WO2009080030A1 - Traitement de l'hépatite auto-immune avec une formule orale à base de tacrolimus administrée une fois par jour - Google Patents

Traitement de l'hépatite auto-immune avec une formule orale à base de tacrolimus administrée une fois par jour Download PDF

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Publication number
WO2009080030A1
WO2009080030A1 PCT/DK2008/000440 DK2008000440W WO2009080030A1 WO 2009080030 A1 WO2009080030 A1 WO 2009080030A1 DK 2008000440 W DK2008000440 W DK 2008000440W WO 2009080030 A1 WO2009080030 A1 WO 2009080030A1
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Prior art keywords
dosage form
tacrolimus
hours
extended release
administered
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PCT/DK2008/000440
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English (en)
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Michael Beckert
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Lifecycle Pharma A/S
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Publication of WO2009080030A1 publication Critical patent/WO2009080030A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates a method of treating autoimmune disease by use of an extended release oral dosage form comprising as active substance tacrolimus or a pharmaceutically active analogue thereof for a once daily treatment of patients suffering from autoimmune hepatitis.
  • the dosage form releases the active substance over an extended period of time and in vitro and in vivo and provides a high bioavailability and an improved pharmacokinetic profile compared to conventional dosage forms comprising tacrolimus.
  • tacrolimus The preparation of tacrolimus is described in EP-A-O 184 162 and analogues of tacrolimus are disclosed e.g. in EP-A-O 444659 and US 6,387,918, which are both hereby incorporated by reference.
  • Tacrolimus also known as FK-506 or FR-900506, is the active ingredient of Prograf®, marketed as soft gelatine capsules comprising the equivalent of 0.5, 1 or 5 mg anhydrous tacrolimus, and Advagraf® approved by the European Agency for the Evaluation of Medicinal Products (EMEA) at 23 April 2007.
  • EMEA European Agency for the Evaluation of Medicinal Products
  • Absorption of tacrolimus from the gastrointestinal tract after oral administration is rapid with a mean time-to-peak concentration (tmax) of approximately 1-2 hours after administration to healthy subjects or kidney or liver transplanted patients, but incomplete and variable.
  • the bioavailability is generally as low as at the most about 20% after oral administration.
  • side effects are vomiting and nausea but side effects like tremor, headache, hypertension, renal dysfunction, hyperkalemia, hypomagnesaemia, hyperglycemia, insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity and neurotoxicity are also observed.
  • side effect profile of tacrolimus is a limiting factor for its use in autoimmune disorders.
  • the treatment according to the present invention is related to the use of a extended release formulation which is optimized for improving efficacy and safety whereby use in autoimmune diseases where safety is of special importance due to the fact that the underlying disease is seldom fatal and/or less toxic treatments are available.
  • modified or extended release dosage forms relies in the difficulty in obtaining a sufficient absorption in the lower part of the gastrointestinal tract as oral dosage forms entering the colon may easily be excreted before a substantial release has taken place.
  • the release is generally decreased due to the lack of fluids and physical interaction of the dosage forms with the increasingly more solid content of the colon.
  • the surface of absorption is several times smaller than the absorbing surface of the small intestines and this factor increases the time where the released active substance is subjected to possible degradation and entrapment in the solids present in the colon.
  • an increased bioavailability is not correlated to the extension of the release in a simple linear way.
  • the release may be carefully tailored to level out several counteracting factors of. These factors includes a lower area for absorption, lower content of fluids, higher content of solids, bacterial degradation, higher impact from the P-glycoprotein transporter system, lower motility, differences in mucosal barrier and/or mucous composition and finally further differences in pH along the colon compared with the small intestines.
  • the control and timing of the in vivo release from an extended release dosage form in order to obtain a predictable release under the various physical conditions present along the Gl tract and being extended to the exact level where the resulting pharmacokinetic parameters for that particular active substance are fully optimized is a challenge.
  • the absorption may differ significantly between patients suffering from different disease as specific conditions related to the individual disease may be impact the absorption, distribution, and elimination of the active substance.
  • the bioavailability of tacrolimus is significantly increased and pharmacokinetic parameters substantially improved when tacrolimus is administered to a mammal in a extended release composition where the release and a timing of release of the active ingredient, i.e. an in vitro and vivo release profile, is extended for more than 15 hours measured by conventional dissolution methods used for tacrolimus dosage forms and measured in vivo via pharmacokinetic parameters of clinical relevance and relevant for proving extension of the release in vivo.
  • These pharmacokinetic parameters includes: substantial extended time to reaching the maximal concentration; low maximal concentrations; high minimal concentrations, extended mean residence times and at the same time securing a surprisingly high bioavailability.
  • the present invention provides, in its first aspect, an extended release oral dosage form comprising as active substance tacrolimus or an pharmaceutical active analogue thereof for a once daily immunosuppressive treatment of a patient in need thereof which dosage form releases the active substance over an extended period of time.
  • the extended release is defined by a release of at the most 63.5% of the content of the active substance at the12 hours time point defined by in vitro dissolution and when tested according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
  • the invention relates to use of the present pharmaceutical composition for a more safe immunosuppressive treatment due to the improved pharmacokinetic profile obtained in subjects and demonstrated by several single dose and steady state pharmacokinetic trials in comparison with conventional commercially available dosage forms.
  • active ingredient or “active pharmaceutical ingredient” means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • active pharmaceutical ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • the term includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect.
  • hydrophilic describes that something 'likes water', i.e. a hydrophilic molecule or portion of a molecule is one that typically is electrically polarized and capable of forming hydrogen bonds with water molecules, enabling it dissolve more readily in water than in oil or other "non-polar" solvents.
  • amphiphilic describes a molecule (as a surfactant) having a polar water-soluble group attached to a water-insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other is hydrophobic (non-polar).
  • hydrophobic denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and nonpolar solvents or molecular environments.
  • vehicle means any solvent or carrier fluid in a pharmaceutical product that has no pharmacological role.
  • water is the vehicle for xilocaine and propylene glycol is the vehicle for many antibiotics.
  • solid dispersion denotes a drug or active ingredient or substance dispersed on a particulate level in an inert vehicle, carrier, diluent or matrix in the solid state, i.e. usually a fine particulate dispersion.
  • solid solution denotes a drug or active ingredient or substance dissolved on a molecular level in an inert vehicle, carrier, diluent or matrix in the solid state.
  • analogue means a chemical compound that is structurally similar to another.
  • drug means a compound intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
  • the term “dosage form” means the form in which the drug is delivered to the patient. This could be parenteral, topical, tablet, oral (liquid or dissolved powder), suppository, inhalation, transdermal, etc.
  • bioavailability denotes the degree means to which a drug or other substance becomes available to the target tissue after administration.
  • bioequivalency denotes a scientific basis on which generic and brand name drugs are compared with one another. For example, drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions.
  • Parameters often used in bioequivalence studies are t max , c max , AU Co-i nf i n ity AUC 0 . t .
  • Other relevant parameters may be W 50 , W 75 and/or MRT. Accordingly, at least one of these parameters may be applied when determining whether bioequivalence is present.
  • two compositions are regarded as bioequivalent if the value of the parameter used is within 80-125% of that of Prograf® or a similar commercially available tacrolimus-containing product used in the test.
  • t max denotes the time to reach the maximal plasma concentration (c max ) after administration;
  • AUC 0 -i nf i n ity denotes the area under the plasma concentration versus time curve from time 0 to infinity;
  • AUC 0-t denotes the area under the plasma concentration versus time curve from time 0 to time t;
  • W 50 denotes the time where the plasma concentration is 50% or more of C max ;
  • VV 75 denotes the time where the plasma concentration is 75% or more of C max ;
  • MRT denotes mean residence time for tacrolimus (and/or an analogue thereof). Swing denotes (Cmax-Cmin)/Cmin and fluctuation (Cmax-Cmin)/Caverage.
  • the term “medicine” means a compound used to treat disease, injury or pain. Medicine is justly distributed into “prophylactic,” i.e. the art of preserving health, and “therapeutic” , i.e. the art of restoring health.
  • controlled release and “modified release” are intended to be equivalent terms covering any type of release of tacrolimus from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject.
  • a person skilled in the art knows how controlled release/modified release differs from the release of plain tablets or capsules.
  • release in a controlled manner or “release in a modified manner” have the same meaning as stated above.
  • the terms include slow release (that results in a lower C max and later t max , but t ⁇ /2 is unchanged), extended release (that results in a lower C max , later t max , but apparent t % is longer); delayed release (that result in an unchanged C max , but lag time and, accordingly, t max is delayed, and t % is unchanged) as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, fast release (to obtain an enhanced onset of action) etc. Included in the terms is also e.g. utilization of specific conditions within the body e.g. different enzymes or pH changes in order to control the release of the drug substance.
  • extended release is chosen as this term is believed to most correctly cover the in vivo release of the product.
  • the term “erosion” or “eroding” means a gradual breakdown of the surface of a material or structure, for example of a tablet or the coating of a tablet.
  • the term as used herein generally denotes the dissolution of a polymer responsible for extending the release being is faster than the dissolution of the active substance whereby the polymer erodes faster than the active substance is dissolved. In other words the release is primarily controlled by the erosion and not by the dissolution of the active substance in the polymer matrix system.
  • the present invention provides pharmaceutical products for improved treatment methods of conditions that respond to tacrolimus treatment, especially treatments where an immunosuppressive effect is desired such as in autoimmune hepatitis (AIH).
  • the active ingredient in the inventive compositions is tacrolimus or any analogue or derivative of tacrolimus, which exhibits either a pharmacological or a therapeutical activity, which is at least equivalent to that of tacrolimus (FK-506 or FR- 900506).
  • tacrolimus in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates including the hydrate, anhydrate, complexes thereof etc.).
  • tacrolimus any analogue, derivative or active metabolite of tacrolimus, pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof.
  • a smaller particle size in micro and nano scale and preferable a molecular solution will contribute to a predictable and constant in vivo release of tacrolimus.
  • the present invention provides an extended release oral dosage form comprising as active substance tacrolimus or an pharmaceutical active analogue thereof for a once daily immunosuppressive treatment of an autoimmune hepatitis patient in need thereof which dosage form releases the active substance over an extended period of time defined by a release of at the most 63.5% of the content of the active substance at the 12 hours time point defined by in vitro dissolution and when tested according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
  • the basket dissolution apparatus may be more suitable for capsules and the paddle dissolution apparatus is more suitable for disintegration tablets.
  • the most suitable dissolution apparatus may be easily recognized via testing whether highest conformity is obtained by the one or other apparatus.
  • at the most 63.5% of the active substance is released at the 13 hours time point, more preferred at the 14 hours time point, such as at the 15 hours time point.
  • the in vitro release is taking place at a constant rated whereby a substantial zero order release profile may be obtained over an extended period of time.
  • such corresponding period where zero order release is desired may be defined by the release from 8 hours to 15 hours when tested according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
  • a solid dosage form may leave the stomach soon after ingestion or may be retained there for several hours before reaching the Gl tract, it is also desired that the more initial release is well controlled as measured by a in vitro release which is an substantial zero order release profile over an extended period of time defined by the release from 2 hours to 10 hours when tested according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
  • the addition of a surfactant to the release medium provides a release rate of the substance whereby the release of at the most 80% of the active substances is extended for a period of at least 7 hours, such as at least 8 hours, such as at least 9 hours, such as at least 10 hours, such as at least 11 hours, such as at least 12 hours such as at least 13 hours when tested in vitro according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose and further comprising 0.5% sodium lauryl sulfate (SLS), and a rotation of 50 rpm
  • the dosage form may be excreted before it has released completely or the release takes place too distally for a sufficient distribution. Accordingly, the content of the dosage form should be released with the rates indicated herein, however not be extended beyond a period of at the most 24 hours, such as at the most 23 hours, such as at the most 22 hours, such as at the most 21 hours such as at the most 21 hours, such as at the most 21 hours such as at the most 18 hours such as at the most 17 hours such as at the most 16 hours calculated for 80% of the content and with the addition of 0.5% sodium lauryl sulfate (SLS) to the dissolution medium.
  • SLS sodium lauryl sulfate
  • the dosage form is fulfilling the following condition wherein 63.5% of the release of the active substance is extended for a period of at the most 20 hours such as at the most 18 hours. Shorter dissolution periods may also be preferred as the upper limit such as at the most 16 hours such as at the most 15.5 hours also when tested in vitro according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
  • An extended release oral dosage wherein the release begins within 120 min such as within 90 minutes, such as within 60 minutes after deposition of the dosage form in the dissolution apparatus when tested in vitro according to the USP Il dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm is indicative for a composition which will provide a predictable release profile as long as the release in the initial period, such as within the first 2 hours is not to fast. If no release takes place shortly after administration, the patient is in risk of to low concentrations. The patient is generally titrated according to the blood concentrations observed immediately before ingesting a daily dosage being the minimum concentration observed during the day. A delay in release will provide a later unknown minimal concentration.
  • An extended release oral dosage form wherein the release profile is substantial linear in the period from 4 to 8 hours defined as a gradient or slope being within 25% of the gradient or slope measured at hour 6, such as within 15%, preferable within 10%.
  • release profile characteristics defined above significantly enhances the bioavailability of tacrolimus in mammals, since all or a major part of the active ingredient is in fact released in the gastrointestinal tract in such as manner that CYP3A4 metabolism is substantially avoided or at least significantly reduced. Further, it is contemplated that this effect is correlated to or at least reflected to the in vitro dissolution profile of the pharmaceutical composition and/or dosage forms of the invention, which profile is easily found when subjecting the composition and/or dosage form to a conventional in vitro dissolution method specified.
  • the desired release profile of the pharmaceutical composition may be provided by combining one or more of the following possibilities, i) coating the composition with an enteric coating; and/or ii) using a pharmaceutical composition comprising a solid dispersion or solid solution of active ingredient, i.e. tacrolimus or an analogue thereof, in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or iii) using a pharmaceutical composition comprising a solid dispersion or solid solution of active ingredient, i.e. tacrolimus or an analogue thereof, in a hydrophobic vehicle and optionally one or more modifying release agents.
  • An entero-coated formulation may however have the disadvantage of delaying the release without extending the release and should therefore be used in combination with an extending technology.
  • a extended release tacrolimus-containing pharmaceutical composition having the active ingredient dissolved or dispersed in a hydrophobic vehicle as described herein, preferably in an oil, an oily material, a wax or a fatty acid derivative, more preferably a wax having a low melting point such as for example glyceryl monostearate.
  • a extended release tacrolimus-containing pharmaceutical composition having the active ingredient dissolved or dispersed in a hydrophilic or water-miscible vehicle as described herein, preferably a vehicle selected among polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides such as Gelucire ® , and mixtures thereof, more preferably polyethylene glycol optionally in 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.
  • the present invention relates to a pharmaceutical composition in particulate form comprising tacrolimus and/or an analogue thereof together with one or more pharmaceutically acceptable excipients, wherein the composition upon oral administration to a mammal in need thereof exhibits an AUC/AUCp r og raf® value of at least about 1.3, the AUC values being determined under similar conditions.
  • the bioavailability obtained after administration of a composition according to the invention is markedly improved.
  • the AUC/AUC Pra g ra( ® value is at least about 1.25 such as about 1.5 or more, about 1.8 or more, about 1.9 or more, about 2.0 or more, the AUC values being determined under similar conditions.
  • the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e. the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects.
  • the plasma concentration leads to a therapeutic effect
  • the invention relates to a pharmaceutical composition in particulate form comprising tacrolimus together with one or more pharmaceutically acceptable excipient, wherein the composition upon oral administration to a mammal in need thereof releases tacrolimus in a controlled manner and exhibits a C max that is at the most about 80% of that of C max for Prograf® tablets such as, e.g., at the most about 75%, at the most about 70%, at the most about 65%, at the most about 60%, at the most about 55%, at the most about 50%, at the most about 45% or at the most about 40%.
  • controlled release and extended release are intended to be equivalent terms covering any type of release of tacrolimus from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject.
  • a person skilled in the art knows how controlled release/extended release differs from the release of plain tablets or capsules.
  • the terms "release in a controlled manner” or “release in an extended manner” have the same meaning as stated above.
  • the terms controlled release/extended release include slow release (that results in a lower C max and later t max , but ⁇ ?
  • A is unchanged), extended release (that results in a lower C max , later t max , but apparent t ⁇ /2 is longer); delayed release (that result in an unchanged C max , but lag time and, accordingly, t max is delayed, and t % is unchanged) as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, fast release (to obtain an enhanced onset of action) etc.
  • Included in the terms is also e.g. utilization of specific conditions within the body e.g. different enzymes or pH changes in order to control the release of the drug substance.
  • tacrolimus after oral administration to a mammal, including a human, of a pharmaceutical composition according to the present invention containing a dose of 5 mg tacrolimus, tacrolimus is released in a controlled manner and will exhibit a C max that is at the most about 30 ng/ml such as, e.g. at the most about 25 ng/ml or at the most about 20 ng/ml.
  • the present invention also relates to a pharmaceutical composition, wherein W 50 is at least about 2 hours, such as, e.g., at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.
  • W 50 is at least about 2 hours, such as, e.g., at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or about 14 hours or more.
  • C ⁇ of a composition according to the invention is normally 90 or less such as, e.g., about 85 or less, about 80 or less, about 75 or less, about 70 or less, about 65 or less, about 60 or less, about 55 or less, about 50 or less, about 45 or less or about 40 or less.
  • tacrolimus after oral administration to a mammal, including a human, of a pharmaceutical composition of the invention containing 5 mg of tacrolimus, tacrolimus is released in a controlled manner and exhibits a C d , ff of about 20 ng/ml or less such as, e.g., about 15 ng/ml or less, about 13 ng/ml or less or about 10 ng/ml or less.
  • a pharmaceutical composition according to the invention releases tacrolimus in a controlled manner in order to extend the therapeutic action of tacrolimus.
  • the release may be pH dependant, i.e. the release predominantly takes place after passage of the stomach.
  • Such a pH dependent release is mainly provided by means of enteric coating material as described herein.
  • the release may also be pH independent, e.g. by providing the composition with a controlled release coating such as, e.g. a cellulose based coating like e.g. ethylcellulose or by providing the composition in the form of a matrix composition such as, e.g., a hydrophilic cellulose polymer matrix type e.g. based on HPMC.
  • a combination may of course also be employed.
  • the change in bioavailability and/or the changes in other bioavailability related parameters are normally determined by in vivo studies in a suitable animal model testing the compositions in question together with e.g. Prograf® or a similar commercially available tacrolimus-containing product.
  • the pharmaceutical compositions according to the invention provide significant higher bioavailability of tacrolimus, which may reduce the number of daily administered dosage units, and reduce or abolish the need for administration in connection with food intake, which provide for a higher degree of freedom for the recipient of the pharmaceutical compositions, and consequently the patients acceptance and/or compliance may be significantly improved.
  • compositions provide a significant reduction in side effects, especially side effect related to a high peak concentration (such as, e.g., nephro- and neuro-toxicity or other organ damage, especially in organs where tacrolimus is up concentrated, diarrhea, constipation, abdominal pain, nausea etc) and provide for an extended release of tacrolimus leading to a better therapy.
  • side effect related to a high peak concentration such as, e.g., nephro- and neuro-toxicity or other organ damage, especially in organs where tacrolimus is up concentrated, diarrhea, constipation, abdominal pain, nausea etc
  • a further advantage of a composition of the present invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment.
  • a similar bioavailability including or a lower bioavailability however potentially resulting in the same efficacy and/or an improved profile after administration in a dosis that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of tacrolimus administered in the form of Prograf® or a similar commercially available tacrolimus-containing product or as a commercial available extended release product including Advagraf®.
  • compositions according to the invention will provide a CV (Coefficient of Variation) on Area under Curve data that are significantly smaller than with Prograf® and like products.
  • one of the basic features of the present invention is that it is possible to obtain an improvement in the profile and/or bioavailability by oral administration of a composition of the present invention.
  • a low bioavailability of a drug substance after oral administration is a barrier for design of a controlled or extended release composition of the drug substance due to the fact that it is almost impossible to obtain effective drug levels over a prolonged period of time.
  • the present technology it is possible to obtain a significantly improved bioavailability and thereby possible to design controlled, extended or delayed release compositions.
  • a suitable controlled release composition may be a composition that is designed to release tacrolimus in a very extended manner so as to avoid or reduce the CYP3A4 metabolism in the gastrointestinal tract.
  • a preferable site of absorption includes the ceacum and colon.
  • the release according to the present invention can take place even in the distal part of the colon and still being distributed to the mucosa and absorbed.
  • the absorption of the extended release dosage form according to the invention is one where the in vivo release after oral administration to a subject takes place substantially in the colon such as release in one or more of the locations of colon ascendens, colon transversum and colon decendens.
  • the pharmaceutical compositions may be prepared by any convenient method such as, e.g. granulation, mixing, spray drying etc.
  • a particularly useful method is the method described in WO 03/004001.
  • a process for the preparation of particulate material by a controlled agglomeration method i.e. a method, which enables a controlled growth in particle size.
  • the method involves spraying a first composition comprising e.g. tacrolimus and a carrier, which has been melted, onto a second solid carrier medium.
  • the meltable carrier has a melting point of at least 5 0 C but lower than the melting point of tacrolimus.
  • the melting point of the carrier may be in the range of 10 0 C to 150 0 C, such as, e.g., in the range of 30 0 C to 100 0 C or in the range of 40 0 C to 50 °C is most preferred.
  • a suitable carrier being pharmaceutical acceptable, capable of dissolving or at least partly dissolve tacrolimus and having a melting point in the desired range using general knowledge and routine experimentation.
  • Suitable candidate for carriers are described in WO 03/004001 , which is herein incorporated by reference.
  • suitable carriers are e.g. those mentioned as an oil or an oily-like material (as discussed later herein) as well as those disclosed in WO 03/004001.
  • the particulate material of a pharmaceutical composition has a geometric weight mean diameter dgw of ⁇ 10 ⁇ m such as, e.g. ⁇ 20 ⁇ m, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g.
  • the particulate material obtained by the above-mentioned method has suitable properties with respect to flowability and/or compressibility and is therefore suitable for further processing into pharmaceutical dosage forms.
  • the solid dispersion or solid dispersion used in a preferred embodiment of the invention comprises an active ingredient selected among tacrolimus and analogues thereof, which ingredient is dispersed or dissolved in a hydrophilic or water- miscible vehicle having a melting point (freezing point or pour point) of at least 2O 0 C in a concentration of between about 0.01 w/w% and about 15 w/w%, and which dispersion is forming a solid dispersion or solid solution at ambient temperature (room temperature).
  • a first extended release system includes matrix systems, in which tacrolimus is embedded or dispersed in a matrix of another material that serves to retard the release of tacrolimus into an aqueous environment (i.e., the luminal fluid of the Gl tract).
  • aqueous environment i.e., the luminal fluid of the Gl tract.
  • tacrolimus is dispersed in a matrix of this sort, release of the drug takes place principally from the surface of the matrix.
  • the drug is released from the surface of a device, which incorporates the matrix after it diffuses through the matrix or when the surface of the device erodes, exposing the drug.
  • both mechanisms can operate simultaneously.
  • the matrix systems may be large, i.e., tablet sized (about 1 cm), or small ( ⁇ 0.3cm).
  • the system may be unitary (e.g., a bolus), may be divided by virtue of being composed of several sub-units (for example, several capsules which constitute a single dose) which are administered substantially simultaneously, or may comprise a plurality of particles, also denoted a multiparticulate.
  • a multiparticulate can have numerous formulation applications. For example, a multiparticulate may be used as a powder for filling a capsule shell, or used per se for mixing with food to ease the intake.
  • a matrix multiparticulate comprises a plurality of tacrolimus-containing particles, each particle comprising tacrolimus and/or an analogue thereof e.g. in the form of a solid solution/dispersion with one or more excipients selected to form a matrix capable of controlling the dissolution rate of the tacrolimus into an aqueous medium.
  • the matrix materials useful for this embodiment are generally hydrophobic materials such as waxes, some cellulose derivatives, or other hydrophobic polymers. If needed, the matrix materials may optionally be formulated with hydrophobic materials, which can be used as binders or as enhancers.
  • Matrix materials useful for the manufacture of these dosage forms such as: ethyicellulose, waxes such as paraffin, modified vegetable oils, camauba wax, hydrogenated castor oil, beeswax, and the like, as well as synthetic polymers such as polyvinyl chloride), polyvinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, and the like.
  • Water soluble or hydrophilic binders or release modifying agents which can optionally be formulated into the matrix include hydrophilic polymers such as hydroxypropyl cellulose (HPC) 1 hydroxypropyl methyl cellulose (HPMC), methyl cellulose, poly (N-vinyl-2- pyrrolidinone) (PVP), polyethylene oxide) (PEO), polyvinyl alcohol) (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials.
  • materials, which function as release-modifying agents include water-soluble materials such as sugars or salts.
  • Preferred water-soluble materials include lactose, sucrose, glucose, and mannitol, as well as hydrophillic polymers like e.g. HPC, HPMC, and PVP.
  • a multiparticulate product is defined as being processed by controlled agglomeration.
  • tacrolimus is dissolved or partly dissolved in a suitable meltable carrier and sprayed on carrier particles comprising the matrix substance.
  • Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis and hepatic decompensation. It is characterized by the presence of interface hepatitis and portal plasma cell infiltration on histological examination, hypergammaglobulinemia and autoantibodies. Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals. Although appropriate management can prolong survival, improve the quality of life and avoid the need for liver transplantation, considerable therapeutic challenges remain in the treatment of this disorder.
  • Corticosteroids prednisone
  • azathioprine have been used as initial medical treatment for AlH for more than thirty years.
  • Combination therapy is preferred because lower dosages of corticosteroids are necessary, and thus there is a lower incidence of significant side effects.
  • the requirement for long-term treatment with corticosteroids risks development of serious or disabling adverse events including intolerable cosmetic changes, obesity, osteoporosis, diabetes and gastrointestinal ulceration.
  • Azathioprine-associated cholestatic hepatitis, pancreatitis, rash or cytopenia can require that this steroid-sparing agent be discontinued.
  • Tacrolimus blocks T-cell proliferation by inhibiting the phosphatase activity of the Ca2+-activated enzyme calcineurin (CaN) at nanomolar concentrations. The drug reduces the expression of several cytokine genes that are normally induced on T-cell activation.
  • interleukin (IL)-2 whose synthesis by T-lymphocytes is an important growth signal for T-cells.
  • Tacrolimus inhibits T-cell proliferation in response to either specific antigens or allogeneic cells.
  • This agent is commonly used in combination with corticosteroids and other immunosuppressives for the prevention of acute rejection after organ transplantation, and has been applied in various autoimmune diseases including rheumatoid arthritis and inflammatory bowel disease with some effect.
  • Tacrolimus was approved by the FDA in April of 1994 for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants under the brand name Prograf® (tacrolimus capsules, Astellas Pharma US, Inc.), under NDA No. 050708.
  • the drug has undergone several label revisions, the latest of which describes tacrolimus for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants.
  • Tacrolimus given as Prograf® capsules, exhibits significant inter- and intra- individual variability of its absorption and metabolism. Because of this variability, standard dosing in transplant treatment is not an accurate predictor of drug exposure. In clinical use, tacrolimus trough blood concentrations are measured to ensure efficacy and safety. Furthermore, the relatively low bioavailability of tacrolimus is thought to be a result of the combination of poor water-solubility, pre-systemic metabolism of tacrolimus in the gastrointestinal (Gl) tract and activity of the P-glycoprotein (P-gp) efflux pump found in the enterocytes of the Gl tract.
  • Gl gastrointestinal
  • P-gp P-glycoprotein
  • the tacrolimus formulation used according to the present invention is a modified/extended release formulation of tacrolimus, designed for once a day (q.d.) administration.
  • side effects and risks have the potential to be to less when compared with the products on the market due to reduced maximal blood concentrations (Cmax, rate of absorption).
  • Cmax maximal blood concentrations
  • the toxicities of tacrolimus that are clinically relevant to the target population are nephrotoxicity, neurotoxicity, diabetic effect and hypertension.
  • the extended release of tacrolimus along different intestinal regions also provides the potential to lower the inter- and intra-subject variability of drug absorption in the AIH patients.
  • Tacrolimus is typically initiated at doses of 0.10 - 0.15 mg/kg/day in organ transplant patients with subsequent dosage adjustments to achieve and maintain target whole blood trough concentrations of 5 - 15 ng/mL
  • Prior controlled trials in patients with rheumatoid arthritis demonstrated that fixed doses of 2 mg or 3 mg per day were effective and well tolerated, with resulting concentrations in the range of 2 - 3 ng/mL.
  • a few small uncontrolled studies in patients with AIH have used the immediate release formulation of Prograf ® with starting doses in the range of 1 - 6 mg per day with subsequent dosage changes.
  • patients who are without histological evidence of cirrhosis on liver biopsy and with Model for End-Stage Liver Disease (MELD) score ⁇ 8 are administered with a fixed dose of 2 mg once daily of the controlled release tacrolimus formulation.
  • MELD Model for End-Stage Liver Disease
  • patients with histological evidence of cirrhosis and a MELD score ⁇ 8 are administered with t a fixed dose of 1 mg once daily of the controlled release tacrolimus formulation.
  • whole blood trough concentrations can be measured during the first month, then monthly for a suitable period such as about 3 months, and based on these results the once daily dose can be adjusted to achieve and maintain target levels of 3 - 6 ng/mL.
  • the International Autoimmune Hepatitis Group (IAIHG) has published a scoring system for the diagnosis of AIH .
  • the IAIHG score is based on multiple variables including liver histology; serum biochemistry, immunoglobulins and autoantibodies; viral markers and other etiological factors and is described in International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J
  • a dosage form which when administered to a subject or a number of subjects provides an intra subject and/or an inter subject variability of the mean blood Tmax of tacrolimus which relative to that obtained from administration of the commercial product
  • Advagraf® (MR4) dosage form or a bioequivalent extended release dosage form is decreased with at least 10%, such as at least 15%, such as at least 17.5%, such as at least 20%, such as at least 22.5%, such as at least 25%, such as at least 27.5% such as at least 30% when being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • a dosage form which when administered to a subject or a number of subjects provides an intra subject and/or an inter subject variability of the mean blood Cmax and/or AUC(O- 00 ) of tacrolimus which relative to that obtained from administration of the commercial product Advagraf® (MR4) or a bioequivalent extended release dosage form is decreased with at least 10%, such as at least 15%, such as at least 17.5%, such as at least 20%, such as at least 22.5%, such as at least 25%, such as at least 27.5% such as at least 30% when being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • MR4 commercial product Advagraf®
  • a dosage form which when administered to a subject or a number of subjects provides a decreased Cmax value relative to that obtained by administration of the commercial product Advagraf® (MR4) or a bioequivalent extended release dosage form of at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 35%, or at least about 40 or more, or at least about 45%, or at least about 50%, or at least about 55%, the Cmax values being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • MR4 commercial product Advagraf®
  • a dosage form which when administered to a subject or a number of subjects provides an increased bioavailability relative to that obtained by administration of the commercially product Advagraf® (M R4) or a bioequivalent extended release dosage form of at least about 20%, or at least about 25%, 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 at least about 55%, or at least about 60%, such as at least 65%, the bioavailability being determined as AUC(O- 00 ) and under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • M R4 commercially product Advagraf®
  • a bioequivalent extended release dosage form of at least about 20%, or at least about 25%, 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 at least about 55%, or at least about 60%, such as at least 65%, the bioavailability being determined as AUC
  • a dosage form which when administered to a subject or a number of subjects provides an intra subject and/or an inter subject variability of the mean blood Tmax of tacrolimus which relative to that obtained by administration of the commercially available Prograf® dosage form or a bioequivalent immediate release tacrolims dosage form is decreased with at least 10%, such as at least 15%, such as at least 17.5%, such as at least 20%, such as at least 22.5%, such as at least 25%, such as at least 27.5% such as at least 30% when being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • a dosage form which when administered to a subject or a number of subjects provides an intra subject and/or an inter subject variability of the mean blood Cmax and/or AUC(O-") of tacrolimus which relative to that obtained by administration of the commercially available Prograf® dosage form or a bioequivalent immediate release dosage form is decreased with at least 10%, such as at least 15%, such as at least 17.5%, such as at least 20%, such as at least 22.5%, such as at least 25%, such as at least 27.5% such as at least 30% when being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • a dosage form which when administered to a subject or a number of subjects provides a decreased Cmax value relative to that obtained by administration of the commercially available Prograf® dosage form or a bioequivalent immediate release dosage form of at least 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 at least about 55%, or at least about 60%, or at least about 65%, when being determined under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • a dosage form which when administered to a subject or a number of subjects provides an increased bioavailability relative to that obtained by administration of commercially available Prograf® dosage form or a bioequivalent immediate release dosage form of at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 35%, or at least about 40 or more, or at least about 45%, or at least about 50%, or at least about 55%, the bioavailability being determined as AUC(O- ⁇ ) and under similar conditions and administered in similar molecular dosages of the tacrolimus.
  • a dosage form which when administered to a subject or a number of subjects after at least 4 hours fasted state in the evening provides an bioavailability which relative to that obtained after administration of the dosage form in the morning after at least 4 hours fasted state is at least 70%, such as at least 80%, preferable at least 85% more preferable at least 90% and preferable at least 95% of the value measured after administration in the morning.
  • a dosage form which when administered to a subject or a number of subjects after at least 4 hours fasted state in the evening provides a C(max) which relative to that obtained after administration of the dosage form in the morning after at least 4 hours fasted state is at least 70%, such as at least 80%, preferable at least 85% more preferable at least 90% and preferable at least 95% value measured after administration in the morning.
  • a oral dosage form which when comprising 5 mg of tacrolimus and when administered as a single dose to at least 6 healthy subjects in fasted state provides a mean maximal concentration (Cmax) of tacrolimus of at the most 15 ng/mL, such as at the most 13 ng/mL and a mean AUC(0-96h) of at least 45 mg « h/L, such as at least 55 mg*h/L, such as at least 60 mg « h/L.
  • a dosage form according to wherein the blood concentration 24 after administration of tacrolimus is at least 2 ng/mL such as at least 3 ng/mL such as at least 4 ng,/mL .
  • a dosage form which when administered once daily in steady state to a healthy subject or a patient, the swing of the blood concentrations of tacrolimus measured as (Cmax-Cmin)/Cmin is less than the swing observed when administering the Advagraf® dosage form or a bioequivalent extended release dosage form of tacrolimus in a once daily regimen and being determined under similar conditions and administered in similar molecular daily dosages of the tacrolimus.
  • the decrease is preferable at least 10%, such as at least 20%, preferable at least 30%, such as at least 40%, more preferred at least 50%.
  • a oral dosage form which when administered once daily in steady state to a healthy subject or a patient, the swing of the blood concentrations for total and/or free tacrolimus measured as (Cmax-Cmin)/Cmin is less than the swing observed when administering the Prograf® dosage form or a bioequivalent immediate release composition of tacrolimus in a twice daily regimen and being determined under similar conditions and administered in similar molecular daily dosages of the tacrolimus.
  • the decrease is preferable at least 10%, such as at least 20%, preferable at least 30%, such as at least 40%, more preferred at least 50%.
  • the decrease is preferable at least 10%, such as at least 20%, preferable at least 30%, such as at least 40%, more preferred at least 50%.
  • a dosage form which when administered once daily in steady state to a healthy subject or a patient, the fluctuation of the blood concentrations for total tacrolimus measured as (Cmax-Cmin)/Caverage is less than the fluctuation observed when administering the Prograf® dosage form or a bioequivalent immediate release composition of tacrolimus in a twice daily regimen and being determined under similar conditions and administered in similar molecular daily dosages of the tacrolimus.
  • the decrease is preferable at least 10%, such as at least 20%, preferable at least 30%, such as at least 40%, more preferred at least 50%.
  • a dosage form which when administered to at least 6 healthy subjects in fasted state, the mean residence time, MRT, of tacrolimus measured in blood is at least 10% longer than the mean residence time measured under bioequivalent conditions with the Advagraf® dosage form or a similar extended release dosage form of tacrolimus.
  • the MRT is increased by at least 20% such as by 25%.
  • a oral dosage forms which when administered to at least 6 healthy subjects in fasted state, the mean residence time tacrolimus measured in blood is at least 35% longer than the mean residence time measured under similar conditions with the Prograf® dosage form or a bioequivalent immediate release dosage form of tacrolimus.
  • the present invention provides for a method for providing immunosuppressive treatment of a patient in need thereof in a once daily regimen by administration of an extended release formulation as described herein an providing one or more of decreased Cmax, swing, fluctuation, increased AUC, MRT, Tmax, and Cmin and when compared with a BID regimen with Prograf® or once daily regimen with Advagraf® and measured under similar conditions, whether as a single dose or a multiple dose study.
  • the difference in bioavailability is substantially independent of the time of the day the dosage is administered. This provides the possibility of a once daily dosage regimen at bedtime or in the evening in addition to the normal morning dosing.
  • the risk of decreased exposure if the patient actually ingest the dosage form on a different time than prescribed and expected (non compliance by the patient), the risk for the patient is decreased for reduced exposure and thereby increased risk of e.g transplant rejection.
  • the invention provides for a conversion from a bid regimen with a higher dosage.
  • One method for such conversion is from Prograf® to once daily regimen according to the present invention decreasing the daily dosage of the tacrolimus immediate release regimen with between 25% to 50%, such as with between 30% to 40%, preferable with approximately 33%.
  • the reduction is to the extent possible by use of an extended release once daily dosage forms selected from 0.5 mg 1 mg, 1.5 mg, 2 mg and 5 mg once daily dosage forms.
  • An especially important aspect of the invention is the substantial reduced peak concentrations which provide for a decrease in peak concentration related side effects.
  • Such effect can however be difficult to measure due to th einter and intra subject variation of the present tacrolimus treatments and the nature of the side effects which are often of a subjective character or may require tissue biopsies to determine. Careful questionnaires and high number of patients will be needed for comparison studies to demonstrate such effect with significance.
  • treatment with a extended release formulation according to the present invention may reduce some possible peak concentration related side effects including side effects of a neurological origin such as tremor and headache.
  • the decrease in side effect is related to the risk of prolonged QTc interval due to an effect on ventricular repolarisation.
  • Other toxicities included which are contemplated to be decreased is development of kidney damage, the development of diabetes as well as development of hypertension.
  • the accumulation occurring in some organs may be associated with organ damage, especially as the accumulation or the individual tacrolimus concentration may not decrease during the period with the low blood concentration during the later times of the dosing interval.
  • This lack of clearance from an organ may be related to the high affinity of tacrolimus to that organ overcoming the otherwise expected clearance of such highly vascuralised organs.
  • the high peaks or the present available commercial dosage forms may contribute to tacrolimus being bound in these organs which may comprise as high as nearly 30 times the concentration of the blood in steady state with conventional dosage forms.
  • autoimmune hepatitis can result in excessive hepatitis.
  • the invention also relates to a method of treating patients in risk of organ toxicity form tacrolimus.
  • the organs known to accumulate tacrolimus include the adrenal gland, lung, heart, liver, gastrointestinal tract and kidney.
  • the pancreas and especially the islet of Langerhans may be sensitive for high concentrations, especially during the initiation of tacrolimus, whereby the risk of developing diabetes on a later time may be substantially increased.
  • Other organs correlated with toxicity are the central nervous system.
  • the treatment allow for reducing steroids, such as prednisone.
  • steroids such as prednisone.
  • steroid relates to prednisone or steroids well known in art as being equivalent with prednisone and any dosages referred to herein of steroid is a dose equivalent with the dose of prednisone; generally referred to as prednisolone-equivalent or prednisolone (equivalent).
  • a method according to the invention comprising decreasing any co-administered steroid dosage with 5 mg every 1 to 3 weeks, preferable every 1 to 2 weeks, more preferred every week to maintenance dosage of steroid of at the most 10 mg per day such as of 5 mg per day.
  • the steroid is then prednisolone or a prednisolone equivalent.
  • Prograf 4mg (4x1 mg capsules) demonstrated comparable AUC for both products when administered under fasting conditions. However, they differ in their rate of absorption when administered in the fasted condition, being slower and more sustained for the test formulation, Tacrolimus extended release.
  • Study Tacrolimus extended release PK-003 was designed as a replicate scintigraphic absorption study in 8 healthy volunteers to evaluate the transit time, pharmacokinetic profile and site of release of Tacrolimus extended release 2mg tablets, radiolabeled with a maximum of 1 MBq 153Sm. In this study, an extended release profile could be demonstrated with a Tmax of ⁇ 6.7 hours. Tacrolimus extended release was well tolerated. Overall, this study demonstrated a modified release profile of Tacrolimus extended release tablets and absorption of tacrolimus from distal parts of the gastrointestinal tract as demonstrated in Figure 2.
  • Tacrolimus extended release PK-004 is a multi-dose, steady-state comparative pharmacokinetic study of Tacrolimus extended release 2mg q.d. vs. Prograf 2x1 mg b.i.d in 14 healthy volunteers. This study demonstrated clearly a once-a-day profile of Tacrolimus extended release versus Prograf b.i.d. In addition, this study demonstrated superior bioavailability of Tacrolimus extended release tablets given once- a-day compared to Prograf capsules given twice-a-day.
  • Tacrolimus extended release 2 mg tablets (q.d.) and Prograf 1 mg capsules (b.i.d.) for 10 successive days there were no significant differences observed in the morning pre-dose concentrations between Days 7, 8, 9, and 10, therefore steady state was maintained since Day 7.
  • the systemic exposure over the period of 24 hours of Tacrolimus extended release 2 mg Tablets (q.d.) was about 50% higher than that of Prograf 1 mg capsules (b.i.d.).
  • the time to peak concentration between the single and multiple doses of Tacrolimus extended release 2mg q.d. and Prograf 2x1 mg b.i.d was similar for both treatments.
  • the Tacrolimus extended release 2 mg tablets had higher Cmin values and lower degree of fluctuation than that of the immediate-release Prograf 1 mg capsules (b.i.d.). There was no significant difference observed in Cmax between the 2 treatments.
  • This study investigated the pharmacokinetic profile of tacrolimus after administration of Tacrolimus extended release 2 mg in the morning vs. evening in 26 male and female healthy volunteers under fasting conditions.
  • the study consisted of two eight-day periods separated by at least a two-week washout period between treatments.
  • the mean pharmacokinetic parameters are summarized in theTable below.
  • the release time for the extended release dosage forms according to the invention used in the clinical trials described herein all provides an extended release profile where less than 63.5% is released within 15 hours.
  • a relevant release profile in this respect is demonstrated in Fig 1 , tested according to the USP Il dissolution test (paddle) in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm. Accordingly, a release profile wherein less than 50% is released within 8 hours.
  • the primary objective of this study is to determine and compare the rate and extent of absorption of tacrolimus from a test formulation of Tacrolimus extended release 2 mg Tablets taken once daily (q.d.) versus the reference Advagraf® 2 x 1 mg Capsules (q.d.) under multiple-dose, fasting conditions.
  • Advagraf® is manufactured by Astellas Pharma GmbH Munich, Germany
  • Subjects will receive 1 of the following treatments on Days 1 to 10 of each study period, according to a randomization scheme:
  • a total of 50 blood samples (4 mL each) will be drawn in each period according to the following schedule:
  • Day 1 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 12.00, 14.00, 16.00, 20.00 and 24.00 (pre-dose for Day 2 dosing) hours post- dose.
  • Days 5, 6, 7, 8, and 9 0.00 (pre-dose) and 12.00 hours post-dose.
  • Day 10 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 12.00, 14.00, 16.00, 20.00, 24.00, 48.00, 72.00, 96.00 and 120.00 hours post-dose.
  • PK The PK parameters were calculated using non-compartmental analysis for tacrolimus as follows:
  • the present invention provided a formulation which with an 2 mg oral dosing in the morning provides an average concentration for full 24 hours which is above 4 ng/mL (according to results below a Cmin of 4.66 ng/mL is provided) which is substantially higher than with the marketed once daily product Advagraf® (Cmin 2.80 ng/mL) with the same administered dosage.
  • Treatment A 1 Tacrolimus extended release 2 mg Tablet (q.d.)
  • Treatment A 1 LCP Tacro 2 mg Tablet (q.d.)
  • Treatment A 1 LCP Tacro 2 mg Tablet (q.d.)
  • Treatment B 2 Advagraf ® 1 mg Capsules (q.d.)
  • Treatment A 1 LCP Tacro 2 mg Tablet (q.d.)
  • Test Treatment A: 1 LCP Tacro 2 mg Tablet (q.d.)
  • Treatment A 1 LCP Tacro 2 mg Tablet (q.d.)
  • Treatment A 1 LCP Tacro 2 mg Tablet (q.d.)
  • Treatment B 2 Advagraf® 1 mg Capsules (q.d.) Table 21
  • Tacrolimus extended release tacrolimus
  • a product according to the invention will be started at 2 mg once daily (q.d.) with weekly measurement of tacrolimus whole blood trough levels and adjustment of the daily dose of Tacrolimus extended release to achieve target tacrolimus levels of 3 - 6 ng/mL.
  • AZA will be started at 50 - 100 mg (approximately 1 mg/kg) once daily (q.d.). Patients will also commence treatment with prednisone 30 mg/day for one week, then 20 mg/day for one week, then 15 mg/day for two weeks, then 10 mg/day through Month 6.
  • Tacrolimus tablets will be administered orally once daily in the morning to maintain trough blood levels of tacrolimus of 3 - 6 ng/mL.
  • Azathioprine Dosage azathioprine will be administered orally once daily in the morning at 50 - 100 mg/day (approximately 1 mg/kg/day).
  • Prednisone Dosage Prednisone will be administered orally once daily in the morning at 30 mg/day for one week, then 20 mg/day for one week, then 15 mg/day for two weeks, then 10 mg/day through Month 6.
  • AIH defined by the revised International Autoimmune Hepatitis Group (IAIHG) criteria
  • Women of childbearing potential must have a negative serum pregnancy test within seven days prior to receiving study medication and agree to use contraceptive measures to avoid pregnancy during participation in the trial.
  • the safety population is defined as all subjects who received at least one dose of study medication (intent to treat population; ITT, the ITT population contains all randomized subjects). Standard summary and/or analysis techniques will be used for the evaluation of AEs, SAEs 1 vital sign measurements, clinical laboratory results, physical examinations, and ECGs.
  • Biochemistry and Renal Profile Creatinine, BUN, calculated creatinine clearance, fasting glucose, and electrolytes
  • CBC Hemoglobin, hematocrit, platelets and white blood cell count
  • Hepatic Profile Albumin, gamma globulin, total bilirubin, indirect bilirubin, AST,
  • Tacrolimus is typically initiated at doses of 0.10 - 0.15 mg/kg/day in organ transplant patients with subsequent dosage adjustments to achieve and maintain target whole blood trough concentrations of 5 - 15 ng/mL
  • Prior controlled trials in patients with rheumatoid arthritis demonstrated that fixed doses of 2 mg or 3 mg per day were effective and well tolerated, with resulting concentrations in the range of 2 - 3 ng/mL.Error! Reference source not found..Error! Reference source not found.
  • Small uncontrolled studies in patients with AIH have used starting doses of 1 - 6 mg per day with subsequent dosage adjustments based on clinical response. Error! Reference source not found.-Error! Reference source not found.
  • Whole blood trough concentrations in these studies are reported to range between 2 - 10 ng/mL but these reports lack sufficient information to draw definitive conclusions about the relationship of drug exposure to clinical outcomes.
  • the optimal dose and target concentration of tacrolimus in patients with AIH are unknown.
  • the purpose of the present study is to evaluate the efficacy of tacrolimus extended release product in the treatment of patients with AlH

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Abstract

Cette invention concerne le traitement de l'hépatite auto-immune avec une formule orale à libération prolongée comprenant le tacrolimus comme substance active, ou un analogue pharmaceutiquement actif, administrée une fois par jour chez un patient qui en a besoin. La formule libère la substance active sur une durée prolongée définie par une libération de 63,5 % au plus de la teneur de la substance active au bout de 12 heures de dissolution in vitro et dans le cadre du test de dissolution selon l'USP Il (palette) ou selon l'USP I (panier) dans un milieu de pH 4,5 et comprenant 0,005 % d'hydroxypropyl cellulose à une rotation de 50 tr/min. La formule à libération prolongée donne de meilleurs paramètres pharmacocinétiques à cause de la libération in vivo prolongée et constante comprenant des concentrations maximales diminuées importantes en dépit d'une biodisponibilité accrue, des prolongations importantes de la concentration maximale et des concentrations minimales supérieures par rapport aux formules à libération immédiate classiques et à une formule à libération modifiée récente. Le traitement permet par ailleurs la réduction de la prise de stéroïdes par rapport à la dose nécessaire pour un traitement classique de l'hépatite auto-immune comme avec l'azathioprine.
PCT/DK2008/000440 2007-12-21 2008-12-19 Traitement de l'hépatite auto-immune avec une formule orale à base de tacrolimus administrée une fois par jour WO2009080030A1 (fr)

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DKPA200701855 2007-12-21

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9493477B2 (en) 2009-09-08 2016-11-15 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
US9499581B2 (en) 2011-01-11 2016-11-22 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable oxycodone prodrug
US9585963B2 (en) 2010-04-21 2017-03-07 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
CN109682939A (zh) * 2018-12-26 2019-04-26 四川健能制药有限公司 一种美沙拉秦灌肠液溶出度测定方法
WO2019097136A1 (fr) 2017-11-17 2019-05-23 Safran Transmission Systems Cage de réducteur de vitesse a train planétaire ou épicycloïdal de turbomachine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005020994A1 (fr) * 2003-08-29 2005-03-10 Lifecycle Pharma A/S Dispersions solides comprenant du tacrolimus
WO2005032525A1 (fr) * 2003-10-03 2005-04-14 Lifecycle Pharma A/S Procede de preparation de compositions pharmaceutiques a liberation modifiee
WO2008145143A1 (fr) * 2007-05-30 2008-12-04 Lifecycle Pharma A/S Forme pharmaceutique orale à administrer une fois par jour comportant du tacrolimus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005020994A1 (fr) * 2003-08-29 2005-03-10 Lifecycle Pharma A/S Dispersions solides comprenant du tacrolimus
WO2005032525A1 (fr) * 2003-10-03 2005-04-14 Lifecycle Pharma A/S Procede de preparation de compositions pharmaceutiques a liberation modifiee
WO2008145143A1 (fr) * 2007-05-30 2008-12-04 Lifecycle Pharma A/S Forme pharmaceutique orale à administrer une fois par jour comportant du tacrolimus

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FIRST M ROY ET AL: "Modified release tacrolimus", YONSEI MEDICAL JOURNAL, SEOUL, KR, vol. 45, no. 6, 31 December 2004 (2004-12-31), pages 1127 - 1131, XP002499540, ISSN: 0513-5796 *
HEFFRON T G ET AL: "Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients", AMERICAN JOURNAL OF TRANSPLANTATION, BLACKWELL MUNKSGAARD, DK, vol. 7, no. 6, 1 June 2007 (2007-06-01), pages 1609 - 1615, XP002499541, ISSN: 1600-6135 *
HENEGHAN M A ET AL: "Low dose Tacrolimus as treatment of severe Autoimmune Hepatitis: Potential role in remission induction", GUT, BRITISH MEDICAL ASSOCIATION, LONDON, vol. 44, no. Suppl.1, 1 April 1999 (1999-04-01), pages A61, XP009113006, ISSN: 0017-5749 *
LARSEN FIN STOLZE ET AL: "Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis", WORLD JOURNAL OF GASTROENTEROLOGY, WJG PRESS, CN, vol. 13, no. 23, 21 June 2007 (2007-06-21), pages 3232 - 3236, XP009113015, ISSN: 1007-9327 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9493477B2 (en) 2009-09-08 2016-11-15 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
US10028945B2 (en) 2009-09-08 2018-07-24 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
US9585963B2 (en) 2010-04-21 2017-03-07 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
US9499581B2 (en) 2011-01-11 2016-11-22 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable oxycodone prodrug
WO2019097136A1 (fr) 2017-11-17 2019-05-23 Safran Transmission Systems Cage de réducteur de vitesse a train planétaire ou épicycloïdal de turbomachine
US11143271B2 (en) 2017-11-17 2021-10-12 Safran Transmission Systems Cage for a turbomachine speed reducer with planetary gear set
CN109682939A (zh) * 2018-12-26 2019-04-26 四川健能制药有限公司 一种美沙拉秦灌肠液溶出度测定方法

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