WO2014140695A1 - Formulation orale solide d'un composé de flavone substitué par pyrrolidine - Google Patents

Formulation orale solide d'un composé de flavone substitué par pyrrolidine Download PDF

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Publication number
WO2014140695A1
WO2014140695A1 PCT/IB2013/052069 IB2013052069W WO2014140695A1 WO 2014140695 A1 WO2014140695 A1 WO 2014140695A1 IB 2013052069 W IB2013052069 W IB 2013052069W WO 2014140695 A1 WO2014140695 A1 WO 2014140695A1
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Prior art keywords
pharmaceutical composition
disorder
compound
methyl
chromen
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PCT/IB2013/052069
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English (en)
Inventor
Arno Appavoo Enose
Milind VARTAK
Maneesh Nerurkar
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Piramal Enterprises Limited
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Priority to PCT/IB2013/052069 priority Critical patent/WO2014140695A1/fr
Publication of WO2014140695A1 publication Critical patent/WO2014140695A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (+) trans-2-(2-chloro-phenyl)-57-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl) -chromen-4-one or a pharmaceutically acceptable salt thereof; as the active ingredient and one or more surfactant and a solubilizer; and to methods of preparation of the pharmaceutical composition.
  • the pharmaceutical composition provides for a self emulsifying drug delivery system (SEDDS) for oral administration of the said compound.
  • SEDDS self emulsifying drug delivery system
  • Metabolism plays an important role in the bioavailability of a certain number of active principles. Poor bioavailability of drugs has been a major limitation in the successful utilization of many therapeutically effective molecules. Many of the new drug candidates tend to be poorly absorbed in the aqueous medium present in the gastrointestinal (Gl) tract. The problem of poor bioavailability is at times further compounded by a faster elimination rate which in turn reduces the efficiency of such molecules being used as a drug of choice.
  • Parenterally administered drugs are relatively unstable and also generally potent drugs that require strict control of administration to the patient. Moreover, parenteral administration of drugs is relatively painful and causes distress to the patient. Also, parenteral administration of drugs requires strict aseptic procedures, and parenteral dosage forms are costlier than formulations administered by other routes, particularly oral route.
  • the oral route of drug delivery is the major and most desirable route for the treatment of several diseases. Solid oral dosage forms are popular because of the ease of administration, accurate dosage, self-medication, painless administration, and most importantly the patient compliance. Despite the ease of oral route of administration to patients, the drugs used in the treatment of cancers and certain other proliferative disorders were mostly available in parenteral forms until the recent times. A few new oral chemotherapeutic agents have recently been introduced.
  • Compound A is an effective therapeutic agent for the treatment of an animal or a human suffering from a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • Compound A has been found to be a potent investigational drug particularly in the treatment of cancer amongst other indications specified above but poor bioavailability of the compound may limit its use from the perspective of patient compliance. There exists a need for producing stable oral formulations with improved bioavailability to address the potential problems associated with parenteral forms. The inventors of the present invention have directed their efforts to provide a solution to this problem in the form of a solid oral dosage form which improves the bioavailability of compound A.
  • the present invention provides the required pharmaceutical composition in the form of an oral solid dosage form and the methods for their preparation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (+) trans-2-(2-chloro-phenyl)-5, 7-dihydroxy-8-(2-hydroxy methyl-1 - methyl-pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof, as an active ingredient along with one or more surfactant and a solubilizer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, (+) trans-2-(2-chloro-phenyl)-5, 7-dihydroxy-8- (2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (referred to herein as compound A), along with one or more surfactant and a solubilizer.
  • the present invention provides a pharmaceutical composition for oral administration in the form of a capsule dosage form, comprising the compound A.
  • the capsule may be a hard or a soft gelatine capsule.
  • the present invention provides a pharmaceutical composition for oral administration in the form of a tablet dosage form, comprising the compound A.
  • a method of preparation of a solid oral dosage form comprising the compound A, along with one or more surfactant and a solubilizer.
  • a method for the treatment of a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality comprising administering to the subject therapeutically effective amount of a pharmaceutical composition comprising the compound A, along with one or more surfactant and a solubilizer in the form of a stable oral dosage according to one or more of the embodiments as described herein.
  • pharmaceutically acceptable excipient refers to a non-therapeutic agent such as diluents, binders, disintegrants, lubricants, glidants, colorants, flavorants, sweeteners and desiccants.
  • the non-therapeutic agents have effects on the physical, chemical and biopharmaceutical properties of the finished dosage form e.g. capsules or tablets.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or a diluent that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering a therapeutically active agent to the target site without interfering with the activity of the active pharmaceutical agent.
  • active pharmaceutical ingredient refers to (+) trans-2-(2-chloro-phenyl)- 5, 7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof.
  • active pharmaceutical ingredient refers to (+) trans-2-(2-chloro-phenyl)-5, 7- dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one
  • hydrochloride compound A
  • therapeutically effective amount refers to an amount of active pharmaceutical ingredient effective in producing the desired therapeutic response in a subject in need, for the treatment of a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • carcinoma refers to carcinoma, including that of bladder, breast, colon, kidney, liver, lung, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate, intestine and skin; hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomysarcoma; and other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma and glioma.
  • subject refers to an animal, preferably a mammal.
  • mammal refers to warm-blooded vertebrate animals of the class 'Mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and a human.
  • the preferred mammal is human.
  • treatment refers to alleviate, slow the progression, prophylaxis, attenuation or cure of existing disease or condition (e.g., cancer). Treatment also includes treating the symptoms of the disease or condition.
  • bioavailability refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action (Pharmaceutical Research, 2001 , 18, 12, 1645-1650).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (+) trans-2-(2-chloro-phenyl)-5, 7-dihydroxy-8-(2-hydroxymethyl-1 - methyl-pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof as an active ingredient and one or more surfactant and a solubilizer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (+) trans-2-(2-chloro-phenyl)-5, 7-dihydroxy-8-(2- hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound A) as an active ingredient and one or more surfactant and a solubilizer.
  • a pharmaceutical composition comprising 30 % to 80 % of the active ingredient, 10 % to 30 % of the surfactant and 20 % to 40 % of the solubilizer.
  • a pharmaceutical composition comprising 40 % to 70 % of compound A.
  • the pharmaceutical composition provides for a self emulsifying drug delivery system (SEDDS) for oral administration of (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl- pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof as the active ingredient.
  • SEDDS self emulsifying drug delivery system
  • the pharmaceutical composition provides for a self emulsifying drug delivery system (SEDDS) for oral administration of (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl- pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound A).
  • SEDDS self emulsifying drug delivery system
  • compound A is a representative example of the compounds of formula I as disclosed in US patent no. 7, 271 ,193 and is poorly bioavailable at all physiological pH conditions. Accordingly, an object of the present invention is to increase the bioavailability of the compound A by developing a solid oral dosage form.
  • a process for the preparation of a capsule dosage form comprising (+) trans-2-(2-chloro-phenyl)-5, 7- dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof as the active ingredient, comprising the steps of: step (a): sifting the active ingredient; step (b): heating a surfactant and a solubilizer at a temperature ranging from 65 to
  • a process for the preparation of a capsule dosage form comprising, (+) trans-2-(2-chloro-phenyl)-5, 7-dihydroxy-8-(2- hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound A) as the active ingredient is provided, which process comprises steps (a) to (e) as described above.
  • the pharmaceutically acceptable excipients of step (d) for the preparation of a capsule dosage form are selected from diluents, binders, disintegrants, lubricants, glidants, colorants, flavorants, sweeteners and desiccants, which are described herein below.
  • the surfactant contained in the pharmaceutical composition is selected from ionic or non-ionic surfactant.
  • the surfactant include, but are not limited to, non-ionic surfactant selected from Cremophor ® EL, Cremophor ® RH, d-a- tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS), polysorbate 20, polysorbate 80, Solutol ® HS 15, sorbitan monooleate, poloxamers, Labrafils ® , Labrasol ® , Gellucire ® 44/14, Softigen ® 767, mono- and di-fatty acid esters of polyethylene glycol or a combination thereof.
  • non-ionic surfactant selected from Cremophor ® EL, Cremophor ® RH, d-a- tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS), polysorbate 20, polysorbate 80, Solutol ® HS 15, sorbitan monooleate, poloxamers, Labrafils ® , Labrasol ® ,
  • the surfactant is d-a-tocopherol polyethylene glycol 1000 succinate.
  • This surfactant, d-a-tocopherol polyethylene glycol succinate (Vitamin E TPGS or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG).
  • one or more of the surfactant can act as an emulsifier in the resulting pharmaceutical composition.
  • the solubilizer include, but are not limited to, a group comprising polyethylene glycol (having molecular weight between 300-6000), propylene glycol derivatives, glycerin, Cremophor ® , polysorbates, Lutrol ® CarbitolTM, or a combination thereof.
  • the solubilizer is polyethylene glycol (PEG) with molecular weight of 1000, commonly known as PEG 1000.
  • a pharmaceutical composition comprising 40 % to 70 % of compound A as the active ingredient, 10 % to 30 % of vitamin E TPGS as the surfactant and 20 % to 40 % of PEG 1000 as the solubilizer.
  • the pharmaceutical composition herein described according to the various embodiments may then be further adapted for oral administration in discrete units such as capsules.
  • the capsule may be hard or soft gelatine capsule.
  • the pharmaceutical composition of the present invention is formulated as hard gelatine capsules.
  • the compositions herein described containing the active ingredient may be utilized as is, or can be further combined with one or more of non-toxic pharmaceutically acceptable carrier such as ethanol, glycerol, glycerin, water, and the like.
  • compositions of the invention may be encapsulated in the form of a semisolid or solid matrix or in the form of a liquid in a capsule to yield a solid oral capsule dosage form.
  • Powders may be prepared, for example, by comminuting the composition of the invention, or the active compound, to a suitable fine size and if desired, further mixing with a similarly comminuted pharmaceutically acceptable carrier.
  • hydroxypropyl methylcellulose HPMC
  • cellulose methylcellulose
  • starch or combinations thereof.
  • capsule dosage form both hard and soft
  • Other methods for preparing capsule dosage form known in the art may also be utilized.
  • a process for the preparation of a tablet dosage form comprising (+) trans-2-(2-chloro-phenyl)- 5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one
  • step a) sifting the active ingredient and the diluents
  • step b) mixing the sifted active ingredient with the sifted diluents to obtain a mixture
  • step c) preparing a binder solution containing a surfactant by dissolving the surfactant and binding agent in purified water
  • step d) preparing granules by adding binder solution of step (c) to the mixture of step (b), passing the resultant mixture through sieves to obtain wet granules, drying the wet granules at a temperature ranging from 50 °C to 100°C and passing the dried granules through sieves
  • step e) sifting glidant and disintegrant through sieves, blending the sifted glidant and the disintegrant with the granules prepared in step (d) to obtain a blend, further adding
  • the surfactant used in the preparation of the tablet dosage form is selected from ionic or non-ionic surfactant.
  • the surfactant used in the preparation of the tablet dosage form include, but are not limited to, non-ionic surfactant described herein.
  • the surfactant used in the preparation of the tablet dosage form is d-a-tocopherol polyethylene glycol 1000 succinate.
  • the diluents or fillers used in the preparation of the capsule or tablet dosage form include, but are not limited to, cellulose derivatives, such as microcrystalline cellulose or wood cellulose, anhydrous lactose, lactose monohydrate, directly compressible anhydrous lactose, modified lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, calcium carbonate, calcium phosphate, dibasic calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate, dextrins, dextrates, maltodextrin, compressible sugars, or a combination thereof.
  • cellulose derivatives such as microcrystalline cellulose or wood cellulose
  • anhydrous lactose lactose monohydrate
  • directly compressible anhydrous lactose modified lactose monohydrate
  • sucrose starch
  • binders used in the preparation of the capsule or tablet dosage form include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, polyvinyl pyrrolidone (PVP), carboxymethylcellulose, lactose, polyethylene glycol, gum acacia, tracaganth, sodium alginate, ethyl cellulose, cellulose acetate, carnauba wax, paraffin, polyethylenes or microcrystalline wax, or a combination thereof.
  • PVP polyvinyl pyrrolidone
  • glidants used in the preparation of the capsule or tablet dosage form include but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates or hydrated silica, or a combination thereof.
  • disintegrating agent used in the preparation of the capsule or tablet dosage form include, but are not limited to starch, pregelatinized starch, corn starch, sodium starch glycolate, hydroxypropyl cellulose, agar-agar, calcium carbonate, or sodium carbonate, croscarmellose sodium, crospovidone, or a combination thereof, which can be added to the pharmaceutical composition in order to improve the bioavailability of the medicament when the dosage form is ingested.
  • lubricant used in the preparation of the capsule or tablet dosage form include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium oleate, sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid, hydrogenated vegetable oils and fats, or a combination thereof.
  • the pharmaceutical composition of the present invention may optionally also contain a pharmaceutically acceptable antioxidant for stabilization of the dosage form.
  • a pharmaceutically acceptable antioxidant for stabilization of the dosage form.
  • antioxidants include, but not limited to, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate and vitamin E.
  • a preservative, flavoring, desiccant, dispersing or coloring agent can also be added into the pharmaceutical composition of the present invention.
  • the administration of the pharmaceutical composition of the present invention improves oral bioavailability of the compound A in dogs to 30 % to 40 % in comparison to intravenous administration.
  • a method for the treatment of a disease or disorder in a subject in need thereof comprising administering to the subject, the pharmaceutical composition comprising a therapeutically effective amount of the active pharmaceutical ingredient, (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl- pyrrolidin-3-yl)-chromen-4-one, or a pharmaceutically acceptable salt thereof; wherein the disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • a method for the treatment of a disease or disorder in a subject in need thereof comprising administering to the subject, the pharmaceutical composition comprising a therapeutically effective amount of the active pharmaceutical ingredient, (+) trans-2- (2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)- chromen-4-one, or a pharmaceutically acceptable salt thereof; wherein the disease or disorder is selected from cancer, polycystic kidney disease, radiation induced mucositis or viral infection.
  • the pharmaceutical composition used in the method described herein above is a solid oral capsule dosage form.
  • the active pharmaceutical ingredient used in the method described herein above is (+) trans-2-(2-chloro- phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound A).
  • the pharmaceutical composition comprising a therapeutically effective amount of the active pharmaceutical ingredient, (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8- (2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one, or a pharmaceutically acceptable salt thereof; in the treatment of a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.
  • the pharmaceutical composition comprising a therapeutically effective amount of the active pharmaceutical ingredient, (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2- hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one, or a pharmaceutically acceptable salt thereof; in the treatment of a disease or disorder selected from wherein the disease or disorder is selected from cancer, polycystic kidney disease, radiation induced mucositis or viral infection.
  • the pharmaceutical composition used herein above is a solid oral capsule dosage form.
  • the active pharmaceutical ingredient used herein above is (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2- hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (compound A).
  • AUC(o-t) Area under the curve from the time of dosing to the time of the last measurable concentration
  • reaction mixture was poured over crushed ice (300 g) and made basic using a saturated aqueous Na 2 C0 3 solution.
  • the mixture was extracted using CHCI 3 (3 x 200 mL).
  • the organic extract was washed with water, dried (anhydrous Na 2 S0 4 ) and concentrated to obtain the compound, (+)-irans-2-(2-chloro-phenyl)-8-(2-hydroxymethyl-1 -methyl-pyrrolidin-3-yl)-5,7- dimethoxy-chromen-4-one.
  • the capsule dosage form was prepared using the ingredients as listed in Table 1 .
  • Table 1 lists the ingredients in % of capsule weight and mg/capsule. Table 1
  • the tablet dosage form is prepared using the ingredients as listed in Table 2.
  • Table 2 lists the ingredients in mg/tablet.
  • MCC microcrystalline cellulose
  • sodium starch glycolate colloidal silicon dioxide
  • magnesium stearate magnesium stearate
  • Compound A is sifted through sieve # 20 (A.S.T.M, 850 ⁇ ).
  • MCC and sodium starch glycolate are sifted through sieve # 40 (A.S.T.M, 420 ⁇ ) and mixed with the sifted compound A in a rapid mixer granulator (RMG).
  • RMG rapid mixer granulator
  • a binder solution is prepared by dissolving Speziol® TPGS pharma and polyethylene glycol 1000 in hot purified water at 70° C. The solution is cooled at room temperature.
  • the pharmacokinetic parameters of compound A were determined in three male beagle dogs by a single bolus intravenous (IV) and oral capsule (PO) administration.
  • IV intravenous
  • PO oral capsule
  • the blood samples were collected from the three dogs at pre-dose and post-dose at intervals of 0.25, 0.5, 1 , 2, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h following IV or PO administration. All the dogs underwent a seven or fourteen days wash-out period between IV and PO administration.
  • Compound A was administered via cephalic vein as a single bolus intravenous injection in IV administration.
  • the capsules were administered via a single oral dosing.
  • approximately 10 mL reverse osmosis water was administered. Dose administration information is presented in the following table.
  • Blood samples (approximately 1 mL) were collected via jugular vein, at pre-dose and post-dose at 0.25, 0.5, 1 , 2, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h following IV or PO administration. Blood samples were placed into tubes containing K2-EDTA and centrifuged at 3,500 rpm for 10 min. at 4°C to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes and stored frozen at -80 °C until bioanalysis.
  • PK pharmacokinetic
  • the mean values of half-life and AUC(0- ⁇ ) were 7.69 hours and 1 190.32 ng/ml_ * h, respectively.
  • the Cmax and Tmax were 245.16 ng/mL and 0.83 hour, respectively.
  • the mean bioavailability was 33.32 %.

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Abstract

La présente invention concerne une composition pharmaceutique constituant un système d'administration de médicament auto-émulsifiant (SEDDS) pour administration orale, comprenant un composé, (+)trans-2-(2-chloro-phényl)-5,7-dihydroxy-8-(2-hydroxyméthyl-1-méthyl-pyrrolidin-3-yl)-chromén-4-one ou un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'un ou plusieurs tensioactifs et un solubilisant. La présente invention concerne en outre un procédé pour la préparation de ladite composition pharmaceutique et l'utilisation de la composition pharmaceutique dans le traitement d'une maladie ou un trouble choisi parmi le cancer, la maladie polykystique des reins, un trouble néphrologique, un psoriasis, un trouble immunologique impliquant une prolifération indésirable de leucocytes, une resténose, un trouble de prolifération de muscle lisse, une mucosite induite par rayonnement, une infection virale, une infection fongique ou une anomalie cardiovasculaire.
PCT/IB2013/052069 2013-03-15 2013-03-15 Formulation orale solide d'un composé de flavone substitué par pyrrolidine WO2014140695A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070015802A1 (en) * 2002-07-08 2007-01-18 Nicholas Piramal India Limited Inhibitors of cyclin dependent kinases and their use
WO2007148158A1 (fr) * 2006-06-21 2007-12-27 Piramal Life Sciences Limited Dérivés de flavone enantiomériquement purs pour le traitement de troubles polifératifs et leurs procédés de préparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070015802A1 (en) * 2002-07-08 2007-01-18 Nicholas Piramal India Limited Inhibitors of cyclin dependent kinases and their use
WO2007148158A1 (fr) * 2006-06-21 2007-12-27 Piramal Life Sciences Limited Dérivés de flavone enantiomériquement purs pour le traitement de troubles polifératifs et leurs procédés de préparation

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