucosal barrier and / or mucus barrier in the colon compared to the small intestine The difference in composition and the difference in pH of the colon by part. It is therefore important to note that immunosuppressive therapy, particularly in transplant patients, requires a blood concentration within a very narrow range in order to balance efficacy (lack of rejection) and side effects (infection, nephrotoxicity, metabolism and cardiovascular disease, etc.) , The control and timing of release of in-vivo dosage forms in vivo to obtain predictable release under various physical conditions present along the GI tract is a challenge. Providing improved formulations for once-a-day treatment, wherein the resulting pharmacokinetic parameters extend the release to a precise level that is fully optimized without compromising safety, If there is no correlation between minimum concentration and bioavailability, the significant factors and dose adjustments in treatment with narrow therapeutic index drugs such as tacrolimus, where treatment failure is closely related to organ rejection, . Additional factors that reduce the risk of clinical success with once-daily formulations in organ transplants include high prevalence of gastrointestinal complications that affect gastric parameters, including transit time, pH, bacterial composition, and other functions of the GI tract . These complications include nausea, vomiting and very frequent diarrhea.

Thus, the present inventors have surprisingly found that a dosage form releasing tacrolimus over a very extended and controlled period of time can deliver tacrolimus in vivo in a manner that allows tacrolimus to be fully absorbed simultaneously, And that the release is sufficiently slow so that a very low rate of absorption is possible so that the maximum concentration is controlled at a lower value and that the minimum concentration is increased to ensure the efficacy of the treatment over a total administration interval of 24 hours. Very importantly, the minimum concentration obtained after 24 hours of administration with the sustained release formulations of the present invention is highly predictable and can therefore be used as a marker for overall bioavailability, A high correlation between bioavailability and minimal concentration is achieved. The minimum concentration can therefore be used safely as a means for adjustment and administration during treatment.

Conventional in vitro dissolution methods are believed to be associated with or at least reflect the actual in vivo controlled release profile of humans. Thus, the difference in in vitro release rate between the two formulations tested under the same conditions is expected to reflect the difference in in vivo release rate. However, if one formulation is released in a pH-dependent manner but not the other, and an actual pH value for the test is not selected to detect such a difference, an exception may apply. It is a clear example to provide immediate release in vitro and delayed release in vivo when testing intestinally coated formulations at high pH. In addition, when comparing two expandable formulations having different release mechanisms, for example, when comparing an osmotic pressure-driven release mechanism with an erosive-dependent release mechanism, the same in vitro release profile for two products is theoretically different Profile, but reducing or increasing the rate of dissolution will be reflected in vivo for each product. Thus, unless there is evidence to the contrary, and assuming that the method is performed according to the prescription of the pharmacopoeia, conventional dissolution methods are a useful tool for distinguishing between formulations and corresponding in vivo properties. Accordingly, the present invention provides, in a first aspect, a sustained-release oral dosage form for once-a-day immunosuppressive treatment in a patient in need thereof, comprising tacrolimus or a pharmaceutically active analogue thereof as an active substance, Releases the active substance over a very extended period of time. In a further aspect, the emission is characterized by substantial quadrature emission for most emissions.

Conventional in vitro dissolution methods include the United States Pharmacopoeia (USP), a public public standard setting authority for all prescription and nonprescription drugs in the United States, and methods described in similar pharmacopoeias in Europe and Japan. A preferred method includes USP Dissolution Method I (Basque) and Method II (Paddle) at 50 rpm, use of HPC to prevent drug from adhering to the instrument, pH 4.5 for stability. Although tacrolimus is not protonated, the pH does not affect the solubility of the drug, but pH 4.5 is not a pH that is commonly present in the GI tract, so pH changes may be appropriate if a pH-sensitive inert excipient is used in the formulation. It may therefore be appropriate to describe the degree of expansion of the release by alternative dissolution methods. In addition, the expandable formulations can thus be used by additional dissolution methods, including dissolution media (e.g., simulations of FaSSIP and FeSSIP media, fasting and ingestion), which simulate different rotational speeds, different pH values, and GI conditions , And by using additives such as SLS to reduce the total dissolution time (increase the dissolution rate) by increasing the wettability or solubility of tacrolimus in the dissolution medium.

The inventors have found that the timing of release and release of the active ingredient, i.e., the in vitro and in vivo release profiles, is measured by conventional dissolution methods used for 15 hours (for tacrolimus dosage forms, demonstrating the extension of in vivo release Found that in the case of tacrolimus administered to mammals in a sustained release composition that extends beyond the amount of the active ingredient (measured in vivo via appropriate and clinically relevant pharmacokinetic parameters), the bioavailability of tacrolimus is significantly increased and the pharmacokinetic parameters significantly improved. The pharmacokinetic parameters include: a significantly extended maximum concentration reaching time; Low maximum concentration; Excellent correlation between high minimum concentration, extended mean residence time (this time securing very high bioavailability concurrently) and minimum concentration and bioavailability.

In a medium containing pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (bathket) format, as tested at 50 rpm rotation and by in vitro dissolution The extended release is defined by a release of 63.5% or less of the active substance content at 12 hours. In yet another aspect, up to 63.5% release of the active substance at 12 hours is combined with release of more than 8% at 4 hours and / or more than 15% at 8 hours to ensure continuous release throughout the dosage interval. If the release does not occur for several hours after administration, the patient is at risk of the tacrolimus blood concentration continuing to fall and to fall below the desired lower therapeutic limit for hours in the 24 hour dosing interval.

In another further aspect, the present invention provides a method of treatment for a more safe immunosuppressive treatment, as evidenced by several single dose and steady state pharmacokinetic tests as compared to conventional commercial dosage forms and due to the improved pharmacokinetic profiles obtained in healthy subjects and patients To the use of the sustained release composition. Also, the safe immunosuppressive therapy according to the present invention is directed to a particular dosage regimen for conversion from Prograf®-based therapy twice a day, wherein the conversion is from 1: 0.66 to 0.80, according to the nearest available tablet strength ). ≪ / RTI > The dosing regimen results in similar biological mean concentrations for Prograf® at other parameters such as minimum concentration and AUC as well as similar mean blood concentrations for the dosing interval measured before and after the conversion.

Figure 1 shows the dissolution of the sustained release formulation according to the invention and was tested according to the USP II dissolution test (paddle) method at a pH of 4.5 and a medium containing 0.005% hydroxypropylcellulose and a rotation of 50 rpm.
Figure 2 is a sinti imaging evaluation of the release position by use of a sustained release formulation according to the parameters of Study 003. This figure demonstrates that in vivo release by the formulation according to the invention extends to such an extent that absorption occurs in the colon of the individual.
Figure 3 shows the blood concentration of tacrolimus in a single dose study of healthy volunteers in the fasted state. The closed triangle represents the concentration by the 5 mg formulations according to the invention and the star represents Prograf 5 mg formulations; Open circles represent 2 mg formulations according to the invention; The closed squares represent 2 x 2 mg treatment according to the present invention; Closed diamonds represent Prograf® 4 × 1 mg treatment; Vertical lines represent Prograf® 2 × 1 mg treatment. The study is described as Study 002 in Table A of the present application.
Figure 4 shows the dissolution of a preferred formulation of the present invention having a composition similar to that described in Example 20. The triangle represents treatment with 1 mg formulations, and the square represents treatment with 2 mg formulations. Further, the dissolution of the product Advagraf® used for comparison in Example 20 is shown, with an asterisk representing 0.5 mg, an X table of 1 mg and a circle representing 5 mg Advagraf® product. The release is measured as the percentage dissolved as time elapses. The dissolution method used was a medium containing 0.005% hydroxypropyl cellulose adjusted to pH 4.5 and a USP II dissolution test (paddle) method at 50 rpm rotation.
Figure 5 shows the steady state blood profile obtained prior to the conversion to the sustained release formulations according to the invention in the stable liver patient (Prograf® 7 day steady state) and on days 14 and 21 after conversion. The square represents Prograf® twice daily for 7 days, circle for LCP-Tacro once a day for 17 days, and diamond for LCP tacro once a day for 21 days. Details of the study are disclosed in Example 19 herein. The profile shows the actual profile after conversion to a lower dosage by the formulation according to the invention.
Figure 6 shows the modified steady-state blood profile of Figure 5;
Figure 7 shows the PK profile of LCP-Tacro tablet versus Advagraf® capsules under steady-state, fasting conditions.
Figure 8 shows blood plasma concentrations after administration of the same single dose of tacrolimus as Advagraf 占 2 占 1 mg capsules (open circles) and as LCT-Tacro 2 mg tablets according to the invention.
Figure 9 shows the steady state blood profile obtained prior to the conversion to the sustained release formulations according to the invention (Prograf® 7 day steady state) and in the stable liver patient on days 14 and 21 after conversion. The square represents Prograf® twice daily for 7 days, circle for LCP-Tacro once a day for 17 days, and diamond for LCP-Tacro once a day for 21 days. Details of the study are disclosed in Example 19 herein. The profile shows the actual profile after conversion to a lower dosage by the formulation according to the invention.
Figure 10 shows the modified steady-state blood profile of Figure 9;

Justice

The term " active ingredient "or" active pharmaceutical ingredient ", as used herein, refers to any compound that provides a pharmacological activity or other direct effect in the diagnosis, cure, cure, Means any element that is intended to affect functionality. The term includes components present in the drug as altered forms that may undergo a chemical change in the manufacture of the drug and are intended to provide a particular activity or effect.

In this context, the term "hydrophilic" describes " water-loving ", i.e. a hydrophilic molecule or part of a molecule is typically electrically polarized and can form hydrogen bonds with water molecules, "It is more easily soluble in water than in solvents.

In this context, the term "amphiphilic" describes molecules (as surface active agents) having polar water-soluble groups attached to water-insoluble hydrocarbon chains. Thus, one end of the molecule is hydrophilic (polar) and the other is hydrophobic (non-polar).

In this context, the term "hydrophobic" means a compound that tends to be electrically neutral and non-polar, thus favoring other neutral and non-polar solvents or molecular environments.

The term "carrier" as used herein refers to any solvent or carrier fluid that does not function pharmacologically. For example, water is a carrier for siloxane, and propylene glycol is a carrier for many antibiotics.

In the present context, the term "solid dispersion" means a drug or active ingredient or substance, i.e., a fine particulate dispersion, dispersed at the particulate level in an inert carrier, carrier, diluent or matrix in the solid state.

In this context, the term "solid solution" means a drug or active ingredient or substance dissolved in the solid phase at an molecular level in an inert carrier, carrier, diluent or matrix.

As used herein, the term "analog" refers to structurally similar chemical compounds.

The term "drug" means a compound that is intended to be used in the diagnosis, cure, mitigation, treatment, or prevention of a disease in a human or other animal.

In this context, the term "dosage form" means the form in which the drug is delivered to the patient. It may be parenterally, topically, tablet, orally (liquid or dissolved powder), suppository, inhalation, transdermal, and the like.

The term "bioavailability " as used herein means the extent to which a drug or other substance becomes available in a target tissue after administration.

As used herein, the term "biological equivalence" refers to the scientific basis upon which the replications and original drugs are compared with one another. For example, if similar doses are provided at similar rates under similar conditions, the drugs are bioequivalent if they enter the circulation at the same rate. Commonly used parameters in biological equivalence studies are T _max , C _max , AUC _{0 - infinity} , AUC _{0 -t} . Other relevant parameters may be W ₅₀ , W ₇₅ and / or MRT. Thus, one or more of the above parameters may be applied when determining whether bioequivalence exists. In addition, in this context, if the value of the parameter used is within 80-125% of the parameter value of Prograf® or a similar commercial tacrolimus-containing product used in the test, the two compositions are considered to be bioequivalent.

In the context of the present invention, "T _max " means the time to reach the maximum plasma concentration (C _max ) after administration; AUC _{0 - infinity} refers to the area under the plasma concentration versus time curve from time 0 to infinity; AUC _{0 -t} mean area under the plasma concentration versus time curve up to the time t at time zero and; W ₅₀ means the time at which the plasma concentration is at least 50% of C _max ; W ₇₅ means the time when the plasma concentration is at least 75% of C _max ; And MRT mean the mean residence time of tacrolimus (and / or its analogs). The swing means (C _max- C _min ) / C _min , and the variation means (C _max- C _min ) / C _mean . Variations are suitable for comparison of dosage forms providing different bioavailability.

In this context, the term "about" means a compound used to treat a disease, injury or pain. Medicines are properly categorized as "prophylactic", that is, technologies that preserve health and those that are "therapeutic", that is, restoring health.

In this context, the terms "controlled release type" and "controlled release type" refer to the same term, including the release of any type of tacrolimus from a composition of the present invention suitable for obtaining a particular therapeutic or prophylactic response after administration to a subject . Those skilled in the art know how controlled release / controlled release types differ from those of ordinary tablets or capsules. The term " controlled release "or" controlled release "has the same meaning as above. The term slow-release (which is one resulting in a lower C _max and later T _max, T _1/2 is not changed), slow release (which is a lower C _max, one resulting in the later T _max, apparent T _{1 / 2} is more Kim), delayed release (which is time and, one resulting in a C _max is constant delay Thus, T _max is delayed, T _1/2 is unchanged) as well as pulsatile release, unforeseen release, Sustained release, extended release, time-optimized release, immediate release (to obtain improved initiation of action), and the like. The term also encompasses the use of specific conditions within the body, such as, for example, different enzymes or pH changes to control the release of drug substance. The term "sustained release" is chosen because the term is considered to most accurately encompass the in vivo release of the product.

In this context, the term " erosion "or" erosion "refers to the gradual destruction of the surface of a structure or material, for example a coating of a tablet or tablet. The term as used herein generally means that the dissolution of the polymer, which serves to extend the release, is faster than the dissolution of the active substance, so that the polymer erodes faster than the active substance dissolves. In other words, the release is mainly controlled by erosion and is not controlled by dissolution of the active material in the polymer matrix system.

The present invention provides a medicament for improved treatment of conditions responsive to tacrolimus treatment, particularly treatment in which an immunosuppressive effect is desired.

The active ingredient in the composition of the present invention is preferably tacrolimus or any analog or derivative of tacrolimus (FK-506 or FR-900506) exhibiting at least equivalent pharmacological or therapeutic activity to tacrolimus. However, tacrolimus of any physical form (including any of the possible solvates, including measurements, amorphous powders, any possible polymorphs, hydrates, anhydrides, complexes thereof, etc.) is within the scope of the present invention. Also included are any analogs, derivatives or active metabolites of tacrolimus, pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof. However, it is contemplated that smaller particle sizes of micro- and nanoscale, and preferably molecular solutions, contribute to predictable and consistent in vivo release of tacrolimus.

Thus, in a preferred embodiment, the invention provides a sustained-release oral dosage form for once-a-day immunosuppressive treatment in a patient in need thereof, comprising tacrolimus or a pharmaceutically active analogue thereof as an active agent, The morphology was defined by the medium containing 0.005% hydroxypropyl cellulose at a pH of 4.5 according to the USP II dissolution test (paddle) or USP I dissolution test (basket) format and when tested at a rotation of 50 rpm and by dissolution in vitro The active substance is released over an extended period of time defined by a release of less than 63.5% of the active substance content at 12 hours. It is generally believed that the bauxcrack dissolver may be more suitable for capsules and the paddle dissolver may be more suitable for disintegrating tablets. However, the most suitable dissolution apparatus can be easily found by examining which apparatus has obtained the highest suitability.

In a further embodiment, not more than 63.5% of the active material is released at a time point of 13 hours, more preferably at a time point of 14 hours, e.g., at a time point of 15 hours. In a preferred embodiment, a substantially quadrature emission profile can be obtained over an extended period of time by the in vitro release occurring at a constant rate. Since adequate release is required at the time when the dosage form can reach the colon, the corresponding period of time for which the quasi-oral release is desired is pH 4.5 according to the USP II dissolution test (paddle) or USP I dissolution test (Basquet) Hydroxypropylcellulose and release from 8 to 15 hours when tested at a rotation of 50 rpm. It is also required that the solid dosage form be able to leave immediately after ingestion or stay on top for several hours before reaching the GI tract, so that the initial release needs to be better controlled, as measured by in vitro release, II dissolution test (paddle) or medium containing 0.005% hydroxypropyl cellulose at pH 4.5 according to the USP I dissolution test (baskets) type and by release from 2 to 10 hours when tested at a rotation of 50 rpm Is a substantially zero emission profile over an extended period of time defined.

In another embodiment of the invention, the addition of the surfactant to the release medium is carried out according to the USP II dissolution test (paddle) or the USP I dissolution test (baskets) at pH 4.5, containing 0.005% hydroxypropylcellulose and 0.5% sodium When tested in vitro with media containing lauryl sulfate (SLS) and a rotation of 50 rpm, the release of less than 80% of the active substance is more than 7 hours, such as 8 hours, such as 9 hours or more, such as 10 hours or more , Such as 11 hours or more, such as 12 hours or more, such as 13 hours or more.

As mentioned above, if the release is too extensive, the dosage form may be excreted before the active substance is completely released, or the release may occur too far to be sufficiently distributed. Thus, the contents of the dosage form are released at the rates indicated herein, but are calculated for the content of 80% and for the addition of 0.5% sodium lauryl sulfate (SLS) to the dissolution medium for 24 hours or less, such as 23 hours For example, not more than 22 hours, for example not more than 21 hours, such as not more than 21 hours, such as not more than 21 hours, such as not more than 18 hours, such as not more than 17 hours, such as not more than 16 hours.

Alternatively, or additionally, the dosage form satisfies the following conditions: the release of 63.5% of active material is extended for a period of 20 hours or less, such as 18 hours or less. Also, when tested in the in vitro USP II dissolution test (paddle) or medium containing pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP I dissolution test (Basquet) format and at a rotation of 50 rpm, A shorter dissolution period, for example less than 15.5 hours, may be preferred.

When tested in the in vitro USP II dissolution test (paddle) or medium containing 0.005% hydroxypropyl cellulose at a pH of 4.5 according to the USP I dissolution test (baskets) format and at a rotation of 50 rpm, The sustained release oral dosage form in which release is initiated within 120 minutes, eg, within 90 minutes, eg, within 60 minutes, of precipitation, suggests a composition that will provide a predictable release profile as early as the release, eg, within the first 2 hours is not too rapid . If the release does not occur soon after administration, the patient is at low risk. In general, the patient is titrated according to the observed blood concentration just prior to ingesting the daily dose, which is the lowest concentration observed during the day. The delay in release will then provide an unknown minimum concentration.

The following release features are considered within the scope of the present invention:

a) a medium comprising pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (bathette) format, and, if tested in vitro at a rotation of 50 rpm, Or less than about 20% w / w of the active substance within 2 hours, or within 3 hours, or within 4 hours or 5 hours.

b) a medium containing pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format and, when tested in vitro at a rotation of 50 rpm, For example, about 40% w / w of the active substance within about 11 to 13 hours.

c) a medium comprising pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format and, if tested in vitro at a rotation of 50 rpm, For example, 20% w / w of the total amount of active substance released within about 7 to 9 hours, for example.

d) a medium comprising pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format and, when tested in vitro at a rotation of 50 rpm, For example, about 50% w / w of the active substance within about 14 to 16 hours.

e) a sustained release oral dosage form in which the release profile is substantially linear during a period of from 4 to 8 hours (inclination or inclination of less than 25%, e.g. less than 15%, preferably less than 10% .

f) a sustained release oral dosage form with a substantially linear release profile during the period from 6 to 10 hours (inclusive within 25%, e.g. within 15%, preferably within 10% of the slope or inclination measured at 8 o'clock or Defined as an inclination).

g) a sustained release oral dosage form in which the release profile during the period from 8 to 12 hours is substantially linear (inclination or inclination of less than 25%, e.g. less than 15%, preferably less than 10% .

h) Release profile during the period of release to the point at which 20% is released to 50% release. A substantially linear sustained oral dosage form (at an 80% point within 25% of the slope or gradient measured at 20% Defined as the slope or slope of the slope).

i) a sustained release dosage form according to any one of the above a) to h), wherein the release extension mechanism is not a permeation-controllable coating.

It is believed that the defined release profile characteristics significantly improve the bioavailability of tacrolimus in mammals because all or most of the active ingredient is actually released in the gastrointestinal tract in a manner such that CYP3A4 metabolism is substantially avoided or at least significantly reduced . Furthermore, the effect is correlated with or at least reflects the in vitro dissolution profile of the pharmaceutical composition and / or dosage form of the present invention, and the profile can be determined by conventional in vitro dissolution methods specified for the composition and / It is easily found when performing.

A preferred release profile of the pharmaceutical composition may be provided by combining one or more of the following possibilities.

i) coating the composition with enteric coating; And / or

ii) using a pharmaceutical composition comprising a solid dispersion or solid solution of the active ingredient, tacrolimus or its analog, in a hydrophilic or water-hydratable carrier and in at least one release modulating agent; And / or

iii) a pharmaceutical composition comprising a solid dispersion of the active ingredient, tacrolimus or an analogue thereof, or a solid solution, in a hydrophobic carrier and optionally in at least one release modulating agent.

However, enteric coated formulations should be used in combination with dilatation techniques as they may have the disadvantage of delaying release without extending the release.

In yet another embodiment of the invention, and more preferably within the hydrophobic carrier as described herein, a wax, preferably oil, oily substance, wax or fatty acid derivative, more preferably a low melting point wax, There is provided a sustained-release tacrolimus-containing pharmaceutical composition comprising an active ingredient dissolved or dispersed in glyceryl monostearate.

In another embodiment of the invention, a hydrophilic or water-miscible carrier as described herein, preferably polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycol There is provided a sustained-release tacrolimus-containing pharmaceutical composition comprising an active ingredient dissolved or dispersed in a carrier selected from a glycerol, a glyceride, such as Gelucire, and a mixture thereof, more preferably, optionally, a polyethylene glycol in a mixture with a poloxamer. A specific example of a useful mixture is a mixture of 70 w / w% polyethylene glycol 6000 (PEG6000) and 30 w / w% poloxamer 188.

In a further aspect, the present invention relates to a pharmaceutical composition in the form of a particulate comprising tacrolimus and / or an analogue thereof together with one or more pharmaceutically acceptable excipients, said composition comprising orally administered to a mammal in need thereof, 1.3 represents the least AUC / AUC _{prograf ®} value, AUC values are measured under similar conditions.

As shown in the examples herein, the bioavailability obtained after administration of the composition according to the present invention is significantly improved. Thus, In certain embodiments, AUC / AUC _{prograf ®} value of about 1.25 or higher, for example about 1.5 or more, about 1.8 or more, about 1.9 or more, about 2.0 or more, AUC values are measured under similar conditions.

After oral administration of a pharmaceutical composition according to the present invention, the plasma concentration versus time profile can be used to determine whether the plasma concentration is maintained within the therapeutic window (i. E., The plasma concentration results in a therapeutic effect) Time period. Thus, a reduction in maximum concentration is also observed. Accordingly, the present invention relates to a pharmaceutical composition in the form of microparticles comprising tacrolimus in combination with one or more pharmaceutically acceptable excipients, wherein the composition releases tacrolimus in a controlled manner after oral administration to a mammal in need thereof, Such as, for example, 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% C _max for Prograf® tablets %, or about 40% or less C indicates the _maximum.

In this context, the term controlled release and sustained release are intended to be equivalent terms that include the release of any type of tacrolimus from a composition of the present invention suitable for obtaining a particular therapeutic or prophylactic response after administration to a subject. Those skilled in the art know how controlled release / sustained release is different from the release of a conventional tablet or capsule. The term " controlled release "or" extended release "has the same meaning as above.

The term controlled release / sustained release is a slow-release (which is one resulting in a lower C _max and later T _max, T _1/2 is not changed), slow release (that results in a lower C _max, later T _max one apparent T _1/2 is more Kim), delayed release (that results in a C _max is constant, and the lag time and, therefore, a T _max is delayed, T _1/2 is not changed) pulsatile release, as well as , Spontaneous release type, sustained release type, extended release type, time-optimized release type, rapid release (to obtain improved initiation of action), and the like. The term also encompasses the use of specific conditions within the body, such as, for example, different enzymes or pH changes to control the release of drug substance.

More specifically, following oral administration of a pharmaceutical composition according to the present invention containing 5 mg dose of tacrolimus to a mammal including a human, tacrolimus is released in a controlled manner and is administered at a dose of about 30 ng / ml or less, e.g., Will show a C _max of about 25 ng / ml or less or about 20 ng / ml or less.

However, as long as the plasma concentration of tacrolimus is maintained in the therapeutic window, a reduction in the maximum concentration will not result in a reduction in the therapeutic effect. Thus, the present invention also encompasses compounds of formula (I) wherein W < ₅₀ > is at 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, About 9 hours or more, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.

Has a - [C _{t (t} = 12 sigan) C _max] Furthermore Furthermore, the composition according to the invention is less than the _difference between C Prograf® C = _difference under the same conditions. When the _difference C for Prograf® is set to 100, _{the difference} C of the composition according to the present invention is usually 90 or less, for example, for instance, about 85 or less, about 80 or less, about 75 or less, about 70 or less, about 65 or less, About 60 or less, about 55 or less, about 50 or less, about 45 or less, or about 40 or less.

More specifically, following oral administration of the pharmaceutical composition of the present invention containing 5 mg of tacrolimus to a mammal including a human, the tacrolimus is released in a controlled manner and is administered at a dose of about 20 ng / ml or less, for example, about 15 ng / ㎖ or less, C indicates a _difference of about 13 ng / ㎖ or not greater than about 10 ng / ㎖.

The pharmaceutical composition according to the present invention releases tacrolimus in a controlled manner to expand tacrolimus therapeutic action. In one aspect, the release may be pH dependent, i.e. the release predominates after passing over the stomach. Such pH-dependent release is mainly provided by enteric coating materials as described herein. It is also possible, for example, to provide the composition in a form of a hydrophilic cellulose polymer matrix type based on a matrix composition such as HPMC, for example, by providing the composition with a controlled release coating, e. G. A cellulosic substrate coating, The release may be pH dependent. Combinations of course can also be used.

In general, changes in bioavailability and / or other bioavailability-related parameters are generally determined by in vivo studies in suitable animal models that test the composition being discussed with, for example, Prograf (R) or similar commercial tacrolimus- do. The use of dog models to establish evidence of the bioavailability of a particular formulation is a common practice in the pharmaceutical industry.

Appropriate studies for tacrolimus are non-randomized, cross-over, and each dog is its own control. Usually 4 dogs, and 4 treatments are applied. Since intravenous injection is not provided, the bioavailability obtained is relative.

It has also been surprisingly found that the need for simultaneous food ingestion to ensure adequate absorption of tacrolimus is significantly reduced or even extinguished completely.

Thus, the pharmaceutical compositions of the present invention provide significantly higher bioavailability of tacrolimus, which can reduce the number of dosage units administered per day, reduce or eliminate the need for administration associated with food ingestion, It may provide a higher degree of freedom to the recipient of the pharmaceutical composition and consequently significantly improve patient acceptance and / or compliance. In addition, the compositions provide a significant reduction of side effects, especially side effects associated with high peak concentrations (e.g., nephrotoxicity and neurotoxicity, diarrhea, constipation, abdominal pain, nausea, etc.), tacrolimus Lt; / RTI >

A further advantage of the slow release dosage form invention is the possibility of obtaining an effective therapeutic response at a reduced dosage compared to traditional oral treatment. For example, about 80% w / w or less, about 75% w / w or less, about 75% w / w or less of the dose of tacrolimus, About 70% w / w or less, about 65% w / w or less, about 60% w / w or less, about 55% w / w or about 50% w / w or less in the form of Prograf® or similar tacrolimus- Or as a commercial sustained release product comprising Advagraf®.

Commonly used parameters in biological equivalence studies are T _max , C _max , AUC _{0 - infinity} , and AUC _{0 - t} . Other relevant parameters may be W ₅₀ , W ₇₅ and / or MRT. Thus, one or more of the above parameters may be applied when determining whether biological equivalence exists. In addition, in this context, if the value of the parameter used is within 80-125% of the parameter value of Prograf® or a similar commercial tacrolimus-containing product used in the test, the two compositions are considered to be bioequivalent.

In the context of the present invention, "T _max " means the time to reach the maximum plasma concentration (C _max ) after administration; AUC _{0 - infinity} refers to the area under the plasma concentration versus time curve from time 0 to infinity; AUC _{0 -t} mean area under the plasma concentration versus time curve up to the time t at time zero and; W ₅₀ means the time at which the plasma concentration is at least 50% of C _max ; W ₇₅ means the time when the plasma concentration is at least 75% of C _max ; MRT means the mean residence time of tacrolimus (and / or its analogs).

Two other major disadvantages associated with treatment or prevention by tacrolimus are the relatively high incidence of adverse events and relatively high interpersonal variability. The compositions according to the invention are expected to result in a reduction in side effects. The reduction may be in terms of reduced frequency or severity. The side effects discussed include, for example, nephrotoxicity and neurotoxicity, diarrhea, constipation, abdominal pain, nausea and the like. In one aspect, the invention is directed to a pharmaceutical composition in the form of a particulate comprising tacrolimus or an analogue thereof in combination with one or more pharmaceutically acceptable excipients, wherein the composition is administered to a mammal in need thereof with tacrolimus or an analog thereof In a controlled manner and reduces side effects compared to the case of Prograf® administered under the same conditions and at doses providing equivalent therapeutic effects.

Increasing the bioavailability, Area Under the Curve (AUC), will usually reduce the endogenous and inter-variability associated with absorption of the drug substance. This is especially true if low and poor bioavailability is the result of poor water solubility. It is contemplated that the composition according to the present invention will provide a CV (coefficient of variation) for an area under the curve that is significantly smaller than that for Prograf® and similar products.

As mentioned herein, one of the essential features of the present invention is that oral administration of a sustained release dosage form according to the present invention can result in improved bioavailability. Due to the fact that it is nearly impossible to obtain an effective drug level over an extended period of time, the low bioavailability of the drug substance after oral administration is usually a barrier to the control of the drug substance or the design of the sustained release composition. However, it is possible to obtain a significantly improved bioavailability by the technique of the present invention, whereby it is possible to design a controlled, extended or delayed release type composition.

Tacrolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. Thus, a suitable controlled release composition may be a composition designed to release tacrolimus in a delayed manner to avoid or reduce CYP3A4 metabolism in the gastrointestinal tract.

Delayed release is achieved by some type of enteric coating. Semi-permeable coatings will show some kind of delayed release, but do not "delay" release very well. In addition, semi-permeable coatings require a certain amount of time to release the contents. The coating for the present invention is a pH dependent coating. This type of coating is highly resistant to release of the drug until a certain pH is reached. Within a very low 1/10 pH, the membrane changes properties and changes to permeability. Examples of pH-sensitive polymers that are relatively insoluble and impermeable at the pH above but which are more soluble and permeable at the pH of the small intestine and colon include polyacrylamides, phthalate derivatives such as the acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, Cellulose ester phthalate, cellulose ether phthalate, hydroxypropyl cellulose phthalate, hydroxypropylethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinylacetate phthalate, polyvinylacetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid Phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymer It includes copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymer without limit.

PH-sensitive polymers of particular interest include shellac; Phthalate derivatives, especially cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate; Polymethyl methacrylate combined with polyacrylic acid derivatives, especially acrylic acid and acrylic ester copolymers; And vinyl acetate and crotonic acid copolymers.

For example, where a zein or mono / di-glyceride mixture is used as the coating material, the release of the active substance from the composition with delayed release coating may also be an enzymatic reaction.

The controlled release pharmaceutical composition according to the present invention may be administered orally to a mammal, including a human, in need thereof, for a time period of at least about 24 hours, e.g., at least about 5 ng / ml, such as at least about 7.5 ng / Tacrolimus is released in such a way that plasma concentrations of about 10 ng / ml or more are obtained. In certain aspects of the invention, the difference between the plasma concentration measured and the plasma concentration measured 24 hours after administration is less than or equal to about 20 ng / ml, such as less than or equal to about 10 ng / ml, less than or equal to about 7.5 ng / ng / ml or less.

In a particular aspect, the present invention provides a pharmaceutical composition or solid dosage form that allows relatively rapid release of tacrolimus and / or its analogs relatively quickly, thus enabling a relatively rapid onset of therapeutic effect. In one aspect, the invention relates to a pharmaceutical composition in the form of a particulate comprising tacrolimus and / or an analogue thereof in combination with one or more pharmaceutically acceptable excipients, wherein the composition is administered to a mammal in need thereof, About 50% w / w or more of the total amount of tacrolimus or analogs thereof in a given manner within about 24 hours, such as within about 22 hours, within about 20 hours, within about 18 hours, within about 15 hours, Release within 12 hours.

Additionally or alternatively, when using a dissolution medium that has been tested in an in vitro dissolution test and comprises a buffer at pH 7.5, greater than or equal to about 50% w / w of the total amount of tacrolimus and / Within 22 hours, within about 20 hours, within about 18 hours, within 15 hours, within about 12 hours. Guidance for appropriate dissolution testing is provided herein in the Examples, but variations on the specific methods employed and ingredients contained in the dissolution medium, etc. are within the scope of the present invention. For example, USP, Ph.Eur., Including the FDA database of Dissolution Method for Drug Products. The skilled artisan will know how to perform a suitable dissolution test. Suitable conditions for the in vitro dissolution test are a USP dissolution test (paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1 g / ml of pancreatin as the dissolution medium.

In another embodiment, the following conditions are met for the in vitro dissolution test:

In another embodiment, the following conditions are met for an in vitro dissolution test performed under acidic conditions:

i) In vitro dissolution tests using a dissolution medium having a pH of less than or equal to about 5, such as less than about 4.5, less than about 4.0, less than about 3.5, less than about 3, less than about 2, For example less than about 25% w / w, less than about 20% w / w, less than about 15% w / w, or less than about 10% w / w are released within 2 hours;

ii) in vitro dissolution tests using a dissolution medium having a pH of less than or equal to about 5, such as less than about 4.5, less than about 4.0, less than about 3.5, less than about 3, less than about 2, For example less than about 7.5% w / w, less than about 5% w / w, or less than about 2.5% w / w are released within 2 hours;

iii) when tested in an in vitro dissolution test using a dissolution medium having a pH of not greater than about 4.5, such as not greater than about 4.0, not greater than about 3.5, not greater than about 3, not greater than about 2, or about 1.5, the drug of tacrolimus or analog thereof For example less than about 60% w / w, such as less than about 50% w / w, less than about 40% w / w, or less than about 30% w / being;

iv) when tested in an in vitro dissolution test using a dissolution medium having a pH of not greater than about 4.5, such as not greater than about 4.0, not greater than about 3.5, not greater than about 3, not greater than about 2, or not greater than about 1.5, the medicament of tacrolimus or an analogue thereof For example less than about 30% w / w, less than about 25% w / w, or less than about 20% w / w are released within 6 hours, and / or

v) when tested in an in vitro dissolution test using a dissolution medium having a pH of not greater than about 4.5, such as not greater than about 4.0, not greater than about 3.5, not greater than about 3, not greater than about 2, or about 1.5, the drug of tacrolimus or analog thereof For example less than about 25% w / w, less than about 20% w / w, or less than about 15% w / w are released within 4 hours.

In addition to tacrolimus, the compositions of the present invention may further comprise a therapeutically, prophylactically and / or genetically active substance. Of particular interest is the combination of tacrolimus with one or more of the following active substances: substances which are indicated to be used in connection with organ transplantation such as, for example, steroids, calcineurin inhibitors and / or antiproliferative agents. Specific examples include prednisone, prednisolone, methyl prednisone, cyclosporine, mycophenolate mofetil, azathioprine, sirolimus, everolimus, sodium mycophenolate, and FTY720 (Novartis).

The pharmaceutical compositions may be prepared by any convenient method such as, for example, granulation, mixing, spray drying and the like. A particularly useful method is the method described in WO 03/004001. A controlled agglomeration method, i. E., A method for producing particulate material by a method that allows controlled growth of the particle size is described herein. The method includes spraying a first molten first composition comprising, for example, tacholium and a carrier onto a second solid carrier medium. Usually, the melting point of the fusible carrier is 5 ° C or higher, but lower than the melting point of tacrolimus. The melting point of the carrier may be in the range of 10 占 폚 to 150 占 폚, and is most preferably in the range of, for example, 30 占 폚 to 100 占 폚 or 40 占 폚 to 50 占 폚.

It is within the skill of the art to select suitable carriers that are pharmaceutically acceptable, capable of dissolving or at least partially dissolving tacrolimus, and having a preferred range of melting points, using routine knowledge and routine experimentation. Suitable candidates for carriers are described in WO 03/004001, incorporated herein by reference.

In this context, suitable carriers are those mentioned in WO 03/004001 as well as those mentioned as substances such as, for example, oils or oils (as discussed herein below).

The advantage of using the controlled flocculation method described in WO 03/004001 is that it is possible to apply a relatively large amount of melt to the particulate material without undesirable growth of the particle size. Thus, in one embodiment of the invention, the particulate material of the pharmaceutical composition has a geometric weight average diameter d _gw of > = 10 μm, such as, for example, ≥ 20 μm, from about 20 to about 2000, from about 30 to about 2000, Such as from about 100 to about 1500 microns, from about 100 to about 1000 microns, or from about 100 to about 700 microns, or from about 400 microns or less, or from about 300 microns For example, from about 50 to about 400 microns, such as from about 50 to about 350 microns, from about 50 to about 300 microns, from about 50 to about 250 microns, or from about 100 to about 300 microns.

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

Solid dispersions of tacrolimus and / or solid solutions

The solid dispersion or solid dispersion used in a preferred embodiment of the present invention comprises an active ingredient selected from tacrolimus and its analogs and which is present in a hydrophilic or water-miscible carrier having a melting point (freezing point or pour point) Dispersed or dissolved at a concentration of from about 0.01 w / w% to about 15 w / w%, and the dispersion forms a solid dispersion or solid solution at ambient temperature (room temperature).

The concentration of the active ingredient in the hydrophilic or water-miscible carrier is no more than 15 w / w%, preferably no more than 10 w / w%, preferably no more than 8 w / w%, more preferably no more than 6 w / w% , Preferably not more than 5 w / w%, not more than 4 w / w%, in particular not more than 3 w / w%, in particular not more than 2% 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%, of at least about 0.05 w / w%, preferably at least about 0.1 w / w%

Physically, the combination of active ingredient and carrier can form a solid dispersion (i. E., The active ingredient is dispersed in particulate form in the carrier) to form a solid solution (i. E., The active ingredient is dissolved in the carrier at the molecular level being). The active ingredient and carrier can also form a solid dispersion in which a portion of the active ingredient is dissolved at the molecular level therein. The physical state of the dispersion and / or solution may be determined by various techniques such as scanning electron microscopy combined with high temperature microscopy (HSM), differential scanning calorimetry (DSC), optionally energy dispersive X-ray (EDX) (SEM). ≪ / RTI > In a preferred embodiment, the active ingredient is completely dissolved in the carrier at ambient temperature to form a solid solution.

 When the composition comprising the dispersion or solution is tested in a dissolution test according to USP using an aqueous dissolution medium, the solid dispersion of the present invention exhibits very rapid immediate release of tacrolimus and exhibits a 50 w / w % Or more is released within about 30 minutes, preferably within 20 minutes, more preferably within 15 minutes; E. G., Within about 40 minutes of the active pharmaceutical ingredient of at least about 75 w / w%, or more preferably within about 60 minutes, preferably within about 45 minutes, of at least 90 w / w% of the active pharmaceutical ingredient. For example, the test can be performed according to any method and any specification mentioned in the USP. Thus, the dissolution test can be carried out in an aqueous dissolution medium at any pH close to neutral or neutral, for example pH 6.8, or any acidic pH simulating gastrointestinal pH conditions. However, variations to the specific methods employed and ingredients contained in the dissolution medium and the like are within the scope of the present invention. One of ordinary skill in the art can, for example, refer to USP, Ph.Eur. And the like will be known how to perform a suitable dissolution test. Suitable conditions for the in vitro dissolution test are a USP dissolution test (paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1 g / ml pancreatin as the dissolution medium.

The hydrophilic or water-miscible carrier to be used in accordance with the present invention preferably has a melting point (frozen point or pour point) of at least 20 ° C, more preferably at least 30 ° C, more preferably at least 40 ° C, more preferably at least 50 ° C More preferably at least 52 캜, even more preferably at least 55 캜, even more preferably at least 59 캜, particularly at least 61 캜, particularly at least 65 캜.

Examples of useful hydrophilic or water-miscible carriers to be used in accordance with the present invention include polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycated glycerides such as Gelucire, Lt; / RTI >

In a preferred embodiment of the invention, the carrier is a polyethylene glycol (PEG), in particular a PEG having an average molecular weight of 1500 or more, preferably 3000 or more, more preferably 4000 or more, especially 6000 or more. Polyethylene glycol is advantageously present in an amount of from 1: 3 to 10: 1, preferably from 1: 1 to 5: 1, more preferably from 3: 2 to 4: 1, especially 2: 1 to 3: 1, especially about 7: 3 (on a weight / weight basis). Specific examples of useful mixtures are mixtures of PEG6000 and non-7: 3 of Poloxamer 188.

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

Useful poloxamers (also represented by polyoxypropylene-polyoxyethylene block copolymers) include, for example, Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide, Pluronic® and / or Tetronic® series. Suitable block copolymers of the Pluronic® series have a molecular weight of greater than or equal to about 3,000, such as from about 4,000 to about 20,000 and / or a Brookfield viscosity of from about 200 to about 4,000 cps, such as from about 250 to about 3,000 cps, / RTI > Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, . Suitable block copolymers of the Tetronic® series have a molecular weight of greater than about 8,000, such as from about 9,000 to about 35,000 and / or a Brookfield viscosity of from about 500 to about 45,000 cps, such as from about 600 to about 40,000 / RTI > The viscosities given are measured at 60 캜 for paste-like materials at room temperature and 77 캜 for materials that are solid at room temperature.

In a preferred embodiment of the present invention, the poloxamer is Poloxamer 188 having an average molecular weight of about 8400 and a melting point of about 50-54 占 폚.

Other useful hydrophilic or water-miscible carriers include polyvinylpyrrolidone, polyvinyl-polyvinyl acetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic polymers (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, pectin, cyclodextrin, galactomannan, alginate, Gum, and mixtures thereof.

Refers to a mixture of mono-, di-, and triglycerides and polyethylene glycol (PEG) mono- and diesters, preferably glycerol and free PEG, having a molecular weight of 200 to 600, and HLB The value is adjusted by the length of the PEG chain and the melting point is adjusted by the length of the fatty acid, the chain of the PEG and by the degree of saturation of the fatty acid and thus the starting oil; An example of such a mixture is Gelucire®. The Gelucire® composition is an inactive semi-solid waxy material, characterized by its amphiphilic character and being available in a variety of physical properties. Gelucire® compositions are surface-active in nature and are dispersed or dissolved in an aqueous medium to form micelles, microspheres or vesicles. This is identified by the melting point / HLB value. The melting point is expressed in degrees Celsius and the HLB (hydrophilic-lipophilic balance) is a numerical grade that includes from 0 to about 20. Lower HLB values mean more lipophilic and hydrophobic materials, higher values mean more hydrophilic and osmotic materials. The affinity of the compound to water or to an oily substance is measured and the HLB value is given experimentally. One or a mixture of different grades of Gelucire (R) excipients may be selected to achieve the melting point and / or HLB value of the desired characteristics. Wherein the long chain (C ₁₂ to C ₁₈₎ of the fatty acid glyceride monoesters, diesters and / or triesters, and long chain (C ₁₂ to C ₁₈₎ PEG of fatty acids (mono- and / or di) a mixture of ester And may include free PEG. Gelucire® compositions are generally described as fatty acid esters of glycerol and PEG esters or as polyglycated glycerides. Gelucire® compositions have a melting point in the wide range of from about 33 ° C to about 64 ° C, and most typically from about 35 ° C to about 55 ° C, and various HLB values from about 1 to about 14, most typically from about 7 to about 14 Feature. For example, Gelucire® 50/13 has a melting point of about 50 ° C and an HLB value of about 13 for this grade of Gelucire®.

A pharmaceutically acceptable excipient

Examples of suitable excipients for use in compositions or solid dosage forms according to the present invention include fillers, diluents, disintegrants, binders, lubricants, and the like and mixtures thereof. Since the compositions or solid dosage forms according to the present invention can be used for different purposes, the excipients are usually chosen in consideration of such different uses. Other pharmaceutically acceptable excipients for suitable use include, for example, acidifying agents, alkalizing agents, preservatives, antioxidants, buffers, chelating agents, coloring agents, complexing agents, emulsifying and / or solubilizing agents, spices and perfumes, , Wetting agents and the like.

Examples of suitable fillers, diluents and / or binders include lactose (e.g., spray-dried lactose, alpha-lactose, beta-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast- (Various grades of Avicel, Elcema, Vivacel, Ming Tai or Solka-Floc), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropylmethylcellulose (HPMC) Methocel E, F and K of Shin-Etsu, Ltd., Metolose SH, such as Methocel E and Metolose 60 SH of the 4,000 cps rating, Methocel F and Metolose 65 SH of the 4,000 cps rating, 4,000, Methocel K of the order of 100,000 cps and Metolose 90 SH of the 4,000, 15,000, 39,000 and 100,000 grades), methylcellulose polymers (such as Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, Sodium carboxymethylcellulose, carboxymethylene, carboxy Starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (e. G., Basic starch, e. G. Calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen and the like.

Specific examples of the diluting agent include calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microtiter cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, Sorbitol, starch, pregelatinized starch, sucrose, and sugar.

Specific examples of disintegrants include, for example, alginic acid or alginate, micro-measured cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, , Carboxymethyl starches (such as Primogel® and Explotab®), and the like.

Specific examples of the binder include cellulose derivatives such as acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethyl cellulose, micronized cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethyl cellulose, methylcellulose, PEG, povidone, pregelatinized starch, and the like.

Also lubricants and lubricants may be included in the composition. Examples are 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 sulphate, sodium benzoate, sodium acetate and the like.

The compositions of the present invention or other excipients that may be included in solid dosage forms include, for example, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffers, preservatives, stabilizers, antioxidants, wetting agents, humidity control agents, surface active agents, Enhancers, and materials for extended release.

The compositions according to the present invention or other additives in solid dosage forms may contain antioxidants such as ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, Potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives. The carrier composition may also contain, for example, a stabilizer. The concentration of antioxidant and / or stabilizer in the carrier composition is usually from about 0.1% w / w to about 5% w / w.

Compositions or solid dosage forms according to the invention may also comprise one or more surface active agents or substances with surface active properties. It is contemplated that the material participates in the wetting of the slightly soluble active material and thus contributes to the improved solubility characteristics of the active material.

Suitable excipients for use in compositions or solid dosage forms according to the present invention are the amphoteric surface active agents such as those disclosed in WO 00/50007 in the name of surface active agents such as Lipocine, Examples of suitable surfactants are:

i) polyethoxylated fatty acids such as fatty acid mono- or diesters of polyethylene glycols or mixtures thereof such as, for example, polyethylene glycols and monoesters of lauric, oleic, stearic, myristic, ricinoleic acid - or a diester wherein said polyethylene glycol is selected from the group consisting of PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, , PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000)

ii) polyethyleneglycol glycerol fatty acid esters, i.e. esters in the form of the glyceryl esters of the respective fatty acids as mentioned above,

iii) glycerol, propylene glycol, ethylene glycol, PEG or a mixture thereof with vegetable oils such as hardened castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil, peanut oil, Sorbitol esters,

iv) polyglyceride fatty acids such as polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linolate,

v) propylene glycol fatty acid esters such as propylene glycol monolaurate, propylene glycol monolaurate,

vi) mono- and diglycerides such as glyceryl monooleate, glyceryl diol ae, glyceryl mono- and / or dioleate, glyceryl caprylate, glyceryl caprate and the like;

vii) sterol and sterol derivatives;

viii) Polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG having various molecular weights indicated above, and various Tween® series;

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

x) sugar esters such as sucrose mono palmitate and sucrose monolaurate;

xi) polyethylene glycol alkylphenols such as Triton (R) X or N series;

xii) polyoxyethylene-polyoxypropylene block copolymers such as, for example, Pluronic® series, Synperonic® series, Emkalyx®, Lutrol®, Supronic® and the like.

A general term for the polymer is "poloxamer ", and suitable examples in this context are Poloxamers 105,108, 122,123,124,181,182,183,184,185,188,212,215,217,231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407;

xiii) sorbitan fatty acid esters such as Span® series or Ariacel® series such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like;

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

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

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

In a specific aspect of the present invention, at least one of the one or more pharmaceutically acceptable excipients is selected from the group consisting of silica acids or derivatives or salts thereof, including silicates, silicone dioxides and polymers thereof; Magnesium aluminosilicate and / or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and / or saponite.

The material is particularly useful as a sorbent material for materials such as oil or oil in pharmaceuticals, cosmetics and / or foodstuffs. In certain embodiments, the material is used as a sorbent material for a material such as oil or oil in a medicament. A substance that can function as a sorbent material for a substance such as oil or oil is also referred to as an "oil sorbent material ". In addition, the term "sorption" in this context is used to mean "adsorption" as well as "adsorption. &Quot; It is to be understood that when one of the above terms is used it is intended to include adsorption as well as adsorption phenomena.

In particular, pharmaceutically acceptable excipients may include a silicic acid or derivative or salt thereof, such as, for example, silicone dioxide or a polymer thereof, as a pharmaceutically acceptable excipient. Depending on the quality used, the silicon dioxides can be lubricants or oil sorbent materials. The quality that meets the latter function seems to be the most important.

In certain embodiments, the composition or solid dosage form according to the present invention comprises a pharmaceutically acceptable excipient that is a silicone dioxide product having properties corresponding to Aeroperl 300 (available from Degussa, Frankfurt, Germany).

As shown in the examples herein, a highly suitable material is Aeroperl 300 (including materials having properties corresponding to or similar to those of Aeroperl 300).

The use of oil sorptive materials in the compositions or dosage forms according to the invention is highly advantageous for the manufacture of medicaments, cosmetics, nutrients and / or food compositions wherein the composition comprises a substance such as oil or oil. One of the advantages is that it can contain a relatively large amount of substances, including oil and oil, but still solid. Accordingly, it is possible to produce a solid composition containing a relatively high loading amount of oil or oil-like material by the use of the oil sorption material according to the present invention. It is advantageous to be able to include relatively large amounts of oil or oil in the solid composition in the pharmaceutical field, especially when the active material is water-soluble (e.g. poorly water-soluble), stable in the aqueous medium Or a pulsatile delivery of the active substance, or when the active substance (s) is / are released from the composition in order to obtain controlled, delayed, sustained and / or pulsatile delivery of the active substance Lt; RTI ID = 0.0 > desirably < / RTI > Thus, in certain embodiments, the foregoing is used in the preparation of a pharmaceutical composition.

In an important embodiment of the invention, at least a portion of tacrolimus and / or its analog is present in the composition in the form of a solid solution comprising a molecular dispersion and a solid dispersion. Usually 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more of tacrolimus and / , E. G., Greater than 95%, or about 100% w / w, are present in the composition in the form of a solid dispersion.

The solid dispersion can be obtained in a different manner, for example, by using an organic solvent or by dispersing or dissolving the active material in another suitable medium (e.g., oil or oil like material in liquid form at room temperature or elevated temperature) .

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

Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamer, polyoxyethylene stearate, poly-epsilon -caprolactone, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-polyvinyl acetate copolymer PVP-PVA VA64), poly-methacrylic acid polymers (Eudragit® RS, Eudragit® RL, Eudragit® NE, Eudragit® E) and polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose , Methylcellulose, and poly (ethylene oxide) (PEO).

Polymers containing acidic functional groups may be suitable for solid dispersions, which release the active substance in a desired pH range that provides acceptable absorption in the intestines. The polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate (HMPCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer L, Eudragit S), shellac, cellulose acetate phthalate (CAP), starch glycolate, polyacrylic, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate And < RTI ID = 0.0 > tate. ≪ / RTI >

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

The solid dispersion is preferably formed by a spray drying technique, controlled agglomeration, lyophilization or coating on carrier particles or any other solvent removal method. The dried product contains the active material present in the form of a solid dispersion comprising a molecular dispersion and a solid solution.

As an alternative to the use of organic solvents, drugs and polymers can be co-milled or extruded at elevated temperatures (melt extrusion).

Pharmaceutical compositions comprising tacrolimus, at least partially in the form of a solid dispersion or solution, may in principle be prepared using any suitable method of preparing pharmaceutical compositions known in the art.

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

In yet another aspect, the invention is directed to a method of making a pharmaceutical composition in accordance with the present invention. In general, any suitable method of pharmaceutical field can be used. However, the methods described in WO 03/004001 have proved particularly useful in order to enable the inclusion of relatively large amounts of oil or oil-like substances. WO 03/004001 is incorporated herein by reference. The process comprises contacting a first composition in liquid form, said composition comprising a first carrier or carrier and having a melting point above 5 DEG C, in a second composition comprising a second support or carrier material, said second composition being in a fluidized state, Lt; RTI ID = 0.0 > temperature < / RTI > below the melting point of the carrier or carrier). The active material may be present in the first carrier or carrier composition and / or in a second support or carrier composition. However, when tacrolimus and / or an analogue thereof is at least partially present in the form of a solid dispersion, it is advantageous to include or dissolve tacrolimus and / or its analogs in the first carrier or carrier composition. In addition, the inventors WO05020993A1 and WO05020994A1 describe tacrolimus compositions by use of the techniques described above, together with their sustained release formulations, and are incorporated herein by reference.

Solid dosage form

The pharmaceutical compositions according to the invention are in particulate form and can be used as such. In many cases, however, it is more convenient to present the composition in the form of granules, pellets, microspheres, nanoparticles, or the like, or in the form of solid dosage forms including tablets, capsules,

The solid dosage form according to the present invention may be a single unit dosage form or it may contain a plurality of individual units such as, for example, pellets, beads and / or granules in the form of a poly-depot dosage form.

Solid dosage forms according to the present invention include pharmaceutical compositions in particulate form as described above. The details and specifications disclosed in the main aspects of the present invention are applied to other aspects of the invention with only minor modifications as needed. Thus, properties associated with the release of tacrolimus and / or its analogs as well as the increase in bioavailability, changes in bioavailability parameters, lack of day effect, as described and / or claimed herein for pharmaceutical compositions in particulate form, Lt; / RTI > is similar to that for the solid dosage form according to < RTI ID =

The recommended dosage range for Prograf® is 0.1 to 0.2 mg / kg / day (administered every 12 hours with two divided doses). Importantly, blood levels should be monitored.

Typical levels for 1-3 months should be 7-20 ng / ml, and 4-12 months should be 5-15 ng / ml. This is only a guideline value and may vary depending on the type of implant and race.

For kidney transplant patients:

The expected recommended dosage for the products of the present invention will be from 0.02 mg / kg / day to 0.15 mg / kg / day, once a day. A suitable dosage form (strength) ranges from 0.1 mg to 15 mg tacrolimus, preferably 0.5 mg, 1 mg, 2 mg and 5 mg.

As described herein by Sintigraphy and shown in Fig. 2, the release according to the invention can also take place in the distal part of the colon and can still be distributed and absorbed into the mucosa. Absorption of a sustained release dosage form according to the present invention occurs at a location where the in vivo release substantially occurs in the colon following oral administration to the subject, such as at least one of the ascending colon, the transverse colon and the descending colon.

Different embodiments of the present invention relating to the preferred pharmacokinetic parameters obtained in the sustained release dosage forms according to the present invention are listed below.

In one embodiment, the invention relates to the use of a product Advagraf® (MR4) dosage form or a biologically-equivalent, sustained-release dosage form when administered to a subject or to a plurality of subjects, administering similar molecular doses of tacrolimus and determining under similar conditions more than 10% compared to T _max obtained from, for example 15% or more, such as 17.5% or more, such as mean blood of tacrolimus decreases by more than 20%, for example more than 22.5%, for example at least 25%, for example more than 27.5%, for example more than 30% T < / RTI > _maximal subject and / or inter-subject variability.

In one embodiment, the invention relates to a method of obtaining tacrolimus from an administration of a product Advagraf (MR4) or a biologically equivalent sustained-release dosage form when administered to a subject or to a plurality of subjects, administering similar molecular doses of tacrolimus and determining under similar conditions that C _max and / or AUC at least 10% compared to the _(0-∞), for example 15% or more, such as 17.5% or more, such as 20% or more, such as at least 22.5%, such as at least 25%, for example more than 27.5%, for example 30% Or inter-subject variability of the mean blood C _max and / or AUC _(0-∞) of reduced tacrolimus.

In one embodiment, the present invention provides a pharmaceutical composition comprising about 10% or more, or about 15% or more, more preferably about 10% or more, more preferably about 10% or more, or about 20%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50% or more, or decreases by more than about 55% of C sustained release that provides the _maximum value (C _max values are measured under similar conditions by administering similar molecular doses of tacrolimus).

In one embodiment, the present invention provides a pharmaceutical composition comprising at least about 20%, or at least about 25%, more preferably at least about 25%, more preferably at least about 25%, more preferably at least about < RTI ID = Or about 30% or more, or about 35% or more, or about 40% or more, or about 45% or more, or about 50% or more, or about 55% or more, or about 60% or more, such as 65% (The bioavailability is measured as AUC _(O-∞) under similar conditions of administration of a similar molecular dose of tacrolimus).

In one embodiment, the present invention provides a method of treating a subject or a plurality of subjects by administering a similar molecular dose of tacrolimus and determining under similar conditions, by administration of a commercially available Prograf® dosage form or a biologically equivalent cyclosporine tacrolimus dosage form more than 10% compared to the T _max is obtained, for example, 15% or more, such as mean blood of 17.5% or more, and the example of 20% or more, such as at least 22.5%, such as at least 25%, for example more than 27.5%, for example reduced by at least 30% tacrolimus T To a sustained dosage form that provides _maximum intra-subject variability and / or inter-subject variability.

In one embodiment, the invention provides a method of treating a subject or a plurality of subjects when administered to a subject in a similar molecular dose of tacrolimus and, when measured under similar conditions, by administration of a commercially available Prograf® dosage form or a biologically equivalent intrathecal dosage form that C _max and / or AUC at least 10% compared to the _(0-∞), for example 15% or more, such as 17.5% or more, such as 20% or more, such as at least 22.5%, such as at least 25%, for example more than 27.5%, for example 30% Or inter-subject variability of the mean blood C _max and / or AUC _(0-∞) of reduced tacrolimus.

In one embodiment, the present invention provides a pharmaceutical composition comprising about 20% or more, or about 30% or more, or more than about 30%, or more than about 30% To provide a C _{max of} less than about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60% (C _{max is} measured at similar molecular doses of tacrolimus administered and under similar conditions).

In one embodiment, the present invention provides a pharmaceutical composition comprising about 10% or more, or about 15% or more, or about 20% or more, or about 30% or more of the compound of the present invention, as compared to that obtained by administration of a commercially available Prograf Or about 35% or more, or about 40% or more, or about 45% or more, or about 50% or more, or about 55% or more of the bioavailability Similar molecular doses of tacrolimus are administered and measured as AUC _(O-∞) under similar conditions.

In one embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is administered to a subject or a plurality of subjects after a fasting time of at least 4 hours in the evening, To about 70% or more, such as 80% or more, preferably 85% or more, more preferably 90% or more, and preferably 95% or more.

In one embodiment, the present invention relates to a method of treating a subject, comprising administering to a subject or a plurality of subjects after a fasting period of at least 4 hours in the evening, To a sustained release dosage form that provides a C _{max of} at least 70%, such as at least 80%, preferably at least 85%, more preferably at least 90% and preferably at least 95%.

In one embodiment, the present invention relates to a sustained release dosage form suitable for bedtime administration therapy, as the bioavailability is independent of the time of day administration.

In one embodiment, the present invention provides a pharmaceutical composition comprising tacrolimus at a concentration of less than or equal to 15 ng / ml, such as less than or equal to 13 ng / ml of tacrolimus when administered as a single dose to 5 or more healthy subjects in a fasting state, It relates to the concentration (C _max) and 45 ㎎ · hour / L or more, such as 55 ㎎ · hour / L or more, such as sustained release dosage forms that provide 60 ㎎ · hour / mean AUC _{(O-96 hour)} or more L.

In one embodiment, the invention relates to a sustained release dosage form wherein the blood concentration is greater than 2 ng / ml, such as greater than 3 ng / ml, such as greater than 4 ng / ml, after 24 hours of administration of tacrolimus.

In one embodiment, the present invention if a healthy subject or a patient to be administered once a day at steady state (C _max - C _Min) / C 1 daily dosage are fluctuations in plasma concentrations of tacrolimus, a similar molecule to be measured as _{the minimum} Amount of tacrolimus and measured under similar conditions and which is less than the observed fluctuation when administering the Advagraf® dosage form or the biologically equivalent sustained-release dosage form of tacrolimus once daily. The reduction is preferably at least 10%, such as at least 20%, preferably at least 30%, such as at least 40%, more preferably at least 50%.

Of blood level fluctuations of the total and / or free tacrolimus measured as - (C _minimum C _max) / C _{at least} in one embodiment, the invention if a healthy subject or a patient to be administered once a day in a stable state , A similar molecule is administered with tacrolimus at a daily dose of tacrolimus and measured under similar conditions, and when the Prograf® dosage form or the biologically equivalent isochronous composition of tacrolimus is administered twice daily, will be. The reduction is preferably at least 10%, such as at least 20%, preferably at least 30%, such as at least 40%, more preferably at least 50%.

In one embodiment, the invention provides a method of treating a subject or patient suffering from a change in plasma concentration of total and / or free tacrolimus, measured as (C _max -C _min ) / C _average , when administered once daily in a stable state to a healthy subject or patient This similar molecule is administered in a single daily dose of tacrolimus and measured under similar conditions, and when administering the Advagraf® dosage form or the biologically equivalent sustained-release dosage form of tacrolimus once daily, the sustained release dosage form . The reduction is preferably at least 10%, such as at least 20%, preferably at least 30%, such as at least 40%, more preferably at least 50%.

In one embodiment, the present invention provides a method of treating a subject or patient in need thereof, wherein the change in blood concentration relative to total tachylymus as measured as (C _max -C _min ) / C _average , when administered once daily in a stable state, To a sustained release dosage form that is administered at a daily dose of tacrolimus and measured under similar conditions and which is less than the variability observed when the Prograf® dosage form or the biologically equivalent isochronous composition of tacrolimus is administered twice daily. The reduction is preferably at least 10%, such as at least 20%, preferably at least 30%, such as at least 40%, more preferably at least 50%.

In one embodiment, the present invention provides a method of treating a condition in which the average residence time MRT of tacrolimus measured in the blood, when administered to six or more healthy subjects in a fasted state, is increased by an Advagraf® administration form or a similar sustained dosage form of tacrolimus, Lt; RTI ID = 0.0 > 10% < / RTI > longer than the mean residence time measured under the condition. Preferably, the MRT is increased by 20% or more, for example 25%.

In one embodiment, the present invention provides a method of treating a condition wherein the average residence time of tacrolimus measured in the blood, when administered to six or more healthy subjects in a fasted state, is determined by a Prograf® administration form or a biologically equivalent ischemic administration form of tacrolimus, Lt; RTI ID = 0.0 > 35% < / RTI >

In yet a further aspect, the invention provides a method as described herein for providing at least one of a reduced C _max , a reduced change, a reduced variability, an increased AUC, an increased MRT, a longer T _max , and a higher C _min The present invention provides a method of providing immunosuppressive therapy to a patient in need thereof by once-a-day therapy by administration of the same sustained release formulation. In addition, the method to more than 0.75. 1, for example 0.80 or higher, preferably 0.85, more preferably 0.90, still more preferably a C _minimum associated with the bioavailability by at least 0.95, and even more preferably at least 0.97 correlation coefficient to provide.

In a preferred embodiment, the difference in bioavailability is substantially independent of the time of administration of the daily dose. This provides the possibility of once daily dosing at bedtime or evening in addition to normal morning dosing. More importantly, however, if the patient actually takes the dosage form at a different time than the one prescribed and expected (compliance with the patient's compliance), the risk of reduced exposure, reduced exposure and, for example, increased risk of graft rejection The risk for the patient is reduced.

In a further aspect, the invention provides for a conversion from a once-a-day regimen to a higher dosage. Among them, one method for such a conversion from Prograf to once-a-day therapy is to administer a daily dose of tacrolimus immediate-release therapy by 25% to 50%, such as 30% to 40%, preferably about 33% . 0.5 mg, 1 mg, 2 mg, and 5 mg once daily in a single dose form. Thus, the conversion ratio of 1: 0.66 to 0.80 depends on the available dosage strength as mentioned above. In addition, the present invention relates to a pharmaceutical composition comprising a sustained-release formulation according to the invention, which comprises a sustained-release formulation of Advagraf® at a ratio of 1: 0.30 to 0.75, such as 1: 0.33 to 0.7, depending on the available dosage strengths selected from 0.5 mg, 1 mg, 2 mg and 5 mg. Conversion.

A particularly important aspect of the present invention is a significantly reduced peak concentration, which provides a reduction in side effects associated with peak concentrations. However, this effect may be difficult to measure due to the nature of the side effects of the present tacrolimus treatment and the nature of the side effects that may require tissue biopsy to belong to, or often belong to, mutations and often subjective features. An accurate questionnaire and a large number of patients will be needed for comparative studies to prove significantly this effect. However, it is contemplated that treatment with a sustained release formulation according to the present invention may reduce some possible maximum concentration related side effects, including side effects of neurogenic factors such as tremor and headache.

In a preferred embodiment, the reduction of side effects is associated with the risk of an extended QTc interval due to the effect on ventricular repolarization. Other toxicities included to be considered to be reduced are the development of kidney damage, the development of hypertension as well as the development of diabetes.

Accumulation, especially in some organs, may be associated with organ damage, especially since accumulation during periods of low blood concentrations at the end of the dosing interval or individual tacrolimus concentrations may not decrease. May be associated with the high affinity of tacrolimus for, which overcomes the removal from the highly vascularized organ, which is expected when the affinity is not high. Thus, the high peak of currently available dosage forms can contribute to the accumulation of tacrolimus in these organs, and the organs can have a concentration almost 30 times higher than the concentration of blood in the steady state by conventional dosage forms.

A newly transplanted patient can be extremely sensitive to high concentrations due to the overall bad condition of the body, and low levels of plasma proteins further increase the part of the tacrolimus that can enter the organ. The use of the dosage forms according to the invention, which in particular can reduce the scale of accumulation or extend the time before tacrolimus reaches high concentrations in toxic organs, prevents high blood concentrations during titration, especially in these patients. Thus, the present invention also relates to a method of treating a patient at risk of organ toxicity due to tacrolimus. Organs known to accumulate tacrolimus include adrenals, lungs, heart, liver, gastrointestinal tract and kidney. However, it is also believed that according to the present invention, the pancreas and especially the Langerhans isomer may be susceptible to high concentrations, especially during the onset of tachronomy, thereby greatly increasing the risk of developing diabetes later. Other organs related to toxicity are the central nervous system. Many patients discontinue treatment due to headaches and tremors which are likely to be reduced by treatment according to the present invention. In particular tremor is a side effect associated with toxic effects on the central nervous system caused by tacrolimus across the blood brain barrier. According to the present invention, higher concentrations may facilitate the capture of tacrolimus in the central nervous system, as there is a higher concentration difference across the blood brain barrier when the concentration in the circulation is high, As compared to a situation in which a constant and lower concentration is provided, as in the case of < RTI ID = 0.0 > a < / RTI >

According to a further aspect of the present invention, the sustained release formulations according to the present invention provide a therapeutic safety profile that allows treatment from the time of implantation as soon as the patient is healthy enough to be treated with the oral dosage form. Thus, the patient will not need to switch to treatment according to the invention after the first titration with the conventional twice-a-day formulations such as Prograf®, but the tacrolimus by the once-daily formulation according to the invention Lt; RTI ID = 0.0 > immunosuppressive < / RTI > therapy.

In a further embodiment, the treatment of a new transplant patient is provided, since the formulation according to the invention can ensure sufficient systemic exposure even within the first 24 hours after initiation, thereby not only the initiation of tacrolimus oral therapy, Lt; RTI ID = 0.0 > a < / RTI > same dosage form can be used. It is believed that the number of administration modifications can be reduced and compliance with the once-daily treatment of the present invention by reduced-size tablet formulations compared to other available tacrolimus products is expected to increase.

The use of Advagraf® within the first 24 hours is observed to provide approximately 30% and 50% lower systemic exposure, respectively, compared to administration of Prograf® formulations administered to new kidney and new liver transplant patients. The general description of the reduced bioavailability is that the Prograf® formulation administered in the evening compared to the first morning after transplantation is due to the absence of a day-to-day effect on absorption of tacrolimus, According to the Scientific Discussion published in connection with the approval of Advagraf® by EMEA. However, according to the present inventor, a lower exposure of the Advagraf® product may primarily be associated with a relatively higher effect of gastrointestinal metabolism, possibly in combination with a lower absorption rate which promotes a higher first pass extract fraction by the liver. GI metabolism in liver transplant patients may even have a higher impact since liver metabolism may be reduced early after transplantation. Thus, the effect of GI metabolism by the provision of the expandable formulations according to the invention is less due to the fact that the formulation mainly releases tacrolimus in the lower ileum and colon with fewer metabolisms and at the same time releases the tacrolimus in the manner in which absorption actually takes place, That is, it releases tacrolimus in an improved manner, such as in molecular or substantial molecular form.

Thus, less than 50% of the tacrolimus content in the oral dosage form, when measured in vitro, is released after 10 hours (as measured by the dissolution method published for the FDA database of Dissolution Methods For Drug Products) There is provided an initial method of treatment of a new liver transplant patient by tacrolimus, comprising administering once a day a tacrolimus oral dosage form having a profile, wherein said oral dosage form is the same daily dose on day 1, Provides a systemic exposure of greater than 50% of the exposure obtained on Day 1 after administration administered as a fast oral dosage form.

Similarly, a tacrolimus oral dosage form having a sustained release profile (measured according to the FDA method for Prograf®), wherein less than 50% of the tacrolimus content in the oral dosage form, measured in vitro, is released after 10 hours The present invention provides an initial treatment method for a new kidney transplant patient by tacrolimus which comprises administering the same daily dose on the first day but is administered twice a day as an immediate oral dosage form Provides systemic exposure that is greater than 70% of the exposure obtained on day one after administration being administered.

The method also comprises administering a tacrolimus oral dosage form having a sustained release profile (measured according to the FDA method for Prograf®) wherein less than 50% of the tacrolimus content in the oral dosage form as measured in vitro is released after 10 hours The present invention relates to an initial treatment method of a new liver transplant patient by tacrolimus, which comprises administering the same daily dose on day 1 but releases more than 30% of tacrolimus within 5 hours Provides a systemic exposure of greater than 100% of the exposure obtained on day 1 after administration administered as a sustained release oral dosage form.

Similarly, a tacrolimus oral dosage form having a sustained release profile (measured according to the FDA method for Prograf®), wherein less than 50% of the tacrolimus content in the oral dosage form, measured in vitro, is released after 10 hours The present invention provides an initial treatment method for a new kidney transplant patient by tacrolimus which comprises administering the same daily dose on the first day but not more than 30% Provides a systemic exposure of greater than 100% of that obtained on day one after administration administered as an oral dosage form.

For example, solid dosage forms according to the present invention may also be coated to obtain suitable properties for controlled release of the active substance. The coating may be applied to a single unit dosage form (e.g., tablet, capsule) or may be applied to a poly-depot dosage form or to its individual units.

Suitable coating materials include, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylalcohol, sodium carboxymethyl Cellulose, cellulose acetate, cellulose acetate phthalate, gelatin, methacrylic acid copolymer, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, fine measuring wax, glyceryl monostearate, and zein.

Plasticizers and other components may be added into the coating material. Also the same or different active materials may be added in the coating material.

In a preferred embodiment of the invention, the solid dosage form is designed to release tacrolimus and / or its analogs in a controlled manner. In this context, the term "controlled manner" is intended to include any type of release that differs from that obtained from conventional tablets. Accordingly, the term is intended to encompass all types of fluids, including so-called "controlled release", "sustained release", "sustained release", "pulsatile release", "extended release", " , But also the terms "delayed release" and pH-dependent release type. However, certain aspects of the present invention are directed to delayed release compositions or dosage forms which, after administration in the context and / Or less of the active substance within the first 2 hours after the start of the dissolution test using the dissolution medium with a dissolution rate of less than 10% w / w of the active substance.

Sustainable system

The first sustained-release system includes a matrix system in which tacrolimus is embedded or dispersed within a matrix of another substance that serves to retard the release of tacrolimus into the aqueous environment (i.e., the intracavitary fluid of the GI tract). When tacrolimus is dispersed in a matrix of this type, the release of the drug mainly occurs from the surface of the matrix. Thus, when the drug is diffused through the matrix or when the surface of the device is eroded to expose the drug, the drug is released from the surface of the device comprising the matrix. In some embodiments, both of these mechanisms can act simultaneously. The matrix system may be large, i.e., tablet size (about 1 cm), or small (< 0.3 cm). The system may be integral and may be divided (e.g., by a crawling), composed of several subunits that are administered at substantially the same time (e.g., several capsules that make up a single dose), or multiple microparticles Which may include a plurality of particles. Multiparticulates can have numerous formulation uses. For example, the multiparticulates can be used as a powder to fill the capsule shell, or can be used itself to mix with the food to facilitate ingestion.

In certain embodiments, the matrix multiparticulates comprise a plurality of tacrolimus-containing particles, each particle containing one or more excipients selected to form a matrix capable of controlling the rate of dissolution of the tacrolimus into the aqueous medium, / Tacrolimus in the form of dispersions and / or analogs thereof. Matrix materials useful in this embodiment are generally hydrophobic materials such as waxes, some cellulose derivatives, or other hydrophobic polymers. If desired, the matrix material may optionally be formulated with a hydrophobic material, which may be used as a binder or as an enhancer. Matrix materials useful for preparing such dosage forms are: ethylcellulose, waxes such as paraffin, modified vegetable oils, carnauba wax, hardened castor oil, beeswax, as well as synthetic polymers such as poly (vinyl chloride), poly (Vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, and the like. The water soluble or hydrophilic binder or release modifier which may optionally be formulated into the matrix may be a hydrophilic polymer such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, poly (N-vinyl-2-pyrrolidinone (PVP), poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials. In addition, the substance functioning as a release modifier includes a water-soluble substance such as sugar or salt. Preferred water-soluble materials include lactose, sucrose, glucose, and mannitol, as well as hydrophilic polymers such as, for example, HPC, HPMC and PVP.

In certain embodiments, the multiparticulate product is defined as being processed by controlled agglomeration. In this case, the tacrolimus is dissolved or partially dissolved in a suitable fusible carrier and sprayed onto carrier particles comprising the matrix material.

Suitable melt carriers are mentioned herein above.

Alternatively, tacrolimus is dissolved in an organic solvent together with the matrix material, spray dried or applied as carrier particles (see below). Typical solvents used in the process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

Once formed, the tacrolimus matrix multiparticulates may be combined with a compressible excipient such as lactose, microcrystalline cellulose, dicalcium phosphate, etc., and the formulation may be compressed to form tablets. Also useful are disintegrating agents such as sodium starch glycolate or crosslinked poly (vinylpyrrolidone). Tablets prepared by this method collapse when placed in an aqueous medium (e.g., a GI tract) to expose the multiparticulate matrix and release tacrolimus from the multiparticulate matrix.

In a further embodiment, the matrix system comprises tacrolimus and / or an analogue thereof (e. G. In the form of a solid dispersion) as a multiparticulate product and a hydrophilic polymer in an amount sufficient to provide a degree of control useful for tacrolimus dissolution Lt; / RTI &gt; is a form of a hydrophilic matrix tablet. Hydrophilic polymers useful for forming the matrix include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), poly (ethylene oxide), poly (vinyl alcohol), xanthan gum, carbomer, carrageenan and zugran do. A preferred material is HPMC. Other similar hydrophilic polymers may also be used. In use, the hydrophilic material is swollen and eventually dissolved in water. Tacrolimus is released by diffusion from the matrix and by erosion of the matrix. The tacrolimus dissolution rate of the hydrophilic matrix tablet can be controlled by the amount of hydrophilic polymer used, the molecular weight and the gel strength. In general, the use of higher amounts of hydrophilic polymers reduces the rate of dissolution, even when polymers of higher molecular weight are used. The use of lower molecular weight polymers usually increases the dissolution rate. The matrix tablet typically comprises about 20 to 90% by weight tacrolimus and about 80 to 10% by weight polymer.

Preferred matrix tablets contain from about 30% to about 80% by weight of a solid dispersion containing tacrolimus and / or its analogs, from about 15% to about 35% by weight of a matrix forming agent (e.g., HPMC) From 0 wt% to about 35 wt% lactose, from 0 wt% to about 20 wt% micronised cellulose and from about 0.25 wt% to about 2 wt% lubricant (e.g., magnesium stearate).

The matrix system as a whole often exhibits unfavorable release of the drug from the matrix. This result may be the result of a diffusive mechanism of drug release, and changes to the geometry of the dosage form may be advantageously exploited to make the release rate of the drug more consistent.

A second type of tacrolimus controlled-release dosage form of the invention comprises a membrane-regulating or reservoir system. In this type, for example, the reservoir of tacrolimus in the solid solution / dispersion as a multiparticulate product is surrounded by a rate-limiting membrane. Tacrolimus traverses the membrane by mass transport mechanisms well known in the art including, but not limited to, diffusion across the membrane after dissolution within the membrane or diffusion through a hole filled with liquid in the membrane. The individual reservoir system dosage forms may be as large as in the case of tablets containing a single large reservoir, or may be formed from multiple particulates, such as in the case of poly-depot tablets or capsules, each containing a plurality of reservoir particles individually coated with a membrane. Lt; / RTI &gt; The coating may be nonporous but still permeable to tacrolimus (e.g., tacrolimus may diffuse directly through the membrane), or it may be porous. As with other embodiments of the present invention, the specific mechanism of transport is not considered important.

Sustained release coatings known in the art, particularly polymer coatings, such as cellulose esters or ethers, acrylic polymers, or mixtures of polymers, can be used to make the film. Preferred materials include ethylcellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be applied as a solution in an organic solvent or as an aqueous dispersion or a latex. The coating operation can be performed in standard equipment such as a fluidized bed coater, a Wurster coater, or a rotating fluidized bed coater.

If desired, the permeability of the coating may be adjusted by combining two or more materials. A particularly useful method of adjusting the porosity of the coating is by adding a predetermined amount of a finely divided water soluble substance such as a sugar or salt or a water soluble polymer to a solution or dispersion (e.g., an aqueous latex) of the film-forming polymer to be used . When the dosage form is ingested into the aqueous medium of the GI tract, the water-soluble membrane additive leaches out of the membrane leaving a hole to facilitate the release of the drug. As is known in the art, film coatings can also be modified by the addition of plasticizers.

A particularly useful variant of the method of applying a film coating comprises dissolving the coating polymer in a mixture of solvents selected to cause a phase change in the applied coating solution to occur as the coating dries, resulting in a film having a porous structure.

In general, a support for mechanically strengthening the membrane is not required.

The form of the membrane is not critical as long as the permeability characteristics listed herein are satisfied. Membranes are amorphous or measurement quality. The membrane may have any of the categories of form prepared by any particular method and may be, for example, an interfacially polymerized membrane (which includes a thin rate-limiting skin on a porous support), a porous hydrophilic membrane, a porous hydrophobic membrane, Hydrogel membranes, ionic membranes, and other such materials characterized by controlled permeability to tacrolimus.

In one embodiment of the present invention, it is an object to reduce exposure to high concentrations of tacrolimus in the upper GI tract. Thus, suitable dosage forms include those that involve a certain delay prior to the onset of controlled release of tacrolimus. One exemplary embodiment includes a first coating of a polymeric material of the type useful for sustained release of tacrolimus and a core containing tacrolimus coated with a second coating of the type useful for delaying the release of the drug when the dosage form is ingested Can be described by tablets (or particulate materials). The first coating is applied over and surrounding the tablet or individual particles. A second coating is applied over and surrounds the first coating.

Tablets may be prepared by techniques well known in the art and contain therapeutically useful amounts of tacrolimus and the excipients necessary to form tablets by such techniques.

The first coating may be a sustained release coating as is known in the art, particularly a polymer coating to make the film as discussed above for the reservoir system, or it may be a controlled release matrix core coated second with a delayed release material have.

Useful materials for preparing the second coating over the tablet include polymers known in the art as enteric coatings for delayed release of the drug. These are most commonly pH-sensitive substances such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (vinyl acetate phthalate), and acrylic copolymers such as Eudragit L-100 (Rohm Pharma) It is a related substance that is more fully described under "delayed release ". The thickness of the delayed release coating is adjusted to provide the desired retarding properties. In general, thicker coatings are more resistant to erosion and consequently produce longer and more effective delays. Preferred coating thicknesses range from about 30 [mu] m to about 3 mm.

When hydrophobic matrix materials such as glyceryl monostearate are used, delayed coatings are not required. The tablets do not release tacrolimus until they reach the enzyme degradation site, more specifically after the duodenum has passed.

When ingested, the twice coated tablets pass through the stomach, and the second coating from above prevents the release of tacrolimus under predominantly acidic conditions there. When the tablet goes through the stomach and enters the higher intestine, the second coating erodes or dissolves depending on the physico-chemical properties of the selected material. Once the second coating is eroded or dissolved, the first coating prevents immediate or rapid release of tacrolimus and minimizes side effects by controlling release and preventing the occurrence of high peak concentrations.

A further preferred embodiment is the use of a polymer designed to produce sustained release of tacrolimus first and a polymer coated with a polymer designed to delay the onset of release in the environment of the GI tract when the dosage form is ingested, Each particle comprises a multiparticulate coated as described above with respect to the tablet.

The rate of tacrolimus release from the sustained release coated multiparticulates (i.e., the multiparticulates prior to receiving the delayed release coating) and the method of controlling the coating are also controlled by the factors discussed above with respect to the reservoir system tacholimase multiparticulates.

The second film or coating for the double coated multiparticulates is a delayed release coating applied over the first sustained release coating as described above with respect to the tablet and can be formed from the same material. It should be noted that the use of so-called "intramuscular" materials to practice this embodiment is quite different from the use for preparing conventional enteral dosage forms. The purpose of conventional enteral forms is to delay the release of the drug until the dosage form passes over the stomach and then deliver the dose in the duodenum. However, due to side effects sought to be minimized or avoided by the present invention, direct and complete administration of tacrolimus to the duodenum may not be desirable. Therefore, when conventional enteric polymers are used to practice this embodiment, it may be necessary to apply polymers that are significantly thicker than in conventional practice, in order to delay drug release until the dosage form reaches the lower GI tract have. However, also the sustained or controlled delivery of tacrolimus may take place after the delayed release coating has been dissolved or eroded, and therefore the benefits of this embodiment may be realized by proper combination with the sustained release feature of the delayed release feature And the delayed release fraction alone does not necessarily follow the USP intestinal standards. The thickness of the delayed release coating is adjusted to provide the desired retarding properties. In general, thicker coatings are more resistant to erosion and consequently produce longer delays.

The first delayed release embodiment according to the present invention is a "pH-dependent coated dosage form ", such as, for example, a tablet or capsule. In the case of tablets it comprises, for example, a tablet core comprising tacrolimus in a solid solution / dispersion as a multiparticulate product and a controlled release matrix of, for example, HPMC, a disintegrant, a lubricant, and one or more pharmaceutical carriers, The core is coated with a material, preferably a polymer, which is highly insoluble and impermeable at the pH above and is more soluble and permeable at the pH of the small intestine. Preferably, the coating polymer is highly insoluble and impermeable at pH < 5.0 and is water soluble at pH > 5.0. It is ensured that the release of tacrolimus from the dosage form does not substantially occur until the dosage form goes out and stays in the small intestine for about 15 minutes or more, preferably for about 30 minutes or more, and thus minimally releases tacrolimus in the duodenum The tablet cores may be coated with a sufficient amount of polymer. Mixtures of pH-sensitive polymers and water-insoluble polymers may be used. The tablets are coated with an amount of polymer that constitutes from about 10% to about 80% of the weight of the tablet core containing tacrolimus. Preferred tablets are coated with an amount of polymer that constitutes from about 15% to about 50% of the weight of the tacrolimus tablet core.

The pH-sensitive polymers which are highly insoluble and impermeable at the pH above, but which are more soluble and permeable at the pH of the small intestine and the colon are polyacrylamides, phthalate derivatives such as the acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose esters Hydroxyethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinylacetate phthalate, polyvinylacetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, hydroxyethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, Styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene and maleic acid copolymer, Polyacrylic acid derivatives such as acrylic acid and acrylic ester 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, especially cellulose acetate phthalate, polyvinylacetate phthalate and hydroxypropylmethylcellulose phthalate; Polymethyl methacrylate combined with polyacrylic acid derivatives, especially acrylic acid and acrylic ester copolymers; And vinyl acetate and crotonic acid copolymers.

After the "pH-Dependent Coated Tablet" dosage form leaves the top, the pre-release delay time of tacrolimus can be controlled by the choice of the relative amounts of Eudragit-L® and Eudragit- have. The Eudragit-L® membrane at pH> 6.0 dissolves the Eudragit-S® membrane at> 7.0 and the mixture dissolves at its intermediate pH. Since the duodenum has a pH of about 6.0 and the pH of the colon is about 7.0, a coating consisting of a mixture of Eudragtt-L® and Eudragit-S® provides protection from tacrolimus in the duodenum. Dew et al. , It is desirable to delay the release of tacrolimus until the "pH-dependent coated tablet &quot; containing tacrolimus reaches the colon, as described by Br J. Clin. Pharmac. 14 (1982) 405-408 , Eudragit-S® may be used as the coating material. In order to delay the release of tacholimus for more than about 15 minutes, preferably more than 30 minutes, after the dosage form has gone out, the preferred coating is about 9: 1 to about 1: Eudragit-L® / Eudragit-S® of about 9: 1 to about 1: 4, and more preferably Eudragit-L® / Eudragit-S® of about 9: 1 to about 1: The coating may comprise from about 3% to about 70% of the weight of the uncoated tablet core. Preferably, the coating comprises from about 5% to about 50% of the weight of the tablet core.

Usage

Solid dispersions and / or solutions may be formulated for sustained release solid oral dosage forms such as tablets, capsules or sachets; Or granules, pellet microspheres or nanoparticles.

A further advantage of the sustained release dosage forms of the invention is the possibility of obtaining an effective therapeutic response at a reduced dosage compared to traditional oral treatment. Thus, the solid dosage forms of the present invention can comprise up to about 85% w / w or less of the dose of tacrolimus administered in the form of Prograf or similar commercial tacrolimus-containing product, such as up to about 80% w / w, 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% When administered orally to the mammal in need, it is considered to be essentially bioequivalent to Prograf® or similar commercial tacrolimus-containing products.

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

Tacrolimus is recommended (or recommended) for the treatment of, for example, diseases such as: an organ or tissue such as heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, , Rejection by transplantation of organs, myoblasts, and cartilage; Graft versus host response after bone marrow transplantation; Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, severe muscle weakness, type I diabetes mellitus and the like; An infection caused by a pathogenic microorganism (e.g., aspergillus fumigatus, fusarium oxysporum, tricophytone asteroid, etc.); Inflammatory or hyperplastic inflammatory skin disease or skin findings (e.g., psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, squamous cell palsy, pemphigus vulgaris, bullous pemphigoid, vesicular epidermolysis, urticaria, Edema, vasculitis, erythema, dermal eosinophilia, systemic lupus erythematosus, acne and alopecia areata); (Including keratoconjunctivitis, conjunctivitis conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpes keratitis, keratoconjunctivitis, corneal epithelial dystrophy, corneal alveolus, pemphigus, muller's corneal ulcer, scleritis, Grave's ophthalmopathy, - Koyanagi-Harada syndrome, dry corneal conjunctivitis (dry eye), flicker tenuin, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, etc.); Bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, and dust asthma), especially chronic or intractable asthma (such as late asthma and airways hypersensitivity); Mucosal or vascular arthritis (e.g., gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel disease, bowelitis, necrotizing enterocolitis, bowel damage associated with thermal burns, leukotriene B4-mediated disease); Intestinal inflammation / allergy (e.g., celiac disease, rectalitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis); Food-related allergic diseases (eg, migraine, rhinitis and eczema) with distant symptomatic features in the gastrointestinal tract; Renal diseases (e.g., interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, and diabetic nephropathy); Neurodegenerative diseases such as multiple myositis, Guillain-Barré syndrome, Meniere's disease, multiple neuritis, mononeuritis, cerebral infarction, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and neuromuscular disease; Cerebral ischemic diseases such as head injury, intracerebral hemorrhage (e.g. subarachnoid hemorrhage, intracerebral hemorrhage), cerebral hemorrhage, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA), hypertensive encephalopathy, ); Endocrine disorders (e.g., hyperthyroidism, and bassadoes disease); Hematopoietic diseases such as pure erythrocyte anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, malignant anemia, macroscopic hemorrhagic anemia, and aneritroplasia; Bone disease (e.g., osteoporosis); Respiratory diseases (such as sarcoidosis, pulmonary fibrosis, and idiopathic interstitial pneumonia); Skin diseases such as skin myositis, psoriatic alopecia, psoriasis, photosensitivity, and skin T-cell lymphoma; Cardiovascular diseases (such as arteriosclerosis, atherosclerosis, aortitis syndrome, nodular polyarteritis and cardiomyopathy); Collagen diseases (e.g., skin sclerosis, Wegener's granulomatosis, and Sjogren's syndrome); Lipemia; Eosinophilic fasciitis; Periodontal disease (e.g., damage to the gums, tissues surrounding the teeth, alveolar bone, or pubic bone); Nephrotic syndrome (e.g., glomerulonephritis); Male pattern alopecia, senile alopecia; Muscle regressive atrophy; Encephalopathy and Trigeminal Syndrome; A chromosomal aberration related disorder (e.g. Down's syndrome); Edison's disease; An ischemic stroke disorder of an organ that is associated with an active oxygen-mediated disease [e.g., an organ trauma (e.g., preservation, an organ associated with a transplant (e.g., heart, liver, kidney, digestive tract, etc.), or an ischemic disease such as thrombosis, myocardial infarction ))]; Intestinal disorders (e.g., endotoxic shock, false gauge colitis, and drug or radiation-induced colitis); Renal diseases (e.g., ischemic acute renal failure, chronic renal failure); Lung diseases (e.g., addiction caused by lung oxygen or drugs (e.g. paracort, bleomycin, etc.), lung cancer and emphysema); Ocular diseases such as cataracts, iron deficiency (ocular hypertension), retinitis, pigmented degeneration, senile plaques, vitreous scarring, corneal alkali burns; Dermatitis (e.g., polymorphic erythema, linear immunoglobulin A, hypersensitivity dermatitis, cement dermatitis); And diseases caused by other diseases such as gingivitis, periodontitis, sepsis, pancreatitis, and environmental pollution (e.g., air pollution), aging, carcinogens, metastasis of carcinoma, and altitude sickness); A disease caused by histamine release or leukotriene C4 release; Prevention of coronary artery restenosis and postoperative adhesion after angioplasty; The present invention relates to a method for the treatment and prophylaxis of autoimmune diseases and inflammatory conditions such as primary mucosal edema, autoimmune atrophic gastritis, early menopause, male infertility, pediatric diabetes, pemphigus pemphigus, pemphigus, sympathetic ophthalmia, Idiopathic sclerosis, lupus erythematosus, autoimmune testis, arthritis (e. G., Arthritis), or multiple chondritis); Human immunodeficiency virus (HlV) infection, AIDS; Allergic conjunctivitis; Keloids and hypertrophic scars due to trauma, burns, or surgery.

Also, for example, tricyclic macrolides, such as tacrolimus, have activity to stimulate liver regeneration activity and / or hypertrophy and hyperproliferation of hepatocytes. Therefore, the sustained release dosage forms of the present invention are useful for the treatment of a wide variety of conditions, including liver disease (e. G., Immunological diseases such as chronic autoimmune liver diseases such as autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis), partial hepatectomy, (Eg, necrosis caused by toxins, viral hepatitis, shock, or anoxia), hepatitis B, non-A type non-B hepatitis, liver cirrhosis and hepatic insufficiency (such as fulminant hepatitis, Acute "hepatic failure (acute hepatic dialysis of chronic liver disease))). &Lt; / RTI &gt;

In addition, the sustained release dosage forms according to the present invention are useful for increasing the effectiveness of the prevention and / or treatment of various diseases, including the beneficial pharmacological activity of the tricyclic macrolide, such as the activity of increasing the chemotherapeutic effect, Activity, anti-inflammatory activity, inhibitory activity against peptidyl-prolyl isomerase or rotamase, anti-malarial activity, anticancer activity and the like.

The invention is further illustrated by reference to the following examples. It should be noted, however, that the following embodiments are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

Example

Materials and methods

matter

Tacrolimus (supplied by Eurotrade); Batch No. RD 03-111

Lactose monohydrate 200 mesh (DMV)

Granular silicic acid, Aeroperl 300 (Degussa)

Polyethylene glycol 6000, Pluracol 占 E6000 (BASF)

Poloxamer 188, Pluronic® F-68 (BASF)

Glyceryl monostearate, Rylo (R) MD50 (Danisco Cultor), Ph. Eur .; Batch number 4010056276

Avicel PH200 (Microcrystalline Cellulose) (FMC)

Lactose DCL 11 (DMV)

Magnesium stearate

Croscarmellose sodium, Ac-Di-Sol (FMC)

Eudragit (R) L30D.55 (Degussa)

Triethyl citrate (Merck)

Anti-bubble emulsion (Unikem)

Fine talc

HPMC refers to Metolose 90SH (type 2910, 2208) or Metolose 60SH (type 2910) available from ShinEtsu at various degrees of polymerization (viscosity 3-100,00OcP).

Tablets, capsules or granules may be prepared using different types of polymers such as hydroxypropylmethylcellulose acetate succinate (Aqoat), cellulose acetate phthalate CAP, hydroxypropylmethylcellulose phthalate HPMCP, or methacrylic acid copolymers such as Eudragit L30D, Eudragit 100 / S , &Lt; / RTI &gt; Eudragit 100 / L.

Comparative Prior Art for In Vivo Studies Tacrolimus Formulation :

Prograf® hard gelatin capsules (manufactured by Fujisawa Ireland Ltd.)

Ingredient mg

Tacrolimus, anhydrous 1.0

Gelatin 6.9

Hypromellose 1.0

Lactose monohydrate 24.7

Magnesium stearate 0.3

Shellac suitable amount

Soy lecithin suitable amount

Red iron oxide (E172) Appropriate amount

Titanium dioxide (E171) Appropriate amount

Dimeticone (E900) Appropriate amount

Way

Measurement of weight variation

For the tablets prepared in the examples herein, Eur. Were subjected to the test for the weight variation according to the weight change.

Measurement of average refined hardness

Tablets made in the Examples herein were tested for tablet hardness according to the general instructions for the device using a Schleuniger Model 6D device for tablets.

Measurement of decay time

The time at which the tablet disintegrates, that is, decomposes into particles or aggregates, Eur. .

Geometric weight average diameter d _gw  of  Measure

The geometric weight average diameter was measured using a laser diffraction method in which the obtained particulate material (or starting material) was dispersed in air. Measurements were made at 1 bar dispersion pressure in a Sympatec Helos instrument recording equivalent spherical diameter distributions. The distribution was fitted to a log-normal volume-size distribution.

As used herein, "geometric weight average diameter" means the average diameter of the log normal volume-size distribution.

In vitro  Dissolution test

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

Test 1:

In vitro dissolution test according to USP method A, delayed release product (USP paddle method; rotation speed: 50 rpm; 37 캜; after 2 hours in acid medium, medium is replaced with phosphate buffer pH 6.8).

Test 2:

In vitro dissolution test in an aqueous dissolution medium adjusted to pH 4.5 (900 ml water containing 0.005% HPC (hydroxypropylcellulose) adjusted to pH 4.5; 37 캜; USP paddle method; rotation rate: 50 rpm) .

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

Pharmaceutical compositions and dosage forms that can be optimized to provide a preferred release profile in accordance with the present invention are illustrated in Examples 1-16 and the formulations are disclosed in patent application WO 2005/020993, . However, the dissolution profile described above and in Example 17 of the present application may be further optimized to provide a release profile that meets the sustained parameters according to the present invention. Optimization can include changes in the grade of the excipient, formulation changes including changes in the ratio of excipients, manufacturing variations such as changes in punch pressure, changes in hardness or decay time. As molecular solutions are preferred, suitable changes include the use of certain excipients which tend not to interact with the active substance and / or its degradation products, as well as the use of excipients to prevent the breakdown of the active substance.

Example 1

Of hydroxypropyl cellulose Swelling  Modulated release based on aqueous colloidal matrix Poly - Depot ( poly - depot ) capsule

Tacrolimus was dissolved at 70 DEG C in polyethylene glycol 6000 and Poloxamer 188 (70:30 w / w ratio). The solution was sprayed onto a mixture of 150 g lactose and 100 g HPMC in fluidized bed Strea-1. The granulation product was filtered through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

Example 2

Of hydroxypropyl cellulose Swelling  Modulated release based on aqueous colloidal matrix Poly - Depot  capsule

Tacrolimus was dissolved in glyceryl monostearate at 70 &lt; 0 &gt; C. The solution was sprayed onto a mixture of 150 g lactose and 100 g HPMC in fluidized bed Strea-1. The granulation product was filtered through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

Example 3

A sustained-release matrix tablet based on a swellable aqueous colloid matrix of hydroxypropyl cellulose

Tacrolimus was dissolved at 70 DEG C in polyethylene glycol 6000 and Poloxamer 188 (70:30 w / w ratio). The solution was sprayed over 250 g of lactose in the fluidized bed Strea-1. The resulting granulation product was filtered through a 0.7 mm sieve and blended with HPMC and magnesium stearate for 0.5 minute in a Turbula mixer.

The mixture was compressed into 8 mm tablets (200 mg tablets) in a compound cup shape containing 1 mg active ingredient.

Average decay time: 20 minutes. Hardness: 45 N

Example  4

Glyceryl Monostearate Lipophilic  Matrix-based controlled release matrix tablets

Tacrolimus was dissolved in glyceryl monostearate at 70 &lt; 0 &gt; C. The solution was sprayed over 250 g of lactose in the fluidized bed Strea-1. The granulation product was filtered through a 0.7 mm sieve and blended with magnesium stearate for 0.5 minutes in a Turbula mixer.

The resulting mixture was compressed into 8 mm tablets (200 mg tablets) in the form of a complex cup containing 1 mg active ingredient.

Average decay time: 20 minutes. Hardness: 45 N

Example  5

Glyceryl Monostearate Lipophilic  Matrix-based controlled release All Storage capsule

Tacrolimus was dissolved in glyceryl monostearate at 70 &lt; 0 &gt; C. The solution was sprayed over 250 g of lactose in the fluidized bed Strea-1. The granulation product was filtered through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

Example  6

Gelucire ® 44 / 14 of Lipophilic  Matrix-based controlled release Poly - Depot  refine

Tacrolimus was dissolved in Gelucire® at 70 ° C. The solution was sprayed onto 250 g Aeroperl (R) in the fluidized bed Strea-1. The granulation product was filtered through a 0.7 mm sieve and filled into hard gelatin capsules (200 mg).

The obtained granules were compressed into 8 mm tablets (200 mg tablets weight) containing 1 mg active ingredient. The tablets were cup-shaped.

Average decay time: 25 minutes. Hardness: 43 N.

Example  7

Intestinal  coating

To obtain delayed release of the active ingredient after administration, the capsules and tablets of Examples 1, 2, 3, 5 and 6 were subsequently coated with the following enteric coating.

The coating suspensions were prepared by mixing triethyl acetyl citrate, anti-foam emulsion and purified water at 9500 rpm for 30 minutes in an Ultra Turrax device. Talc was added after 1 minute. The mixture was filtered through a sieve no. 300, and stirred with a magnetic stirrer. Eudragit to the body no. 300, and the mixture was added and stirred for 5 minutes.

The process conditions for the coating process were as follows: inlet temperature 40 占 폚, discharge temperature 31 占 폚, 140 cbm per air inlet time, and coating time about 50 minutes (300 g of coating material). Approximately 400 g of tablets or 200 g of capsules were coated.

The film-coated tablets and capsules were cured at 30 캜 for 48 hours before the dissolution test.

Example  8

Glycerol Monostearate Lipophilic  Matrix-based controlled release matrix tablets

Tacrolimus was dissolved in glycerol monostearate at temperatures above 80 &lt; 0 &gt; C. The solution was sprayed over 60 g of lactose and 60 g of HPMC in fluidized bed Phast FB100 by Feed Unit Phast FS 1.7. The granulation product was cured in a heating oven at 50 캜 for 4 hours. The resulting granulation product was filtered through 0.71 mm sieve and blended with lactose for 3 minutes in a Turbula mixer.

Magnesium stearate and talc are added to the column no. 300, and mixed for 3 minutes in a Turbula mixer. The granulate was mixed with the above mixture of magnesium stearate and talc (1: 9) for 0.5 minutes in a Turbula mixer.

The final mixture was compressed into 8 mm tablets (210 mg tablets) in the form of a complex cup containing 2 mg active ingredient.

Mean decay time: 2 hours. Hardness: 50 N

Example  9

PEG  6000 / core based on poloxamer 188 and Eudragit L30D  Coated tablets with enteric coating based on &lt; RTI ID = 0.0 &gt; 55 &

Tablet core composition:

Tacrolimus tablet cores were prepared by dissolving in PEG 6000 at temperatures above 80 &lt; 0 &gt; C. Poloxamer 188 was added and the solution was heated to a temperature above 80 &lt; 0 &gt; C. The solution was sprayed onto 200 g lactose monohydrate in fluid bed Phast FB100 by Feed Unit Phast FS 1.7. The resulting granulate was filtered through Comill sieve 1397, 4500 rpm and blended with croscarmellose sodium for 3 minutes in a Turbula mixer.

Magnesium stearate and talc are added to the column no. 300, and mixed for 3 minutes in a Turbula mixer. The granulate was mixed with magnesium stearate and talc (1: 9) for 0.5 minutes in a Turbula mixer.

The resulting mixture was compressed into a 6 mm tablet (100 mg tablets) in the form of a complex cup containing 2 mg active ingredient.

Mean decay time: 7 minutes. Hardness: 65 N

Enteric coating :

The enteric coating was based on acrylic polymer Eudragit L30D-55. Eudragit L30D was supplied as an aqueous latex suspension which produced a water-insoluble film when water evaporated during coating. The polymer was insoluble at pH-values below 5.0 and was highly soluble at pH-values above 6.0. The film coating composition was as follows:

The amount of applied membrane polymer (Eudragit) was based on the calculation of mg membrane polymer per cm ² tablet surface. The thickness of enteric coating was 80 탆. Verification of the applied film thickness was based on measuring the increase in tablet height with a digital micrometer. A film coating process was performed in a Phast FB100 fluidized bed with Wurster-like inserts. The process conditions were as follows: inlet air temperature 50 캜; 100 m3 per hour of inlet air flow; Product temperature 38 [deg.] C; Feed rate 15 g / min.

After coating, proper film formation required curing of the coated tablets, i. E. Curing in an oven at &lt; RTI ID = 0.0 &gt; 30 C &lt; / RTI &gt; for 48 hours. Alternatively, the coated tablets could be more effectively cured at &lt; RTI ID = 0.0 &gt; 40 C &lt; / RTI &gt; within 24 hours.

Example  10

HPMC  Matrix-based controlled release PEG  6000 / Poloxamer 188 Tablet.

Tablet composition:

Tacrolimus was dissolved in PEG 6000 at a temperature above 80 &lt; 0 &gt; C. Poloxamer 188 was added and the solution was heated to a temperature above 80 &lt; 0 &gt; C. The solution was sprayed onto 200 g lactose monohydrate in fluid bed Phast FB100 by Feed Unit Phast FS 1.7. The granulation product was filtered through Comill, sieve 1397, 4500 rpm and blended with hydroxypropyl methylcellulose for 3 minutes in a Turbula mixer.

Magnesium stearate and talc were filtered through sieve 300 and mixed for 3 minutes in a Turbula mixer. The granulate was mixed with magnesium stearate: talc (1: 9) for 0.5 minutes in a Turbula mixer. The mixture was compressed into 8 mm tablets (165 mg tablets in the form of a cup) having a strength of 2 mg. Mean decay time: 2 hours and 34 minutes. Hardness: 50 N

Example 11

Intestinal  Coated tablet formulations. Wet granulation and Intestinal  Coated tablets

Tablet composition:

The tablet formulation was based on wet granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 640 g of lactose 125 mesh and 80 g of sodium lauryl sulfate in a high shear mixer. A 15% aqueous solution of the binder Kollidon VA64 was pumped into the mixture at an impeller speed of 500 rpm at a feed rate of 20 g / min and kneaded at the same rate for 3 minutes. The granulate was dried in a tray drier and squeezed through a sieve of size 0.7 mm.

The granulate was mixed with 240 g of Avicel PH200 for 3 minutes, added with 4 g of magnesium stearate and then mixed for another 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20.

Tablet diameter: 6 mm. Tablet shape: round, composite cup.

The tablets were then coated with an enteric coating of the acrylic type described in Example 9.

The amount of applied membrane polymer (Eudragit) had to be based on the calculation of mg membrane polymer per cm ² tablet surface. The intestinal coating thickness should be 50-80 탆. Verification of the applied film thickness was based on measuring the increase in tablet height with a digital micrometer. The membrane coating process was carried out in a Stre-1 fluidized bed equipped with a Wurster insert under the following process conditions:

After coating, proper film formation requires curing of the coated tablets, i. E., Curing in an oven at &lt; RTI ID = 0.0 &gt; 30 C &lt; / RTI &gt; Alternatively, the coated tablets could be more effectively cured at &lt; RTI ID = 0.0 &gt; 40 C &lt; / RTI &gt; for 24 hours.

Example 12

Erosion HPMC  Matrix-based controlled release tablet formulations

HPMC was added as part of the extragranular phase. Wet granulation.

Tablet composition:

The tablet formulation was based on wet granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 640 g of lactose 125 mesh and 80 g of sodium lauryl sulfate in a high shear mixer. A 15% aqueous solution of binder Kollidon VA64 was pumped into the mixture at an impeller speed of 500 rpm at a feed rate of 20 g / min and kneaded at the same impeller speed for 3 minutes. The granulate was dried in a tray drier and squeezed through a sieve of size 0.7 mm.

The granulate was mixed with 240 g Avicel PH200 and 480 g hydroxypropyl methylcellulose Metolose SH 90 100 cP for 3 minutes and 8 g magnesium stearate added and mixed for a further 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20.

Tablet diameter: 7 mm. Tablet shape: round, composite cup.

Example 13

Erosion HPMC  Matrix-based controlled release tablet formulations

HPMC was added as part of the intragranular phase. Wet granulation.

Tablet composition:

The tablet formulation was based on wet granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 64.0 g of lactose 125 mesh and 80 g of sodium lauryl sulfate and 640 g of hydroxypropyl methylcellulose Metolose SH 90 15.000 cP in a high shear mixer. Purified water was pumped into the mixture at an impeller speed of 500 rpm at a feed rate of 20 g / min and kneaded for 3 minutes. The granulate was dried in a tray drier and squeezed through a sieve of size 0.7 mm.

The granulate was mixed with 480 g Avicel PH200 for 3 minutes, added with 16 g magnesium stearate and mixed for an additional 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20.

Tablet diameter: 8 mm. Tablet shape: round, composite cup.

Example 14

Erosion HPMC  Matrix-based controlled release tablet formulations

HPMC is added as part of the granular phase. Fusing granulation

Tablet composition:

The tablet formulation was based on melt granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 640 g of lactose 125 mesh and 120 g of polyethylene glycol 6000, 48 g of poloxamer 188 and 640 g of hydroxypropyl methylcellulose Metolose SH 90 15.000 cP in a high shear mixer. The jacket of the mixer bowl was heated to 80 DEG C and the blend was heated to the melting point of PEG and poloxamer at an impeller rotational speed of 1000 rpm. The dough was continued at 800 rpm for 4 minutes after thawing. The granulate was filtered through a 0.7 mm sieve and cooled on a tray. The granulate was mixed with 480 g Avicel PH200 for 3 minutes, added with 16 g magnesium stearate and mixed for an additional 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20. Tablet diameter: 8 mm. Tablet shape: round, composite cup.

Example 15

Granule et al  &Lt; / RTI &gt; Erosion Kollidon SR  Controlled release tablet formulation based on matrix.

Tablet composition:

The tablet formulation was based on wet granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 640 g of lactose 125 mesh and 80 g of sodium lauryl sulfate in a high shear mixer. A 15% aqueous solution of a binder Kollidon VA64 (Kollidon SR is a mixture of polyvinyl acetate and polyvinylpyrrolidone 80:20) was pumped to the mixture at an impeller speed of 500 rpm at a feed rate of 20 g / min, During the kneading. The granulate was dried in a tray drier and squeezed through a sieve of size 0.7 mm. The granulate was mixed with 400 g of lactose DC Lac 14 and 480 g of Kollidon SR for 3 minutes, added with 8 g of magnesium stearate and mixed for a further 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20.

Tablet diameter: 8 mm. Tablet shape: round, composite cup.

Example 16

Intestinal  Coated Tablet formulations (melt granulation and Intestinal  Coated tablets)

Tablet composition:

The tablet formulation was based on melt granulation in a high shear mixer Pellmix 1/8. 16 g of undifferentiated tacrolimus was mixed with 640 g of lactose 125 mesh and 120 g of polyethylene glycol 6000 and 48 g of Poloxamer 188 in a high shear mixer. The jacket of the mixer bowl was heated to 80 DEG C and the blend was heated to the melting point of PEG and poloxamer at an impeller rotational speed of 1000 rpm. The dough was continued at 800 rpm for 4 minutes after thawing. The granulate was filtered through a 0.7 mm sieve and cooled on a tray. The granulate was mixed with 480 g Avicel PH200 for 3 minutes, added with 16 g magnesium stearate and mixed for an additional 0.5 minutes. The mixture was compressed into tablets with a single punch tablet Diaf TM20. Tablet diameter: 7 mm. Tablet shape: round, composite cup. Enteric coatings of the tablets were carried out according to the procedure described in Example 11.

Example 17

In vitro dissolution data

In vitro dissolution tests were performed using two different dissolution media / tests for the composition and dosage form according to the previous examples.

A. Dissolution medium / test: A 900 ml aqueous medium (USP paddle method; rotation speed: 50 rpm) containing 0.005% HPC (hydroxypropyl cellulose) adjusted to pH = 4.5 was used to reveal the following dissolution profile:

Dissolution medium: Dissolution profile for the tablet core of Example 9 in 900 ml aqueous medium containing 0.005% HPC (hydroxypropylcellulose) adjusted to pH = 4.5. USP paddle method. Rotation speed: 50 rpm:

The dissolution profile for enteric coated tablets of Example 9 in a dissolution medium according to a delayed release product, USP Method A. USP paddle method. Rotation speed: 50 rpm:

Example 18

List of safety improvement measures to improve and optimize sustained release tacrolimus formulations containing tacrolimus in solid solution.

The dissolved form of tacrolimus is prone to collapse, and several degradation products may be generated during storage. The stability improvement measures tested to improve the stability of tacrolimus are disclosed in the following list.

Carrier, antioxidant formulations

The following additions

1000 ppm propyl gallate

500 ppm alpha-tocopherol + 500 ppm maintenance

500 ppm ascorbyl palmitate

1000 ppm? -Tocopherol

500 ppm? -Tocopherol

50 ppm? -Tocopherol

1000 ppm ascorbyl palmitate + 1000 ppm? -Tocopherol

500 ppm ascorbyl palmitate + 500 ppm alpha-tocopherol

250 ppm ascorbyl palmitate + 250 ppm alpha-tocopherol

50 ppm ascorbyl palmitate + 50 ppm alpha-tocopherol

Removal of impurities in poloxamer by filtration through AI2O3 (Compalox)

Addition of Dimeticone

Addition of BHT

Addition of organic acids including tartaric acid

A mixture of 0.01% tartaric acid, 0.05% tartaric acid, 0.10% tartaric acid, 0.20% tartaric acid, 0.40% tartaric acid, 0.50% tartaric acid, 0.60% tartaric acid, 0.75% tartaric acid, 1% tartaric acid,

Variations of about 0.15% tartaric acid containing 200 ppm alpha-tocopherol

Tablet, dried with N2 in the following

N2, low heat 65 ° C, low temperature 25 ° C for 4 hours,

N2, low heat 65 ° C Drying at 25 ° C for 24 hours,

N2, low heat 65 ° C 40 ° C for 4 hours at low heating time,

N2, low heat 65 ° C, 40 ° C for 24 hours with low heating time

Tablets, open storage at different controlled humidities,

11% humidity by LiCl

32% humidity by MgCl ₂ ,

48% humidity by K ₂ CO ₃ , 75% humidity by NaCl

89% humidity by KNO ₃

Example 19

Patients with stable kidney and liver transplant From each  The sustained release formulation according to the invention Prograf Clinical studies comparing with

Blood concentration profiles for stable renal patients are shown in Figures 5 and 6.

Research Title:

LCP-Tacro Tablet Phase II, open label, multi-centered omnidirectional, conversion studies in stable kidney transplant patients comparing once daily pharmacokinetics with twice daily Prograf® capsules. LCP-Tacro 1 mg, 2 mg, 5 mg tablets

Active ingredient: tacrolimus.

Instructions: Prograf® was used to prevent rejection of liver, kidney and heart transplants.

Research design and stage of progress: 3-order, open-label, omnivorous, multi-center, transition test (phase II).

Title of the study: LCP-Tacro Tablets One daily pharmacokinetic study of Prograf® Phase II, open label, multidirectionality, and conversion studies in patients with stable renal transplantation compared with capsules twice daily

Purpose: To investigate the effects of tacrolimus exposure (AUC _{O- 24} ) and the lowest level (C ₂₄ ) in a 3-sequence study design on stable renal transplant recipients converted from Prograf® capsules (Tacrolimus, Astellas Pharma US, Inc.) to LCP- To evaluate the stability of LCP-Tacro compared to Prograf.

Main inclusion criteria: 18-65 year old male and female who have received a kidney transplant more than 6 months ago.

Test product / research product and method of administration: LCP-Tacro 1 mg, 2 mg, 5 mg tablets, orally once a day in the morning.

Reference product, serial number and mode of administration: Prograf® 0.5 mg, 1 mg, 5 mg capsules, once daily in the morning and once in the evening, twice daily with two equally divided doses.

METHODOLOGY: Three sequences, open-label, multi-center, and three-dimensional, in a stable kidney transplant patient evaluating and comparing the pharmacokinetics (C _max , C ₂₄ , and AUC) and safety of LCP-Tacro (tacrolimus) tablets versus Prograf® capsules Orientation, Research.

A stable kidney transplant patient who met all inclusion / exclusion (I / E) criteria was enrolled and received Prograf® I continued taking. Following a 24-hour PK study measuring pharmacokinetics on Prograf® on day 7, all patients switched to LCP-Tacro (ratio 1: 0.66-0.80) once daily for 7 days, which did not allow dose changes . A 24-hour LCP-Tacro PK study was performed on day 14. For each individual patient, 10 ± 1, 12 ± 1 (separated by more than 48 hours from the previous sample) compared to the three lowest level averages measured at 0, 7, and 8 days and 3 When the lowest mean level changed by more than 25%, one scheduled dose change was allowed on day 15.

During another seven days that did not allow dose changes, the patient maintained the dose measured at day 14. At day 21, another 24-hour LCP-Tacro PK study was performed. On day 22, the patient switched back to twice the original dose of Prograf® and terminated the safety assessment on day 52 after a 30-day safety-follow-up period. Ten patients completed an intermediate PK analysis before continuing enrollment after completing day 21.

Blood sampling time: The following blood samples were collected during this study:

For LCP-Tacro: Blood sample extraction time points include: 0.001 (before dosing), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 14.00 , 16.00, 20.00 and 24.00.

For Prograf®: Blood sample extraction times include: On day 7, 0.00 (before dosing), 0.50, 1.00, 1.50, 2.00, 3.00, 4.0O1 6.00, 8.00, 12.00, 12.50, 13.00 , 13.50, 14.00, 15.00, 16.00, 20.00 and 24.00.

Evaluation criteria: Pharmacokinetic analysis was performed on 47 patients. All patients who received more than one dose during the course of the study received a safety assessment.

(PK): The following pharmacokinetic parameters for tacrolimus were calculated by the standard non-compartment method: AUCτ (τ = 24), C _max , C _min , C _average , T _max ,% fluctuation,% fluctuation and C _max / C _Minimum .

Statistical methods: All demographic data, pharmacokinetic parameters, laboratory data and AE were summarized using descriptive statistics. For continuous data, mean, standard deviation, median, min and max values were reported. For nomadic data, we reported the percentage and frequency.

It was calculated for the non-compartment pharmacokinetic parameters from the time data [AUCτ (τ = 24), C _max, C _{minimum, average} C, T _max] - blood level.

Statistical methods: ANOVA for the natural log (ln) transformed parameters AUCτ, C _max , C _min and C _mean and non-transformed parameter% variation,% variation, and C _max / C _min using the GLM procedure in SAS . The model included treatment as an argument. The ratio of geometric LSM to 90% CI was calculated according to the following three comparisons for AUC, C _max, and C _min :

Day 14 vs. Prograf Day 7 LCP-Tacro

Day 21 vs. Prograf Day 7 LCP-Tacro

Day 21 LCP-Tacro vs. Day 14 LCP-Tacro.

The parameter T _max was analyzed using a non-parametric method. A Wilcoxon signed rank test was used for comparison of treatments by pair. Mean shifts (as described above) between the two treatments were estimated by median deviation non-biased Haggis-Lehmann estimates and 90% accurate confidence intervals.

The data for the 7th, 14th, and 21st days were tabulated and the correlation coefficient was calculated to quantify the degree of correlation between AUCτ and C _minima . Both of the two parameters were internally transformed before correlation analysis. A statistical analysis was performed on the subgroups (black vs non-black) because the appropriate divisions were obtained between the two groups.

Summary of pharmacokinetic results:

Pharmacokinetic parameters for tacrolimus in all patients:

Summary of pharmacokinetic results (continued from above):

Pharmacokinetic parameters for tacrolimus in black patients:

Pharmacokinetic Parameters for Tacrolimus in Non-Black Patients:

Summary of pharmacokinetic results (continued from above):

Evaluation of comparative bioavailability on day 14 vs. day 7 of tacrolimus in all patients:

Evaluation of comparative bioavailability on day 21 vs. day 7 of tacrolimus in all patients:

Evaluation of relative bioavailability of Tacrolimus at day 21 vs. day 14 in all patients:

Correlation between AUCτ and C _minima for tacrolimus:

conclusion:

The main objectives of this study were to determine the steady state tacrolimus exposure (AUCτ) and the lowest level (C _min ) of a recipient of a stable kidney transplant switched from Prograf® (tacrolimus, Astellas Pharma US, Inc.) to LCP-Tacro To evaluate.

Post dose modification, a steady-state systemic exposure (AUCτ) and the lowest level of tacrolimus from tacrolimus (C _min) is the LCP-Tacro tablets once daily administration in comparison with the therapy according to the twice Prograf® capsule 1 in a kidney transplant patient Were significantly higher. Systemic exposures (AUCτ and C _minima ) of LCP-Tacro 2 mg tablets (once daily) for 24 hours were ~ 38% and ~ 36% higher than for Prograf® capsules (twice daily). The mean concentration (C _mean ) of the drug during this interval was significantly higher for LCP-Tacro therapy compared to Prograf®.

There was also no statistically significant difference in the maximal systemic exposure (C _max ) of tacrolimus when LCP-Tacro was given on days 14 and 21 and between Prograf® therapies. In addition, treatment with Prograf® showed significantly higher degrees of variability and variability than LCP-Tacro. There was a greater correlation between AUCτ and C _{minima on} days 14 and 21 (LCP-Tacro therapy) compared to Prograf® (day 7), but the magnitude of the difference was not significant. There was no significant difference in overall systemic exposure, lowest tacrolimus level or degree of variability and variability when LCP-Tacro was given on day 14 compared to day 21 case.

A subgroup analysis of black versus non-black subjects treated with Prograf® or LCP-Tacro showed statistically significant differences in tacrolimus levels as well as peak and systemic exposure of tacrolimus, suggesting the need for attention It implies.

The results of this study showed that LCP-Tacro therapy significantly reduced systemic exposure to tacrolimus and lower levels of tacrolimus in stable state compared to Prograf® therapy in patients with stable renal transplantation after conversion from Prograf to LCP-Tacro Fluctuation and fluctuation. In addition, the highest exposure of tacrolimus was similar compared to the different treatments, but the mean concentration during the dosing interval was higher for LCP-Tacro.

DISCUSSION AND CONCLUSIONS: The main objective of this study was to investigate the effects of steady-state tacrolimus exposure (AUCτ) and minimum levels of tacrolimus exposure in stable kidney transplant recipients converted from Prograf® (tacrolimus, Astellas Pharma US, Inc.) to LCP- Level (C _min ).

Post dose modification, a steady-state systemic exposure (AUCτ) and the lowest level of tacrolimus from tacrolimus (C _min) is the LCP-Tacro tablets once daily administration in comparison with the therapy according to the twice Prograf® capsule 1 in a kidney transplant patient Were significantly higher. Systemic exposures (AUCτ and C _minima ) of LCP-Tacro 2 mg tablets (once daily) for 24 hours were ~ 38% and ~ 36% higher than for Prograf® capsules (twice daily). The mean concentration (C _mean ) of the drug during this interval was significantly higher for LCP-Tacro therapy compared to Prograf®.

In addition, there was no statistically significant difference in the maximal systemic exposure (C _max ) of tacrolimus when LCP-Tacro was given on days 14 and 21 and between Prograf® therapies. In addition, treatment with Prograf® showed significantly higher degrees of variability and variability than LCP-Tacro. There was a greater correlation between AUCτ and C _{minima on} days 14 and 21 (LCP-Tacro therapy) compared to Prograf® (day 7), but the magnitude of the difference was not significant. There was no significant difference in overall systemic exposure, lowest tacrolimus level or degree of variability and variability when LCP-Tacro was given on day 14 compared to day 21 case.

A subgroup analysis of black versus non-black subjects treated with Prograf® or LCP-Tacro showed statistically significant differences in tacrolimus levels as well as peak and systemic exposure of tacrolimus, suggesting the need for attention It implies.

The results of this study showed that LCP-Tacro therapy significantly reduced systemic exposure to tacrolimus and lower levels of tacrolimus in the stable state compared to Prograf® therapy in patients with stable renal transplantation after conversion from Prograf to LCP-Tacro Fluctuation and fluctuation. In addition, the highest exposure of tacrolimus was similar compared to the different treatments, but the mean concentration during the dosing interval was higher for LCP-Tacro.

Study of stable liver transplant patients

Administration of tacrolimus in male and female stable liver transplant recipients on days 7, 14, and 21 Summary statistics of unmodified pharmacokinetic parameters

* Geometric mean (% CV)

N = 56 on day 21, N = 57 on day 7 and day 14

^Λ tau = 24 hours

Day 7 - Prograf® capsules Oral administration twice daily

Day 14 - LCP-Tacro Tablets Oral administration once daily

Day 21 - LCP-Tacro Tablet Once daily oral administration

-------------------------------------------------- ---------------------------

Comparison of Unadjusted Pharmacokinetic Parameters of Administration of Tacrolimus in Male and Female Patients Between Days 7 and 14

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 14 - LCP-Tacro Tablets Oral administration once daily

Day 7 - Prograf® capsules Oral administration twice daily

-------------------------------------------------- ---------------------------

Comparison of Uncorrected Pharmacokinetic Parameters of Administration of Tacrolimus in Male and Female Patients Between Days 7 and 21

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 21 - LCP-Tacro Tablet Once daily oral administration

Day 7 - Prograf® capsules Oral administration twice daily

One

-------------------------------------------------- ---------------------------

Comparison of Uncorrected Pharmacokinetic Parameters of Administration of Tacrolimus in Male and Female Patients between Days 14 and 21

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 21 - LCP-Tacro Tablet Once daily oral administration

Day 14 - LCP-Tacro Tablets Oral administration once daily

-------------------------------------------------- ---------------------------

Summary of the modified pharmacokinetic parameters of administration of tacrolimus in male and female stable liver transplant recipients on days 7, 14 and 21

* Geometric mean (% CV)

^Λ tau = 24 hours

Day 7 - Prograf® capsules Oral administration twice daily

Day 14 - LCP-Tacro Tablet Once daily oral administration Day 21 - LCP-Tacro Tablet Once daily oral administration

-------------------------------------------------- ---------------------------

Comparison of Modified Pharmacokinetic Parameters of Administration of Tacrolimus in Male and Female Patients Between Days 7 and 14

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 14 - LCP-Tacro Tablets Oral administration once daily

Day 7 - Prograf® capsules Oral administration twice daily

-------------------------------------------------- ---------------------------

Comparison of modified pharmacokinetic parameters of administration of tacrolimus in male and female patients between days 7 and 21

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 21 - LCP-Tacro Tablet Once daily oral administration

Day 7 - Prograf® capsules Oral administration twice daily

-------------------------------------------------- ---------------------------

Comparison of modified pharmacokinetic parameters of administration of tacrolimus in male and female patients between day 14 and 21

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data.

** Calculated using the geometric mean according to the following equation:

e ((test drug) - (reference drug)) × 100%.

*** Coefficient of variation for log-transformed pharmacokinetic parameters.

Day 21 - LCP-Tacro Tablet Once daily oral administration

Day 14 - LCP-Tacro Tablets Oral administration once daily

As shown in the results of stable liver transplant patients, the following were obtained: about 31% improvement in bioavailability; A decrease of about 30 doses to achieve bioequivalence for AUC _(0-24) and C _{(at least 24 )} ; Decreased C _max : C _min ratio and higher AUC: C _min correlation.

Example 20

Commercially available 1 day  Sustained release for single administration Tacrolimus  Formulation Advagraf ® and the formulation according to the invention ( LCP - Tacro )

The main objective of this study was to evaluate the efficacy of LCP-Tacro 2 mg tablets administered once daily (once a day) under multi-dose, fasting conditions, using the Advagraf® 2 × 1 mg capsules (once daily) To measure and compare the rate and extent of absorption of tacrolimus.

Advagraf® is manufactured by Astellas Pharma GmbH (Munich, Germany).

Research Outline

PK: PK parameters were calculated using non-compartmental analysis for tacrolimus as follows:

Day 1: AUC _0-24 , C _max , C _24, and T _max .

Claim 10 il: AUCτ (τ = 24), C _max, C _minimum, C _average, T _max, T _1/2, Kel,% change,% volatility, AUCτ / C _minimum, C _max / C _min and the accumulation ratio ( R).

Statistic: Technical statistics were calculated for blood concentration and for all PK parameters. AUC _{0 - 24} , AUCτ, C _max , C ₂₄ , C _min , C _average, and the _mean log (In) transformed parameters of the geometric least squares mean (LSM) and the 90% confidence interval (CI) was calculated for the non-transformed parameter% change,% variation, R, C _max / C _{at least,} AUCτ / C _minimum, Kel and T _1/2. T _max was analyzed using a non-parametric method.

According to the results thus obtained, the product according to the present invention exhibits significantly higher bioavailability, with absorption of much more extended drug of almost 50%, much lower concentration of fluctuations during the administration period and until the end of the administration interval It should be noted that a true once-a-day effect is obtained by the product according to the invention, with a profile indicating a high concentration, and that any toxicity or side effect associated with the period of time in which a high concentration occurs is possible to the extent possible by the oral once-daily formulation Removed. The present invention provides formulations that provide an average concentration of greater than 4 ng / ml (with a C _min of less than 4.66 ng / ml provided as a result) over the entire 24 hour period by 2 mg oral administration in the morning, Is considerably higher than when the same daily dose of the commercially available product Advagraf® (C _minimum 2.80 ng / ml) is administered at the same dose.

Pharmacokinetic Parameters for Tacrolimus in Healthy White Male Subjects for Day 1, Treatment A

Treatment A: 1 LCP-Tacro 2 mg tablets (once daily)

Pharmacokinetic Parameters for Tacrolimus in Healthy White Male Subjects on Day 1, Treatment B

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

On day 10, pharmacokinetic parameters for tacrolimus in healthy white male subjects for treatment A

Tau = 24 hours

Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

On day 10, pharmacokinetic parameters for tacrolimus in healthy white male subjects for treatment B

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Comparison of T _max for tacrolimus in healthy white male subjects between days 1 and 10 for treatment A and B

Table 20-5:

* Hotjis - 90% accurate CI for Lehman points estimates and treatment differences.

** p-value for treatment comparison based on Wilcoxon-Man-Whitney test.

Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Summary statistics and comparison of pharmacokinetic parameters for tacrolimus in healthy white male subjects between Day 1, Treatment A and B

* Geometric mean (% CV) ** median (range)

Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Summary statistics and comparison of pharmacokinetic parameters for tacrolimus in healthy white male subjects between Day 1, Treatment A and B

1. Using the log-transformed data, the 90% geometric confidence interval

2. Calculated using the geometric mean according to the formula: e ((test drug) - (reference drug)) × 100%

3. The coefficient of variation in the subject for log-transformed pharmacokinetic parameters

Test: Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

See: Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Summary statistics and comparison of pharmacokinetic parameters for tacrolimus in healthy white male subjects between Day 10, Treatment A and B

* Geometric mean (% CV)

Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Summary statistics and comparison of pharmacokinetic parameters for tacrolimus in healthy white male subjects between Day 10, Treatment A and B

^Λ tau = 24 hours

* 90% geometric confidence interval using log-transformed data

** Calculated using the geometric mean according to the formula: e ((test drug) - (reference drug)) × 100%

*** Coefficient of variance within the subject for log-transformed pharmacokinetic parameters.

Treatment A: 1 LCP Tacro 2 mg tablets (once daily)

Treatment B: 2 Advagraf® 1 mg capsules (once daily)

Example 21

Table showing the dissolution of the preferred embodiment of the present invention having the composition shown in Example 20 above and the dissolution of the product Advagraf® used for comparison in Example 20.

Release measured in percent, with a medium adjusted to pH 4.5 and containing 0.005% hydroxypropyl cellulose and a dissolution method USP II dissolution test (paddle) method at a rotation of 50 rpm. The dissolution is shown in Fig.

As shown in this dissolution, the sustained release formulations according to the present invention provide a much longer and more extended profile with significantly lower release initially, for example 5 hours Lt; RTI ID = 0.0 &gt; 25% &lt; / RTI &gt; In addition, the curved profile according to the present invention has substantial quadrature emission and very extended emission. Extremely extended release is evidenced by less than 50% release at 12 hours and less than 62% release at 15 hours. As shown in Example 20, the pharmacokinetic parameters are significantly improved over the sustained release formulations according to the present invention compared to the commercial Advagraf® product.

In addition, the sustained release formulations according to the invention can be provided in tablets much smaller than Advagraf®, as shown in the table below.

Example 22

New kidney transplant In patients  Sustainable Tacrolimus

New renal transplant patients were randomized (1: 1 ratio) within 12 hours after transplantation (Study Day 0) to receive either: 1) LCP-Tacro tablets (dissolution shown in Example 21 and Example 20 (The starting daily dose for black patients was 0.17 mg / kg), followed by oral administration in the morning once a day, with an interval of 24 +/- 1 hour, 0.14 mg / kg, Or 2) Prograf capsules were divided into two equally divided doses starting at 0.1 mg / kg every 12 hours (0.2 mg / kg total daily dose) Prescribing Information (Astellas Pharma US, April 2006, NDA no. 050708). A 24-hour pharmacokinetic (PK) evaluation was performed on Study Days 1, 7 and 14. Study day 1 was defined as the day when the first morning (AM) administration of the study drug was given, and the transplantation should be within 48 hours. The results are shown in Table 22.

Table 22.

Transplantation after the first day, the AUC _{0 -τ} for LCP-Tacro significantly lower than AUC _{0 -τ} for Prograf® (Claim 1, 2005 the administration of unmodified LCP-Tacro AUC _{0 -τ} is 131.11 ± 76.78 versus 253.45 ± 106.58 (ng · hour / ml)). However, this is considered to be an advantage for the reduction of early hyperimmunosuppression, especially when the patient has received induction therapy and corticosteroids. According to the present invention, a target between the values of 5-10 ng / ml (immunoassay method) as compared with the sustained release formulations according to the invention is considered as the optimal treatment. Preferably mycophenolate mofetil (CellCept®) NDA no. 050722 and 050723 or equivalent doses of mycophenolic acid, such as Myfortic (R) NDA no 050791 (inclusive of transcription).

Examples of immunoassays for tacrolimus minimum value measurements:

In the following table (Table 23) a higher proportion of patients appears to obtain a target minimum concentration of 5-10 ng / ml according to the present invention.

The following table also shows that about two-thirds of patients treated with LCP-Tacro after the first administration of LCP-Tacro are within the range of 5-7 ng / ml and more than 80% of patients treated with LCP-Tacro by day 3 Lt; RTI ID = 0.0 &gt; ng / ml. &Lt; / RTI &gt;

Example 23

Clinical studies with sustained release formulations according to the invention

Table A

Table A lists initial clinical studies with sustained release formulations according to the present invention. The following list includes the improved pharmacokinetic parameters obtained by the sustained release formulations according to the invention claimed herein.

The plasma profiles from the studies shown in Tables A and B are shown in FIG.

Single dose, comparative PK study (Study 002):

A single dose comparative pharmacokinetic study of Study 002, LCP-Tacro 4 mg (2 × 2 mg tablets) versus Prograf® 4 mg (4 × 1 mg capsules) showed similar AUCs for all of the above products when administered under fasting conditions. However, they had different rates of absorption when administered in fasting conditions and the test formulation LCP-Tacro was slower and more persistent. Lower C _max (10.05 ng / ml vs. 32.75 ng / ml) and lower AUC _{(0-> 24)} (122.4 ng / ml) of LCP-Tacro tablets (test; HPMC) compared to Prograf® capsules (tacrolimus; The longer T _max (8.55 versus 1.63 h) combined with the hour / ml versus 157.95 ng * hour / ml supports once-daily administration of LCP-Tacro tablets over Prograf® capsules (tacrolimus).

Study 003:

Study 003 was designed as a repeat-validated cytotoxic absorption study in eight healthy volunteers to assess retention time, pharmacokinetic profile and release site of the radiolabeled LCP-Tacro 2 mg tablet at up to 1 MBq 153Sm. In this study, a sustained profile can be demonstrated with a T _max of ~ 6.7 hours. LCP-Tacro was well tolerated. Overall, the study demonstrated the in vivo sustained profile of LCP-Tacro tablets, indicating release from all parts of the colon and absorption of tacrolimus from the distal portion of the gastrointestinal tract. Sintigraphic photographs taken at 0.02, 0.53, 4.32, 4.57, 11.23 and 23.32 hours after administration were shown in FIG.

Multi-dose, steady-state, comparative PK study (Study 004):

Study 004 is a two-dose, double-dose, steady-state pharmacokinetic study of LCP-Tacro 2 mg once daily versus Prograf® 2 × 1 mg daily in 14 healthy volunteers. This study was supported by Prograf® It clearly demonstrates the once-daily profile of LCP-Tacro in contrast to twice daily. In addition, the study demonstrated excellent bioavailability of LCP-Tacro tablets once-a-day compared to Prograf® capsules twice daily. (10 mg / kg body weight) for 10 consecutive days after administration of LCP-Tacro 2 mg tablets (once daily) and Prograf® 1 mg capsules (twice daily) and between 7, 8, 9 and 10 days No difference was observed, and therefore the steady state was maintained from the 7th day. In steady state, 24-hour systemic exposure of LCP-Tacro 2 mg tablets (once daily) was approximately 50% higher than that of Prograf 1 mg capsules (twice daily). The peak concentration times between LCP-Tacro 2 mg once daily and twice daily Prograf® 2 × 1 mg twice daily and multiple doses were similar for both treatments. As expected due to the sustained profile according to the present invention, LCP-Tacro 2 mg tablets (once daily) had a higher C _minima and lower values than the fast-acting Prograf® 1 mg capsules (twice daily) . As shown in Table 25 below, no significant difference in C _max was found between the two treatments.

Multiple dose, steady state, comparative PK study (Study 1012):

This study was conducted in two doses (twice a day) in group B of the test formulation of LCP-Tacro 2 ㎎ tablets administered once daily (once a day) in group A under multi-dose, fasting conditions The bioavailability of tacrolimus in 1 mg capsules of Prograf was assessed and compared. The study group consisted of 30 healthy volunteers who underwent a two week wash followed by a cross between study groups after 10 days of study treatment. In this study, 25 patients were evaluable. The pharmacokinetics of tacrolimus on day 10 are summarized in Tables 26-27.

Study 1014 (Day Variation, NHV):

This study studied the pharmacokinetic profile of tacrolimus after administration of 2 mg LCP-Tacro in the morning and evening in 26 male and female healthy volunteers under fasting conditions. The study consisted of two 8-day periods separated by a washout period of 2 weeks or more between treatments. The average pharmacokinetic parameters are summarized in Table 29 below.

Research 1015

This study compared the rate and extent of absorption of tacrolimus after administration of 1 mg capsules of LCP-Tacro 1 mg tablet versus Prograf® (tacholimus) under fasting conditions in 17 normal healthy male or female subjects. The study consisted of two 8-day periods separated by a washout period of 2 weeks or more between treatments. The pharmacokinetic results are summarized in the table below. Combination of longer T (in combination with lower C _max (2.54 ng / ml vs. 7.04 ng / ml) and lower AUC _(O-infinity) of LCP-Tacro tablets (71.82 ng * hr / ml vs. 50.18 ng * _Maximum (8.78 o'clock vs. 1.39 o'clock) supports once-daily dosing with LCP-Tacro tablets over Prograf® capsules (tacrolimus).

With reduced peak / minimum fluctuations and delayed T _max in NHV, exposure to tacrolimus was significantly higher after administration of the LCP-Tacro tablet than after administration of the Prograf capsule. The results are consistent with other PK data obtained with the sustained release formulations according to the invention.

Release times for the sustained release dosage forms according to the invention used in the clinical trials described herein provide a sustained release profile with less than 63.5% release within 15 hours. The relevant release profile at this point is shown in Figure 1 (tested in accordance with USP II dissolution test (paddle) at a pH of 4.5 and in a medium containing 0.005% hydroxypropyl cellulose, at a rotation of 50 rpm).

Example 24

Double-cross, open-label, multi-dose, bioequivalence studies comparing the pharmacokinetics (C _max , C ₂₄ and AUC _tau ) and safety of LCP-Tacro tablets versus Advagraf® capsules under steady- .

Twenty healthy male volunteers were randomized to receive one LCP-Tacro 2 mg tablet or two Advagraf® 1 mg capsules daily for 10 days. After a 2-week washout period, each subject received an alternative treatment. The PK profile after each treatment for 10 days is shown in FIG. 7, demonstrating that the LCP-Tacro tablet provides about 50% higher bioavailability of tacrolimus than Advagraf® at similar doses. The PK profile of LCP-Tacro tablets also supports once-daily dosing.

***********************

The patents, patent applications, disclosures, product descriptions and protocols mentioned in this application are incorporated herein by reference in their entirety.

The embodiments described and discussed herein are for the purpose of teaching those skilled in the art how to best make known to the inventors for making and using the present invention. Nothing in this specification should be construed as limiting the scope of the invention. Modifications and variations of the above-described embodiments of the present invention are possible without departing from the invention, as will be understood by those skilled in the art in light of the above teachings. It is therefore contemplated that the invention may be practiced otherwise than as specifically described within the scope of the claims and equivalents thereof.

Claims (137)

1. A sustained-release pharmaceutical composition for immunosuppressive treatment once daily in a patient in need thereof, comprising tacrolimus as an active substance,
When the pharmaceutical composition is tested at a pH of 4.5 according to the USP II dissolution test (paddle) or USP I dissolution test (Basquet) method and in a medium containing 0.005% hydroxypropyl cellulose and at a rotation of 50 rpm,
(a) more than 8% of the active substance is released at 4 hours,
(b) less than 25% of the active material is released at 5 hours,
(c) 40% of the active substance is released within 10 to 14 hours,
(d) no more than 63.5% of the active material is released at the 12 hour time point, and
(e) the pharmaceutical composition releases the active substance to the root release profile over an extended period of time defined by the release to the 15 hour time point from the 8-hour time point, and the quadratic release has a deviation of +/- 15% A sustained release pharmaceutical composition as defined by a linear release profile. The sustained release pharmaceutical composition according to claim 1, wherein not more than 63.5% of the active substance is released at a time point of 13 hours. delete 1. A sustained-release pharmaceutical composition for immunosuppressive treatment once daily in a patient in need thereof, comprising tacrolimus as an active substance,
When the pharmaceutical composition is tested at a pH of 4.5 according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format and in a medium containing 0.005% hydroxypropyl cellulose and at a rotation of 50 rpm,
(a) more than 8% of the active substance is released at 4 hours,
(b) less than 25% of the active material is released at 5 hours,
(c) 40% of the active substance is released within 10 to 14 hours,
(d) no more than 63.5% of the active material is released at the 12 hour time point, and
(e) the pharmaceutical composition releases the active substance into the root release profile over an extended period of time defined by the release to the 10-hour time point at 2 hours, and the quadratic release has a deviation of +/- 15% A sustained release pharmaceutical composition as defined by a linear release profile. 5. The composition of claim 4, further comprising 0.5% sodium lauryl sulfate (SLS) according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) Wherein the release of less than 80% of the active substance is extended over a period of from 7 hours to 24 hours when tested in vitro at a rotation of 50 rpm. The sustained release pharmaceutical composition according to any one of claims 1, 2 and 4, wherein 80% of the release of active substance is extended for a period of less than 24 hours. Use according to any one of claims 1, 2, 4, and 5 for the preparation of a pharmaceutical composition according to any one of claims 1 to 5, wherein the pH is 4.5 according to USP II dissolution test (paddle) or USP I dissolution test And 63.5% of the release of the active substance when tested in vitro at a rotation of 50 rpm extended over a period of 20 hours or less. A pharmaceutical composition according to any one of claims 1, 2, 4 and 5, which comprises a pH 4.5 and 0.005% hydroxypropylcellulose according to USP II dissolution test (paddle) or USP I dissolution test (basket) Wherein the release is initiated within 120 minutes after precipitation of the pharmaceutical composition in the dissolution apparatus, when tested in vitro with a medium comprising lactose and a rotation of 50 rpm. Use according to any one of claims 1, 2, 4, and 5 for the preparation of a pharmaceutical composition according to any one of claims 1 to 5, wherein the pH is 4.5 according to USP II dissolution test (paddle) or USP I dissolution test Of the active substance and less than 20% w / w of the active substance when tested in vitro at a rotation of 50 rpm within 1 hour. delete The pharmaceutical composition according to claim 1, which comprises a medium comprising pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format, and active when tested in vitro at a rotation of 50 rpm Wherein the sustained-release pharmaceutical composition releases 20% w / w of the total amount of the substance within 6 to 10 hours. The composition according to claim 1, which is tested in vitro in a medium comprising pH 4.5 and 0.005% hydroxypropyl cellulose according to the USP II dissolution test (paddle) or USP I dissolution test (baskets) format and with a rotation of 50 rpm, Wherein the sustained-release pharmaceutical composition releases 50% w / w of the active substance within 13 to 17 hours. The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the slope or slope is defined as being within 25% of the slope or slope measured at 6 , Wherein the sustained release profile is linear during a period of from 4 to 8 hours. The method of any one of claims 1, 2, 4, 5, 11, and 12, wherein the slope or slope is defined as being within 25% of the slope or slope measured at 8 , Wherein the release profile is linear during a period of from 6 to 10 hours. The method of any one of claims 1, 2, 4, 5, 11, and 12, wherein the slope or slope is defined as being within 25% of the slope or slope measured at 10 , Wherein the release profile is linear during a period of from 8 to 12 hours. The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the slope or inclination at an 80% point is within 25% &Lt; / RTI &gt; wherein the release profile is linear during the period of release up to the point in time when the &lt; RTI ID = 0.0 &gt; 13. A sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the release expansion mechanism is not by a permeation control coating. 13. A sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the sustained release pharmaceutical composition does not contain ethylcellulose as a release dilutable excipient. 13. A sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the active ingredient is present as a molecular dispersion. 20. The sustained release pharmaceutical composition according to claim 19, wherein release is controlled by dissolution, erosion, or dissolution and erosion of the polymer. 13. A sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the release after oral administration to the subject partially takes place in the colon. The sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, comprising 0.1 mg to 15 mg of tacrolimus. 23. The method of claim 22, wherein administration to a subject or a plurality of subjects results in administration of the product Advagraf (MR4) pharmaceutical composition or a biologically equivalent sustained release pharmaceutical composition when administered at the same molecular dose of tacrolimus and measured under biological equivalent conditions Subject to subject, or between subject and subject, of a mean T-T _max of tacrolimus reduced by 10% or more as compared to that obtained from a subject. 23. A pharmaceutical composition according to claim 22, which is administered to a subject or to a plurality of subjects, wherein the same molecular dose of tacrolimus is administered and measured under biological equivalent conditions, the product being obtained from the administration of the product Advagraf (MR4) or a biologically equivalent sustained- , Or between the subject and the subject in the mean blood C _max , AUC _(0-∞) , or C _max and AUC _(0-∞) of the tacrolimus reduced by more than 10% A pharmaceutical composition. 23. The pharmaceutical composition according to claim 22, which when administered to a subject or a plurality of subjects has a sustained release dosage form which provides a C _{max of at} least 10% reduced compared to that obtained by administration of a product Advagraf (MR4) or a biologically equivalent sustained- Wherein the C _maximal value is determined by administration of the same molecular dose of tacrolimus and under bioequivalent conditions. 23. A pharmaceutical composition according to claim 22 for the manufacture of a medicament for sustained release pharmaceutical administration which, when administered to a subject or a plurality of subjects, provides increased bioavailability by 20% or more as compared to that obtained by administration of the product Advagraf (MR4) or a biologically equivalent sustained- Wherein said bioavailability is measured as AUC _(O-∞) under the same molecular dose of tacrolimus administered under biological equivalent conditions. 23. The method of claim 22, wherein administration to the subject or a plurality of subjects results in administration of the same molecular dose of tacrolimus as measured under bioequivalent conditions, by administration of a commercial Prograf 占 pharmaceutical composition or a biologically equivalent chelating tacrolimus pharmaceutical composition Wherein the composition provides intra-subject, intra-subject, or inter-subject and inter-subject variability in the mean T-T _max of tacrolimus reduced by 10% or more relative to that obtained. 23. A pharmaceutical composition according to claim 22, which is administered to a subject or to a plurality of subjects when administered at the same molecular dose of tacrolimus and measured under bioequivalent conditions, by administration of a commercial Prograf 占 pharmaceutical composition or a biologically equivalent immediate release pharmaceutical composition Which provides a variability within the subject, within the subject, or within the subject and between subject and subject of the mean blood C _max , AUC _(0-∞) , or C _max and AUC _(0-∞) of tacrolimus reduced by more than 10% Lt; / RTI &gt; 23. The pharmaceutical composition according to claim 22, which when administered to a subject or to a plurality of subjects has a sustained release dosage form which provides a C _{max of} 20% or more reduced compared to that obtained by administration of a commercial Prograf 占 pharmaceutical composition or a biologically equivalent immediate release pharmaceutical composition Wherein the C _maximal value is determined by administration of the same molecular dose of tacrolimus and under bioequivalent conditions. 23. The method of claim 22, further comprising administering to the subject or to a plurality of subjects a sustained-release pharmaceutical composition that provides increased bioavailability by at least 10% as compared to that obtained by administration of a commercial Prograf 占 pharmaceutical composition or a biologically equivalent immediate- Wherein said bioavailability is measured as AUC _(O-∞) under the same molecular dose of tacrolimus administered under biological equivalent conditions. The pharmaceutical composition according to claim 22, wherein, when administered to a subject or a plurality of subjects after a fasting time of 4 hours or more in the evening, the value obtained after administration of the pharmaceutical composition after the fasting condition of 4 hours or more in the morning is 70 % &Lt; / RTI &gt; by weight of the composition. The pharmaceutical composition according to claim 22, which is administered to a subject or a plurality of subjects after a fasting state of 4 hours or more in the evening, has a measured value of 70 after administration in the morning compared to that obtained after administration of the pharmaceutical composition after a fasting condition of 4 hours or more in the morning sustained-release pharmaceutical composition which provides a C _max% or more. The sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, wherein the bioavailability is independent of the daily administration time. The sustained-release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11, and 12, for use in bedtime therapy. 24. The sustained release pharmaceutical composition of claim 23, wherein the test conditions are by a single dose study. 24. The sustained release pharmaceutical composition according to claim 23, wherein the test conditions are by a steady-state study. 24. The sustained release pharmaceutical composition according to claim 23, wherein the test conditions are performed by a healthy volunteer. 24. The sustained release pharmaceutical composition according to claim 23, wherein the test conditions are performed by a patient. 23. The method of claim 22, wherein the average maximum concentration of tacrolimus (C _max ) of less than or equal to 15 ng / ml when administered as a single dose to 5 or more healthy subjects in a fasting state and 5 mg / / L _&lt; / _{RTI &gt; (O-96 h)} . 8. The sustained release pharmaceutical composition of claim 7, wherein the C ₂₄ of tacrolimus is greater than or equal to 2 ng / ml. The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein once a day in a stable state or patient is administered to a healthy subject or patient (C _max - C _Minimum ) / C _minimum of the tacrolimus plasma concentration of the tacrolimus is administered with tacrolimus at the same daily dose of the molecule and measured under biological equivalent conditions and the Biologically Equivalent Sustained Release pharmaceutical composition of Advagraf Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein once a day in a stable state or patient is administered to a healthy subject or patient (C _max - C Free, or total and free volume of tacrolimus, measured as a _{minimum of} 1 / C _minimum , is administered with tacrolimus at the same daily dose of the molecule and measured under biological equivalent conditions, and the concentration of the Prograf® pharmaceutical composition or tacrolimus A sustained release pharmaceutical composition that is less than the variation observed when the biologically equivalent immediate-release composition is administered twice daily. In the case that 1, claim 2, claim 4, claim 5, claim 11 and claim 12 according to any one of items, in the steady state once daily administration to a healthy subject or a patient, (C _max - C _Min) / C, measured as the _{average of} total, free, or shot, and the fluctuation of blood levels of the free tacrolimus is administered in the same molecule tacrolimus daily dosage is determined in the biological equivalent conditions Advagraf® of the pharmaceutical composition or tacrolimus A sustained release pharmaceutical composition having less than the variation observed when administering a biologically equivalent sustained-release pharmaceutical composition once a day. In the case that 1, claim 2, claim 4, claim 5, claim 11 and claim 12 according to any one of items, in the steady state once daily administration to a healthy subject or a patient, (C _max - C _min ) / C _means that the change in blood concentration relative to total tachylymus measured as a mean is administered to tacrolimus at the same daily dose of the molecule and measured under biological equivalent conditions and the biological equivalent isoform composition of Prograf Wherein the sustained release pharmaceutical composition is less than the variation observed when administered twice daily. The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein, when administered to six or more healthy subjects in a fasted state, the amount of tacrolimus Wherein the mean residence time is at least 10% greater than the mean residence time measured under biological equivalent conditions by the Advagraf 占 pharmaceutical composition or the biologically equivalent sustained-release pharmaceutical composition of tacrolimus. The method according to any one of claims 1, 2, 4, 5, 11, and 12, wherein, when administered to six or more healthy subjects in a fasted state, the amount of tacrolimus Wherein the mean residence time is at least 35% greater than the mean residence time measured under biological equivalent conditions by the Prograf 占 pharmaceutical composition or the biologically equivalent isotonic pharmaceutical composition of tacrolimus. The sustained release pharmaceutical composition according to any one of claims 1, 2, 4, 5, 11 and 12, wherein the active substance is present in a hydrophilic or water-miscible carrier. 48. The method of claim 47, wherein the hydrophilic or water-miscible carrier is selected from the group consisting of polyethylene glycol, polyoxyethylene oxide, poloxamer, polyoxyethylene stearate, poly-epsilon caprolactone, polyglycated glyceride, polyvinylpyrrolidone, Polyvinyl acetate copolymer (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic polymers (Eudragit RS, Eudragit NE, Eudragit E), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose Wherein the sustained release pharmaceutical composition is selected from the group consisting of HPC, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, pectin, cyclodextrin, galactomannan, alginate, carrageenate, xanthan gum and mixtures thereof. 49. The sustained release pharmaceutical composition of claim 48, wherein the carrier comprises a mixture of polyethylene glycol (PEG) and poloxamer. 50. The sustained release pharmaceutical composition according to claim 49, wherein the polyethylene glycol has an average molecular weight of 1,500 or more. 51. The sustained release pharmaceutical composition of claim 50, wherein the mixture comprises polyethylene glycol and poloxamer in a ratio of 1: 3 to 10: 1. 52. The sustained release pharmaceutical composition of claim 51, wherein the poloxamer is poloxamer 188. &lt; Desc / Clms Page number 36 &gt; 51. The sustained release pharmaceutical composition of claim 50, wherein the average molecular weight of the polyethylene glycol is 6000 (PEG6000). The method of any one of claims 1, 2, 4, 5, 11, and 12, wherein the release expansion mechanism is selected from the group consisting of dissolution, erosion, or dissolution and erosion of the polymer, Gt; 56. The sustained release pharmaceutical composition of claim 54 comprising hydroxypropyl-methylcellulose (HPMC) as a releasable expandable polymer. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete 22. The sustained release pharmaceutical composition according to claim 21, wherein the release after oral administration to the subject occurs at one or more of the ascending colon, transverse colon and descending colon. 40. The method of claim 39, wherein the average maximum concentration of tacrolimus (C _max ) of less than or equal to 13 ng / ml when administered as a single dose to 5 or more healthy subjects in a fasting state and 5 mg / / L _&lt; / _{RTI &gt; (O-96 h)} .

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