WO2010092596A1 - An oral pharmaceutical composition of dutasteride - Google Patents

An oral pharmaceutical composition of dutasteride Download PDF

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Publication number
WO2010092596A1
WO2010092596A1 PCT/IN2010/000073 IN2010000073W WO2010092596A1 WO 2010092596 A1 WO2010092596 A1 WO 2010092596A1 IN 2010000073 W IN2010000073 W IN 2010000073W WO 2010092596 A1 WO2010092596 A1 WO 2010092596A1
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Prior art keywords
pharmaceutical composition
dutasteride
oral pharmaceutical
surfactant
pharmaceutically acceptable
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PCT/IN2010/000073
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French (fr)
Inventor
Deepak Murpani
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Genepharm India Private Limited
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Application filed by Genepharm India Private Limited filed Critical Genepharm India Private Limited
Priority to EP10741016.9A priority Critical patent/EP2395975A4/en
Publication of WO2010092596A1 publication Critical patent/WO2010092596A1/en

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens

Definitions

  • the present invention relates to an oral composition of dutasteride.
  • Dutasteride a synthetic 4- azasteroid compound is an antiandrogen with the chemical name (5 ⁇ , 17 ⁇ ) -N- ⁇ 2, 5 bis (trifluoromethyl) phenyl ⁇ -3- oxo-4-azaandrost -l-ene-17- carboxamide.
  • Dutasteride is indicated for the treatment of symptomatic benign prostate hyperplasia (BPH) in men with enlarged prostate glands.
  • BPH benign prostate hyperplasia
  • Dutasteride a synthetic 4-azasteroid compound is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 ⁇ -reductase (5AR), an intracellular enzyme that converts testosterone to 5 ⁇ -dihydrotestosterone (DHT).
  • 5AR steroid 5 ⁇ -reductase
  • DHT 5 ⁇ -dihydrotestosterone
  • Dutasteride is marketed as 0.5 mg strength soft gelatin capsules for oral administration by M/S Glaxo Smithkline Pharmaceuticals as Avodart. Each capsule contains 0.5 mg dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/ capric acid (349.5mg) and butylated hydroxytoluence (0.035mg).
  • time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in five healthy subjects is approximately 60% (range 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%.
  • the marketed soft gelatin capsules have the following drawbacks.
  • the capsule consists of an oily solution of dutasteride.
  • oily solution of dutasteride.
  • biovailability of oily solution depends on many biopharmaceutical variables the bioavailability may be variable.
  • Lipid based formulation is beautifully classified by Pouton into three broad categories: Type I - Simple solution of Active in Triglycerides and/or mixed glycerides (e.g. Avodart) Type II - Active + Triglycerides and/or mixed glycerides + lipophilic surfactant (HLB ⁇ 12) Type III - Active + Triglycerides and/or mixed glycerides + Hydrophilic surfactant + co-solvent (yielding SMEDDS formulation)
  • SMEDDS Self Microemulsifying Drug Delivery system
  • aqueous media e.g. 0.1 N HCl, Water, pH 4.5 buffer, pH 6.8 buffer (mimicking the GIT fluid pH) can result in a ME.
  • Microemulsion can serve as a very effective dosage form to improve to therapeutic effectiveness of growing number of poorly soluble drugs, both for oral and parenteral route. It has been shown in many cases to significantly increase bioavailability of poorly soluble drugs and also known to improve the inter and intra subject variability, fed/ fasting state bioavailability.
  • Microemulsions is dispersions of oily phase in aqueous phase -o/w ME or vice-versa. The droplet size of dispersed phase below 200 nm makes it transparent or almost transparent (sometimes with bluish tinge).
  • SMEDDS are suitable to be filled in soft gelatin capsule.
  • Hard capsules Gelatin or Non-Gelatin. Conversion of an oily liquid to solid free flowing/ compressible powder is also been increasingly explored.
  • the object of the present invention is to provide dutasteride in a form which may be filled in capsules or converted into powder which may be compressed into pellets or tablets or directly filled in capsules.
  • the present invention provides an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt and the process of its preparation.
  • An oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) /co-surfactant (s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; wherein the composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.
  • a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) /co-surfactant(s) ; c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-75 0 C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and compressed into pellets or tablets or filled into capsules.
  • the present invention relates to oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt which is an admixture of dutasteride or its pharmaceutically acceptable salt, one or more surfactant (s)/ co-surfactant (s), one more oil (s),optionally antioxidant (s) and excipient (s).
  • the admixture may be filled in capsules or adsorbed on a suitable adsorbent to form a free-flowing powder which may be filled in capsules or compressed into pellets or tablets.
  • the oral pharmaceutical composition of the present invention in unabsorbed liquid form upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200nm.
  • Dutasteride is a poorly soluble white to pale yellow powder with its solubility being 0.38 ng/ml in water in water which is below the quantitation limit of the assay. Due to its low solubility it has a correspondingly low degree of bioavailability. Bioavailability of dutasteride or pharmaceutically acceptable salt may be improved by i. Milling /nanonising dutasteride or its pharmaceutically acceptable salt or ii. Dissolving or suspending dutasteride or its pharmaceutically acceptable salt in early stages of production.
  • dutasteride or its pharmaceutically accepted salt generates dust which is hazardous for working personnel.
  • Dissolving dutasteride in solvent like caprylic/capric acid could result in improved bioavailability but it requires very large quantities of solvents such as 349.5 mg for 0.5mg dutasteride.
  • dutasteride or its pharmaceutically acceptable salt when mixed with surfactant (s) / co-surfactant (s) ; oil(s), optionally antioxidant (s) and excipient (s) provides an oral composition which on dissolution with an aqueous medium forms micro emulsion with at least 95% particles having mean particles size below 200nm.
  • dutasteride with surfactant (s), oil(s), optional antioxidant (s) and excipient (s) may be admixture of dutasteride with surfactant (s), oil(s), optional antioxidant (s) and excipient (s)
  • an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of dutasteride or its pharmaceutically acceptable salt; one or more surfactant (s) / co-surfactant(s); one or more oil (s); optionally antioxidant (s); and optionally excipient (s).
  • the admixture may be used as such or filled in capsules or adsorbed on adsorbent and compressed into pellets or tablets or filled in capsules.
  • dutasteride as used herein includes pharmaceutically acceptable salts or solvates and can be in crystalline phase, amorphous phase or a mixture thereof.
  • capsule as used herein includes soft / hard gelatin or hard non-gelatin capsules.
  • Surfactants utilized in the present invention possess an HLB (hydrophilic-lipophilic balance) number greater than 8 based on the HLB system which is well known to those skilled in the art.
  • the HLB number provides a means for ranking surfactants based on the balance between the hydrophilic and lipophilic portions of the surfactant or emulsifying agent. That is, the higher the HLB number, the more hydrophilic the surfactant or emulsifying agent.
  • the surfactant has a hydrophilic-lipophilic balance (HLB) of greater than 8.
  • HLB hydrophilic-lipophilic balance
  • surfactants within HLB in the range of 8-18 form oil/water emulsions.
  • the preferred HLB range for the surfactant is between approximately 10 and 14.
  • composition can also include the addition of an aqueous solvent such as triacetin, an acetylated derivative of glycerol, i.e., glyceryl triacetate or other suitable solvents.
  • an aqueous solvent such as triacetin, an acetylated derivative of glycerol, i.e., glyceryl triacetate or other suitable solvents.
  • Triacetin is suitable since it is miscible in the oil/lipid phase and can be used to solubilize a hydrophobic drug.
  • the oil selected for the oral pharmaceutical composition of the present invention has HLB value below 6 for e.g.
  • Triglycerides of fractionated vegetable C8 and ClO fatty acids usually fractionated coconut oil.
  • the relative proportions of surfactant and co-surfactant in the composition, formulation of the present invention can influence the solubilizing and dissolution properties of the formulation.
  • the range of concentration of the surfactant/ co-surfactant broadly ranges from 15 to 96% (v/v) and more preferably ranges from approximately from 30 to 90% (v/v).
  • the concentration of the co-surfactant broadly ranges from 10 to 80% (v/v).
  • the oil content in the oral composition of the present invention ranges from 4-60%, more preferably 4-44%.
  • the antioxidant used in oral composition of the present invention may be selected from butylated hydroxytoluence, butylated hydroxyl anisole, ⁇ -tocopherol ascorbic acid , ascorbyl palmitate sodium ascorbate, vitamin E, tartaric acid and the like.
  • the excipient used in oral composition of the present invention may be selected from diluents, binders lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners.
  • the adsorbent used in oral composition of the present invention may be selected from kaolin, bentonite, hectorite, colloidal magnesium aluminium silicate, silicon dioxide, magnesium trisilicate, aluminium hydroxide magnesium oxide, talc, calcium - aluminium silicate, lactose.
  • Diluents may be selected from calcium-aluminum silicates (Sipernat 106 PQ), calcium carbonate,calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose,microcrystalline silicified cellulose,powdered cellulose, dextrates, dextrose,fructose,lactitol,lactose anhydrous, lactose monohydrate,lactose dihydrate, lactose trihydrate,mannitol sorbitol, starch, pregelatinized starch ,sucrose,talc,xylitol,maltose maltodextrin,maltitol .
  • Binders may be selected from acacia, alginic acid, carbomer,carboxymethylcellulose calcium, carbomethylcellulose sodium,microcrystalline cellulose,powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulos, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin,methylcellulose,ploydextrose, polyethtylene oxide,povidone,sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose,glucose, sorbitol.
  • Suitable fillers are preferably selected from atleast one of starch derivatives,such as corn starch, potato starch or rice starch.
  • starch derivatives such as corn starch, potato starch or rice starch.
  • Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
  • Disintegrants may for example, example, alginic acid, carbon dioxide, carbonxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low- substituted hydroxypropyl cellulose.
  • Glidants may be , for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.
  • Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
  • Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.
  • Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavour.
  • a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) / co-surfactant (s) ; c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-75 0 C for less than an hour and cooling to ambient temperature.
  • the oral pharmaceutical composition of the present invention upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
  • the admixture may be used as such or filled in capsules or adsorbed on an adsorbent and compressed into pellet or tablets or filled in capsules.
  • a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing, a) dutasteride or its pharmaceutically acceptable salt ; one or more surfactant (s)/ co-surfactant(s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-75 0 C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and filling in capsules or compressing into pellet or tablets.
  • the oral pharmaceutical composition of the present invention wherein the liquid composition, before adsorption on solid, upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
  • PROCEDURE (Example 1-4) :
  • EXAMPLE- 8 and 9 EXAMPLE 10 CONTROL FORMULATON, WET GRANULATION:
  • EXAMPLE 11 DISSOLUTION and GLOBULE SIZE COMPARISON OF ZERO DAY SAMPLE WITH AVODART
  • EXAMPLE 12 DISSOLUTION and GLOBULE SIZE COMPARISON OF 3MONTH ACCELERATED STABILITY STUDY SAMPLE AT 40° C/75% RH
  • EXAMPLE 13 DISSOLUTION COMPARISON OF ZERO DAY SAMPLES WITH AVODART

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Abstract

An oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of a) dutasteride or its pharmaceutically acceptable salt; b) one or more surfactant (s) /co-surfactant(s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s); wherein the composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.

Description

AN ORAL PHARMACEUTICAL COMPOSITION OF DUTASTERIDE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an oral composition of dutasteride. Dutasteride, a synthetic 4- azasteroid compound is an antiandrogen with the chemical name (5α, 17β) -N- {2, 5 bis (trifluoromethyl) phenyl} -3- oxo-4-azaandrost -l-ene-17- carboxamide. Dutasteride is indicated for the treatment of symptomatic benign prostate hyperplasia (BPH) in men with enlarged prostate glands.
BACKGROUND OF THE INVENTION
Dutasteride, a synthetic 4-azasteroid compound is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT).
Dutasteride is marketed as 0.5 mg strength soft gelatin capsules for oral administration by M/S Glaxo Smithkline Pharmaceuticals as Avodart. Each capsule contains 0.5 mg dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/ capric acid (349.5mg) and butylated hydroxytoluence (0.035mg).
Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in five healthy subjects is approximately 60% (range 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%.
The marketed soft gelatin capsules have the following drawbacks.
(a) Capsule cross-linking over a period of time due to gelatin in shell of capsules;
(b) Specialized facility / equipment in manufacturing;
(c) The capsule consists of an oily solution of dutasteride. As biovailability of oily solution depends on many biopharmaceutical variables the bioavailability may be variable. Lipid based formulation is beautifully classified by Pouton into three broad categories: Type I - Simple solution of Active in Triglycerides and/or mixed glycerides (e.g. Avodart) Type II - Active + Triglycerides and/or mixed glycerides + lipophilic surfactant (HLB<12) Type III - Active + Triglycerides and/or mixed glycerides + Hydrophilic surfactant + co-solvent (yielding SMEDDS formulation)
SMEDDS (Self Microemulsifying Drug Delivery system) technically refers to a isotropically clear, thermodynamically stable solution of Active, Oil, surfactant and co-surfactant which when mildly agitated with infinity amount of aqueous medias e.g. 0.1 N HCl, Water, pH 4.5 buffer, pH 6.8 buffer (mimicking the GIT fluid pH) can result in a ME.
In-vivo:
SMEDDS (eg 1.5 gm) + GIT fluid (infinity, e.g. 250 ml) = o/w ME
Microemulsion (ME) can serve as a very effective dosage form to improve to therapeutic effectiveness of growing number of poorly soluble drugs, both for oral and parenteral route. It has been shown in many cases to significantly increase bioavailability of poorly soluble drugs and also known to improve the inter and intra subject variability, fed/ fasting state bioavailability. Microemulsions is dispersions of oily phase in aqueous phase -o/w ME or vice-versa. The droplet size of dispersed phase below 200 nm makes it transparent or almost transparent (sometimes with bluish tinge).
Generally SMEDDS are suitable to be filled in soft gelatin capsule. However recent advancement in Pharma Industry has made it possible to be filled in Hard capsules (Gelatin or Non-Gelatin). Conversion of an oily liquid to solid free flowing/ compressible powder is also been increasingly explored.
However, we have found no report on the use of SMEDDS for dutasteride. OBJECT OF THE INVENTION
The object of the present invention is to provide dutasteride in a form which may be filled in capsules or converted into powder which may be compressed into pellets or tablets or directly filled in capsules.
SUMMARY OF THE INVENTION
The present invention provides an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt and the process of its preparation.
An oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) /co-surfactant (s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; wherein the composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.
A process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) /co-surfactant(s) ; c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-750C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and compressed into pellets or tablets or filled into capsules. DESCRIPTION OF THE INVENTION
The present invention relates to oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt which is an admixture of dutasteride or its pharmaceutically acceptable salt, one or more surfactant (s)/ co-surfactant (s), one more oil (s),optionally antioxidant (s) and excipient (s).The admixture may be filled in capsules or adsorbed on a suitable adsorbent to form a free-flowing powder which may be filled in capsules or compressed into pellets or tablets. The oral pharmaceutical composition of the present invention in unabsorbed liquid form upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200nm.
DETAILED DESCRIPTION OF THE INVENTION
Dutasteride is a poorly soluble white to pale yellow powder with its solubility being 0.38 ng/ml in water in water which is below the quantitation limit of the assay. Due to its low solubility it has a correspondingly low degree of bioavailability. Bioavailability of dutasteride or pharmaceutically acceptable salt may be improved by i. Milling /nanonising dutasteride or its pharmaceutically acceptable salt or ii. Dissolving or suspending dutasteride or its pharmaceutically acceptable salt in early stages of production.
However, milling dutasteride or its pharmaceutically accepted salt generates dust which is hazardous for working personnel. Dissolving dutasteride in solvent like caprylic/capric acid could result in improved bioavailability but it requires very large quantities of solvents such as 349.5 mg for 0.5mg dutasteride.
Also dissolving dutasteride in solvent followed by addition of antioxidant provides an oily solution which forms visual agglomerates on dissolution with aqueous medium.
We have surprisingly found that dutasteride or its pharmaceutically acceptable salt when mixed with surfactant (s) / co-surfactant (s) ; oil(s), optionally antioxidant (s) and excipient (s) provides an oral composition which on dissolution with an aqueous medium forms micro emulsion with at least 95% particles having mean particles size below 200nm.
The admixture of dutasteride with surfactant (s), oil(s), optional antioxidant (s) and excipient (s) may be
(i) used as such or
(ii) filled in capsules or
(iii) adsorbed on adsorbent and filled in capsules or compressed into pellets or tablets.
According to one embodiment of the present invention, there is disclosed an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of dutasteride or its pharmaceutically acceptable salt; one or more surfactant (s) / co-surfactant(s); one or more oil (s); optionally antioxidant (s); and optionally excipient (s).
The admixture may be used as such or filled in capsules or adsorbed on adsorbent and compressed into pellets or tablets or filled in capsules.
The term dutasteride as used herein includes pharmaceutically acceptable salts or solvates and can be in crystalline phase, amorphous phase or a mixture thereof.
The term capsule as used herein includes soft / hard gelatin or hard non-gelatin capsules.
Surfactants utilized in the present invention possess an HLB (hydrophilic-lipophilic balance) number greater than 8 based on the HLB system which is well known to those skilled in the art. The HLB number provides a means for ranking surfactants based on the balance between the hydrophilic and lipophilic portions of the surfactant or emulsifying agent. That is, the higher the HLB number, the more hydrophilic the surfactant or emulsifying agent.
In the present invention, the surfactant has a hydrophilic-lipophilic balance (HLB) of greater than 8. Typically, surfactants within HLB in the range of 8-18 form oil/water emulsions. In the present invention, the preferred HLB range for the surfactant is between approximately 10 and 14. Preferred surfactants utilized in accordance with the present invention include Myrj 45 (PEG 400 monostearate Polyoxy 8 stearate , HLB=I Ll), Solutol HS 15 (PEG 660 hydroxystearate Macrogol 15 hydroxystearate, HLB=14-16),Brij 97 (Polyoxyl 10 oleyl ether Oleth 10 PEG monooleyl ether, HLB= 12.4), Tween 80 (HLB 15), Tween 85 (HLBl 1.5), Cremophor EL (Polyoxyl 35 Castor oil Glycerol polyethylene glycol ricinoleate, HLB= 12- 14), Cremophor RH 40 Polyoxyl 40 hydrogenated castor oil Glycerol polyethylene glycol oxystearate, HLB= 14- 16) Labrasol (PEG 8 caprylic/capric glycerides Caprylcaproyl polyoxyglycerides, HLB= 14), Gelucire 44/14 (hydrogenated palm kernel oil PEG-32 esters lauryl polyoxyglycerides lauryl macrogol glycerides, HLB=14) , Plurol Oleique (polyglyceryl-6-dioleate, HLB = 10)
Preferred co-surfactants have HLB in range of 6-12 e.g. Capryol 90 (Propylene glycol monocaprylate 90%, HLB=6), Plurol Oleique CC497 ((polyglyceryl-3-dioleate, HLB=6),
The composition can also include the addition of an aqueous solvent such as triacetin, an acetylated derivative of glycerol, i.e., glyceryl triacetate or other suitable solvents. Triacetin is suitable since it is miscible in the oil/lipid phase and can be used to solubilize a hydrophobic drug.
The oil selected for the oral pharmaceutical composition of the present invention has HLB value below 6 for e.g
(A) Medium Chain Triglycerides
• Triglycerides of fractionated vegetable C8 and ClO fatty acids (usually fractionated coconut oil).
• Miglyol 810/812, Captex 300, 355, Neobee M5, Crodamol GTC/C
• Labrafac Lipophile WL 1349, Miglyol 818, Captex 810D
(B) Medium Chain Mono and Diglycerides
(Usually mono and diglycerides of capric (ClO) and caprylic (C8) Fatty Acids, with traces of triglycerides)
- Capmul (Abitec),
- Imwitor (Sasol)
- Imwitor 988 (MG/DG/TG of primarily caprylic (C8) acid; 47-57% MG)
- Imwitor 742 (MG/DG/TG of C8 and ClO FA; 45-55% MG)
- Imwitor 928 (MG/DG/TG of saturated FA of coconut oil (mainly C 12) - Imwitor 742 (MG/DG/TG of C8 and ClO FA; 45-55% MG)
- Imwitor 928 (MG/DG/TG of saturated FA of coconut oil (mainly C 12) min 40% MG)
(C) Long Chain Monoiand Diglyceride blends
(Typically a mixture of MG, DG and smaller quantities of TG) • Typical products:
- Peceol (Glyceryl monooleate HLB 3.3)Maisine 35-1 (Glyceryl monolinoleate HLB =4)
(D) Propylene glycol esters:
Capryol PGMC (Propylene glycol caprylate HLB=5), Labrafac PG Propylene glycol dicaprylocaprate (HLB=2), Lauroglycol 90 Propylene glycol monolaurate (HLB= 5), Lauroglycol FCC Propylene glycol laurate (HLB=4), Labrafil M 1944 (PEG 300 oleic glycerides Oleoyl Macrogol-6 glycerides, HLB= 4), Labrafil M 2125 (PEG 300 linoleic glycerides Linoleoyl Macrogol-6-glycerides, HLB=4)
The relative proportions of surfactant and co-surfactant in the composition, formulation of the present invention can influence the solubilizing and dissolution properties of the formulation. In general, the range of concentration of the surfactant/ co-surfactant broadly ranges from 15 to 96% (v/v) and more preferably ranges from approximately from 30 to 90% (v/v). The concentration of the co-surfactant broadly ranges from 10 to 80% (v/v).
The oil content in the oral composition of the present invention ranges from 4-60%, more preferably 4-44%.
The antioxidant used in oral composition of the present invention may be selected from butylated hydroxytoluence, butylated hydroxyl anisole, α-tocopherol ascorbic acid , ascorbyl palmitate sodium ascorbate, vitamin E, tartaric acid and the like.
The excipient used in oral composition of the present invention may be selected from diluents, binders lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners. The adsorbent used in oral composition of the present invention may be selected from kaolin, bentonite, hectorite, colloidal magnesium aluminium silicate, silicon dioxide, magnesium trisilicate, aluminium hydroxide magnesium oxide, talc, calcium - aluminium silicate, lactose.
Diluents may be selected from calcium-aluminum silicates (Sipernat 106 PQ), calcium carbonate,calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose,microcrystalline silicified cellulose,powdered cellulose, dextrates, dextrose,fructose,lactitol,lactose anhydrous, lactose monohydrate,lactose dihydrate, lactose trihydrate,mannitol sorbitol, starch, pregelatinized starch ,sucrose,talc,xylitol,maltose maltodextrin,maltitol .
Binders may be selected from acacia, alginic acid, carbomer,carboxymethylcellulose calcium, carbomethylcellulose sodium,microcrystalline cellulose,powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulos, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin,methylcellulose,ploydextrose, polyethtylene oxide,povidone,sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose,glucose, sorbitol. Suitable fillers are preferably selected from atleast one of starch derivatives,such as corn starch, potato starch or rice starch.Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
Disintegrants may for example, example, alginic acid, carbon dioxide, carbonxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low- substituted hydroxypropyl cellulose.
Glidants may be , for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide. Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.
Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavour.
According to another embodiment of the present invention is provided a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) / co-surfactant (s) ; c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-750C for less than an hour and cooling to ambient temperature.
The oral pharmaceutical composition of the present invention upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
The admixture may be used as such or filled in capsules or adsorbed on an adsorbent and compressed into pellet or tablets or filled in capsules.
More specifically, a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing, a) dutasteride or its pharmaceutically acceptable salt ; one or more surfactant (s)/ co-surfactant(s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-750C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and filling in capsules or compressing into pellet or tablets.
The oral pharmaceutical composition of the present invention wherein the liquid composition, before adsorption on solid, upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
EXAMPLES
Example-1/2 and 3 (S/CoS = 6, Oil = 4%)
Figure imgf000012_0001
PROCEDURE: (Example 1-4) :
1. Weigh accurate amount of Dutasteride.
2. Add Surfactactant, hydrophilic surfactant and oily phase.
3. BHT added in step 2 solution and heated at about 60 C with stirring for 10 min - clear solution
4. Purified water (wherever applicable) added to above solution and mixing continued for 5 min - clear solution achieved. Cooled to ambient temperature (except for Gelucire containing mixture which was maintained at 40-45 C during filling in capsules)
5. Upon cooling at ambient temperature the solution of step 4 filled in size 4 HPMC capsules to desired fill weight. EXAMPLES OF LIQUID/ SEMISOLID LOADED ON SOLID ADSORBENT AND POWDER FILLED IN HARD CAPSULES:
EXAMPLE-5, 6 and 7
Figure imgf000013_0001
EXAMPLE- 8 and 9
Figure imgf000013_0002
EXAMPLE 10 (CONTROL FORMULATON, WET GRANULATION):
Figure imgf000014_0001
EXAMPLE 11: DISSOLUTION and GLOBULE SIZE COMPARISON OF ZERO DAY SAMPLE WITH AVODART
Figure imgf000015_0001
EXAMPLE 12: DISSOLUTION and GLOBULE SIZE COMPARISON OF 3MONTH ACCELERATED STABILITY STUDY SAMPLE AT 40° C/75% RH
Figure imgf000016_0001
EXAMPLE 13: DISSOLUTION COMPARISON OF ZERO DAY SAMPLES WITH AVODART
Figure imgf000017_0001

Claims

Claims
1. An oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising admixture of a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) / co-surfactant (s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; wherein the composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.
2. An oral pharmaceutical composition as claimed in claim 1 wherein the admixture is filled in capsules.
3. An oral pharmaceutical composition as claimed in claim 1 wherein the admixture is adsorbed on suitable adsorbent and filled in capsules or compressed into pellets or tablets.
4. An oral pharmaceutical composition as claimed in claim 1 wherein the surfactant has HLB value above 8.
5. An oral pharmaceutical composition as claimed in claim 1 wherein the co-surfactant has HLB value above 6.
6. An oral pharmaceutical composition as in claim 1 wherein the oil has HLB value below 6.
7. An oral pharmaceutical composition as in claim 1 wherein the antioxidant is selected from butylated hydroxytoluence, butylated hydroxyl anisole,α- tocopherol ascorbic acid , ascorbyl palmitate sodium ascorbate, vitamin E and tartaric acid
8. An oral pharmaceutical composition as claimed in claim 1 wherein the excipient is selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners.
9. An oral pharmaceutical composition as claimed in claim 3 wherein the adsorbent is selected from kaolin, bentonite, hectorite, colloidal magnesium aluminium silicate, silicon dioxide, magnesium trisilicate, aluminium hydroxide magnesium oxide, talc, calcium - aluminium silicate, lactose.
10. A process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a. dutasteride or its pharmaceutically acceptable salt ; b. one or more surfactant (s) / co-surfactant (s); c. one or more oil (s); d. optionally antioxidant (s); and e. optionally excipient (s) ; at ambient temperature or heating at 25-750C for less than an hour and cooling to ambient temperature.
1 1. A process as claimed in claim 10 wherein the composition upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
12.A process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt ; b) one or more surfactant (s) / co-surfactant (s); c) one or more oil (s); d) optionally antioxidant (s); and e) optionally excipient (s) ; at ambient temperature or heating at 25-750C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and filling in capsules or compressing into pellet or tablets.
13. A process as claimed in claim 12 wherein the liquid composition, before adsorption on solid, upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.
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WO2022035003A1 (en) * 2020-08-14 2022-02-17 (주)필인터내셔널 Pharmaceutical composition comprising dutasteride

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