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WO2008040993A1 - Formulation pharmaceutique de risédronate - Google Patents

Formulation pharmaceutique de risédronate Download PDF

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Publication number
WO2008040993A1
WO2008040993A1 PCT/GB2007/003784 GB2007003784W WO2008040993A1 WO 2008040993 A1 WO2008040993 A1 WO 2008040993A1 GB 2007003784 W GB2007003784 W GB 2007003784W WO 2008040993 A1 WO2008040993 A1 WO 2008040993A1
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WO
WIPO (PCT)
Prior art keywords
formulation
risedronate
weight
sodium
following
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2007/003784
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English (en)
Inventor
Snejezana Miric
Marija Ribic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pliva Hrvatska doo
Pliva Istrazivanje i Razvoj doo
Original Assignee
Pliva Hrvatska doo
Pliva Istrazivanje i Razvoj doo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pliva Hrvatska doo, Pliva Istrazivanje i Razvoj doo filed Critical Pliva Hrvatska doo
Publication of WO2008040993A1 publication Critical patent/WO2008040993A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a oral pharmaceutical dosage formulation
  • a oral pharmaceutical dosage formulation comprising sodium (preferably the tri-sodium) salt of [1-hydroxy-2-(3- piridinyl)ethylidene]bisphosphonic acid, hereinafter referred to as risedronate having a specifically selected particle size range and a process of manufacturing of the formulation.
  • Preferred formulations use necessary pharmaceutically acceptable excipients that ensure adequate flowability of a dry blend leading to required content uniformity in the formulation and a good drug release rate of the final product.
  • the first category includes osteoporosis, a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Marrow and bone spaces become larger, fibrous binding decreases, and compact bone becomes fragile. Osteoporosis can be sub classified as menopausal, senile, drug induced (e.g., adrenocorticoid, as can occur in steroid therapy), disease induced (e.g., arthritic and tumor), etc., however, the manifestations are essentially the same.
  • Another condition in the first category is Paget's disease (osteitis deformans).
  • the second category involving-conditions manifested by anomalous calcium and phosphate deposition, includes myositis ossificans progressiva, calcinosis universalis, and such afflictions as arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions which predispose involved tissue to deposition of calcium phosphates.
  • diphosphonates like ethane-1-hydroxy-1,1- diphosphonic acid (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), and dichloromethane diphosphonic acid (CI2MDP) have been the subject of considerable research efforts in this area. Paget's disease and heterotopic ossification are currently successfully treated with EHDP.
  • the diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.
  • EHDP, APD and many other prior art diphosphonates have the propensity of inhibiting bone mineralization when administered at high dosage levels.
  • Risedronic acid is the international non-proprietary name of [1-hydroxy-2-(3- pyridinyl)ethylidene]bisphosphonic acid.
  • Risedronic acid has the following structural formula
  • risedronate When formed as an acid addition salt it is referred to as risedronate.
  • risedronate refers to the sodium salt of risedronic acid, preferably in the form of the tri-sodium salt.
  • EP 1243592B describes a process of preparing risedronic acid by reacting 3- pyridylacetic acid with phosphorous acid and phosphorous trichloride in a solvent.
  • the solvent is chlorobenzene
  • the reaction is carried out at a temperature in the range of 85-100 0 C.
  • the solvent is fluorobenzene
  • the reaction is carried out at the reflux temperature of the reaction medium. Isolation of the risedronic acid involves separation thereof from the reaction mixture by treatment with alkali metal or ammonium hydroxide, bicarbonate or carbonate and subsequent treatment of the resulting alkali metal or ammonium risedronic acid salt with a strong mineral acid.
  • EP 125217OB describes a process for selectively producing risedronate sodium hemipentahydrate or monohydrate comprising the steps of (a) providing an aqueous solution of risedronate sodium, (b) heating the aqueous solution to a temperature from about 45°C to about 75°C, (c) adding a solvent to the aqueous solution, characterised in that the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, amides and nitriles, and (d) optionally cooling the aqueous solution.
  • EP 04949844B also discloses a process of preparing bisphosphonic acids, but not risedronic acid.
  • Bisphosphonic acids, in particular alendronic acid, of the following general formula are prepared according to the process of EP 0494844B
  • the process comprises melting a mixture of the corresponding aminocarboxylic acid and phosphorous acid in the absence of an organic solvent, adding dropwise phosphorous trihalide, adding to the reaction mixture a hydrolyzing agent selected between water and a strong non-oxidizing acid and recovering the diphosphonic acid thus produced.
  • the process is described as being characterised in that the molar ratio between the aminocarboxylic acid, phosphorous acid and phosphorous trihalide in the reaction mixture is 1 :3:2 and 1 :20:6.
  • WO 03/086355 describes polymorph forms B, B1, BB, C, D, E, F, G and H of risedronate sodium and processes of preparing these various polymorphs.
  • WO 04/037252 discloses crystalline hydrated forms of sodium risedronate, which contain from 6.4 up to 22 weight % of sodium based on the anhydrous substance, and in the case where the sodium content is lower than 7.5 weight %, then 15 to 23 weight % of crystalline water is present, or in the case where the sodium content is higher than 7.5 weight %, then 4.5 to 18 weight % of crystalline water is present.
  • the pentahydrate of the monosodium salt which contains from 5.5 to 7.5 weight % of sodium and 20 to 23 weight % of crystalline water
  • the trihydrate of the trisodium salt which contains from 19 to 21 weight % of sodium and 12 to 14 weight % of crystalline water
  • the monohydrate of the disodium salt which contains from 13 to 15 weight % of sodium and 4.5 to 6.5 weight % of crystalline water.
  • WO 2007036688 describes pharmaceutically acceptable tri-(alkali metal) salt of risedronic acid, which is present as the dihydrate form and specifically trisodium risedronate dihydrate. It also discloses a process of preparing a tri- (alkali metal) salt of risedronic acid, or a hydrate mixture, which comprises contacting a suspension of risedronic free acid with a source of a pharmaceutically acceptable alkali metal, adjusting the pH to about 8.5 to 9.5, and thereby converting the risedronic free acid to a tri-(alkali metal) salt of risedronic acid, or a hydrate mixture. Processes for the preparation of the trisodium salt of risedronic acid are described.
  • EP 1051975 describes a process for the preparation of a non-coated tablet containing an active ingredient selected from the group of bisphosphonic acids or pharmaceutically acceptable salts thereof without any description of the particle size.
  • EP 0 613 373 discloses novel, enteric-coated, oral dosage forms of risedronate with delayed release properties and only describes formulation and pH-dependent solubility properties of said enteric coating.
  • composition comprising risedronic acid or a pharmaceutically acceptable salt thereof with a particle size larger then 350 ⁇ m (d 90 > 350 ⁇ m) shows problems such as segregation of tableting blend which can result in problems during tableting. These problems are lamination (a "peeling" defect that occurs in a tablet caused by unfilled spaces between large particles; tablet splits and comes apart at the sides and is ejected in two parts) and capping (upper segment of the tablet separates from the main portion of the tablet and comes off as a cap due to air entrapped in the blend that is compressed in the die during the compression stroke and then expands when the pressure is released).
  • lamination a "peeling” defect that occurs in a tablet caused by unfilled spaces between large particles; tablet splits and comes apart at the sides and is ejected in two parts
  • capping upper segment of the tablet separates from the main portion of the tablet and comes off as a cap due to air entrapped in the blend that is compressed in the die during the compression stroke and then expands when the pressure
  • this invention is directed to providing an oral pharmaceutical dosage formulation comprising risedronate, preferably in the form of the sodium salt and particularly in the form of tri-sodium salt, and suitable pharmaceutical excipients wherein the mean particle size of risedronate is less than 50 ⁇ m. It is preferred that the risedronate in the formulation, has a (dgo) of 50 ⁇ m or less, more preferably of 40 ⁇ m or less and even more preferably of 30 ⁇ m or less.
  • risedronate in the formulation has a (dso) of 15 ⁇ m or less, more preferably of 10 ⁇ m or less and even more preferably of 7 ⁇ m or less. It is further preferred that risedronate in the formulation has a (di 0 ) of 3 ⁇ m or less, more preferably of 2 ⁇ m or less.
  • a preferred mean particle size of risedronate in the formulation is equal to or less than 40 ⁇ m and more preferred the mean particle size of risedronate is equal to or less than 30 ⁇ m.
  • the range of mean particle size preferred for use in the invention is 1 to 40 ⁇ m, more preferably 5 to 30 ⁇ m, and even more preferably 5 to 20 ⁇ m.
  • the risedronate in the form of tri-sodium salt, according to this invention, present in the formulation is preferably dihydrate.
  • Another direction of the present invention is to provide the given oral pharmaceutical dosage formulation formulated in one of following forms; a tablet, a film-coated tablet, a capsule, pellets or mini tablets filled in capsule.
  • the preferred form is that of a tablet and more preferably in form of a film coated tablet.
  • the tablet can be of round or oval biconvex shape with optionally scored or debossed sides if desired.
  • the preferred shape of a tablet is round.
  • Yet another direction of this invention is utilization of antiadherent as one of the excipients in a tableting blend.
  • risedronate with a mean particle size of less than 50 ⁇ m solves the previously described problems, but, on the other hand, may introduce some additional problems.
  • a tableting blend of components with such small particle size shows greatly decreased flowability compared to one with bigger particles. This poses drawbacks to the production process due to the process being more time consuming and costly.
  • This is successfully solved by utilizing a suitable compound hereinafter referred to as antiadherent or antiadhering agent.
  • An antiadherent is added to the tableting blend to increase its flowability and therefore ensure necessary mechanical properties of the blend for optimal production process.
  • the given formulation is prepared by one of following, commonly used, technologies: dry granulation, wet granulation and direct compression.
  • it is prepared by means of direct compression; a process that includes blending of risedronate with excipients without the addition of water.
  • direct compression method a manufacturing process includes following steps:
  • Yet another direction of this invention is introducing an additional step to a standard and above described method to insure required content uniformity (distribution of the active substance).
  • This step includes premixing of the risedronate with a mean particle size of less than 50 ⁇ m and one of the excipients functioning as a filler.
  • the first step of the direct compression method homogenization of risedronate and excipients to obtain tableting blend
  • Step 1 of the above described process for preparation of the formulation comprises following sub-steps: a) premixing of risedronate with starch and homogenization b) intermixing of the above obtained mixture with remaining excipients excluding lubricant and further homogenization c) adding lubricant to obtain adequate tableting blend and further homogenization
  • Produced tablet cores can optionally be subjected to a film coating process with conventional materials used for film.
  • Film coating is a process wherein tablet cores are tumbled in coating pan while heating and applying film coating material are performed. Therefore appropriate friability is essential for maintaining integrity of tablets and thereby acceptable appearance of final product.
  • the total amount of film coating material, if present in the final formulation, is 2 to 5% by weight.
  • oral pharmaceutical dosage formulation as used herein and above means an oral dosage form comprised of a safe and effective amount of risedronate and pharmaceutically acceptable excipients.
  • the pharmaceutical formulation described herein comprises of from 0.5 to 40% by weight, preferably from 1 to 30% by weight; more preferably from 5 to 30% by weight of risedronate and from 60 to 99.5% by weight, preferably from 70 to 99% by weight of pharmaceutically acceptable excipients.
  • the particle size measurements of the risedronate are mean particle size [which means the value (d 4 , 3 ) the volume moment mean of the particles], (dgo), the diameter of which 90% by weight of the particles are smaller than and (d 5 o), the diameter of which 50% by weight of the particles are smaller than. All measurements are made by low angle laser light scattering (LALLS) as determined typically by a Malvern Mastersizer machine.
  • LALLS low angle laser light scattering
  • safe and effective amount means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of active ingredient for use in the method of the invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically- acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician.
  • pharmaceutically acceptable excipients includes any physiologically inert and pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular risedronate selected for use.
  • Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, disinteg rants, binders, antiadherents, solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
  • the risedronate in the form of tri-sodium salt comprised in the formulation, according to this invention is preferably produced by a process wherein a suspension of risedronic free acid and water is heated to a temperature in the range of about 50 0 C to 8O 0 C, preferably in the range of about 6O 0 C to 70 0 C, followed by the addition of a hydroxide of the pharmaceutically acceptable alkali metal, in particular sodium hydroxide, to form a solution.
  • a hydroxide of the pharmaceutically acceptable alkali metal in particular sodium hydroxide
  • the pH is adjusted to a range of about 8.5 to 9.5 by the addition of the alkali metal hydroxide and more preferably to a pH in the range of about 9.0 to 9.1.
  • the resulting solution is typically heated to reflux, suitably at about 100 0 C, and preferably a Ci -4 alcohol, such as methanol or ethanol, is added. Subsequent cooling results in crystallization of a tri-(alkali metal) salt of risedronic acid, or a hydrate.
  • the preferred oral pharmaceutical dosage formulation of the risedronate as an active pharmaceutical ingredient given by this invention also comprise following pharmaceutically acceptable excipients:
  • the filler which can be selected from one or more of the following; lactose monohydrate, lactose anhydrate, starch, sugar or sugar alcohols (such as glucose, sucrose, sorbitol, mannitol), celluloses (in powder forms of different types (eg. microcrystalline cellulose)), and dicalcium phosphate dihydrate.
  • the lactose may be in the form of lactose monohydrate or lactose anhydrate, but will preferably be lactose anhydrate.
  • the lactose may be crystalline or amorphous.
  • the lactose may be spray-dried (eg spray dried lactose anhydrate, eg PharmatoseTM DCL 11).
  • Starch may for example be corn starch
  • the starch may also convey some disintegrant properties to the formulation.
  • the total amount of filler present in the final formulation is 50 to 90% by weight, preferably 55 to 80% by weight.
  • the binder which can be selected from one or more of the following; hydroxypropyl cellulose, hydroxypropylmethyl cellulose or other cellulose ethers, vinylpyrrolidone containing polymers. Preferably it will be microcrystalline cellulose. Suitably the cellulose will be present in the final formulation at a concentration of 10 to 30% by weight, preferably 15 to 28% by weight, more preferably 20 to 25% by weight.
  • the vinylpyrrolidone containing polymer may for example be polyvinylpyrrolidone alone or a mixture of polyvinylpyrrolidone and a co-polymer of vinylpyrrolidone and vinyl acetate or a co-polymer of vinylpyrrolidone and vinyl acetate alone.
  • the binder and the filler combined are present in the final formulation at a concentration of 50 to 97%, preferably 70 to 95% by weight, more preferably 80 to 90% by weight.
  • the antiadherent which can be selected from one or more of the following; colloidal silicon dioxide (eg AerosilTM 200) or talc.
  • colloidal silicon dioxide eg AerosilTM 200
  • talc e.g AerosilTM 200
  • Antiadherent is added to the formulation in order to improve the flowability and mechanical properties of the tableting blend and packing properties of the final formulation.
  • Antiadherent will be included in an amount of 0.1 to 5% by weight, preferably 0.5 to 1.5% by weight.
  • the disintegrant which can be selected from one or more of the following; crospovidone (cross linked polyvinylpyrr lidone), sodium starch glycolate, croscarmellose sodium, powdered cellulose, microcrystalline cellulose or carboxymethylcellulose calcium.
  • crospovidone cross linked polyvinylpyrr lidone
  • sodium starch glycolate croscarmellose sodium
  • powdered cellulose microcrystalline cellulose or carboxymethylcellulose calcium
  • Preferably disintegrant is sodium starch glycolate.
  • Disintegrant is added to the formulation to enhance the disintegrating properties of the formulation and thereby to accelerate dissolution.
  • Disintegrant will be included in an amount of 1 to 10% by weight, preferably 2 to 8% by weight, more preferably 3 to 7% by weight.
  • the lubricant which can be selected from one or more of the following; stearic acid, metal salt stearates (magnesium stearate, zinc stearate and calcium stearate), sodium stearyl fumarate, sodium lauryl sulphate, sodium benzoate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, polyethylene glycol, hydrogenated vegetable oil and talc.
  • lubricant is magnesium stearate.
  • Lubricant will be included in an amount of 0.1 to 5% by weight preferably 0.5 to 1.5% by weight.
  • Particle size of risedronate in the form of tri-sodium salt was, according to this invention, determined by low angle laser light scattering on Mastersizer 2000 (Malvern) with Hydro ⁇ P sample dispersion unit. 2-propanol was used as dispersant and general purpose model with enhanced sensitivity. Results for said particle size analysis are shown in Figure 1. Refraction index of Risedronate was 1 , while absorption index was 1.5. Stirrer speed was 1700 rpm and sample measurement time 2 s. Before measurement, sample is treated with ultrasound to break agglomerate.
  • Figure 1 Particle size analysis results determined by low angle laser light scattering on Mastersizer 2000 (Malvern) with Hydro ⁇ P sample dispersion unit
  • the tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
  • Magnesium stearate screened through a 0.6 mm sieve, was added to the core component above.
  • the Final blend was homogenized for additional 5 minutes and then compressed into tablets.
  • Magnesium stearate screened through a 0.6 mm sieve, was added to the core component above. The final blend was homogenized for additional 5 minutes and then compressed into tablets.
  • the tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
  • risedronate in the form of tri-sodium salt was mixed with starch, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and colloidal silicon dioxide and homogenized for 15 minutes.
  • the tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
  • the tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)

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Abstract

La présente invention concerne une forme pharmaceutique orale qui comprend de l'acide [1-hydroxy-2-(3-piridinyl)éthylidène] bis phosphonique, ci-après appelé risédronate, pour le traitement de l'ostéoporose. La présente invention concerne également un procédé de fabrication pour la préparation de comprimés de risédronate. L'invention concerne également l'utilisation d'un risédronate dont les particules sont dans une plage de taille spécifiquement choisie et l'utilisation d'excipients qui assurent une aptitude à l'écoulement adéquate d'un mélange sec ainsi que l'uniformité du contenu et le taux de libération du médicament requis du produit final.
PCT/GB2007/003784 2006-10-07 2007-10-05 Formulation pharmaceutique de risédronate Ceased WO2008040993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0619891.5 2006-10-07
GBGB0619891.5A GB0619891D0 (en) 2006-10-07 2006-10-07 Pharmaceutical composition of risedronate

Publications (1)

Publication Number Publication Date
WO2008040993A1 true WO2008040993A1 (fr) 2008-04-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104721165A (zh) * 2015-03-25 2015-06-24 河北仁合益康药业有限公司 一种利塞膦酸钠包衣片组合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037252A1 (fr) * 2002-10-25 2004-05-06 Zentiva, A.S. Nouvelle forme cristalline de sel de sodium d'acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique
US20050142185A1 (en) * 2003-12-29 2005-06-30 Beleno Alfredo B. Softgel formulations of bisphosphonates bone resorption inhibitors
US20060210639A1 (en) * 2005-03-17 2006-09-21 Elan Pharma International Limited Nanoparticulate bisphosphonate compositions
WO2007036688A1 (fr) * 2005-09-30 2007-04-05 Pliva Hrvatska D.O.O. Sels et hydrates pharmaceutiquement acceptables de l’acide risédronique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037252A1 (fr) * 2002-10-25 2004-05-06 Zentiva, A.S. Nouvelle forme cristalline de sel de sodium d'acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique
US20050142185A1 (en) * 2003-12-29 2005-06-30 Beleno Alfredo B. Softgel formulations of bisphosphonates bone resorption inhibitors
US20060210639A1 (en) * 2005-03-17 2006-09-21 Elan Pharma International Limited Nanoparticulate bisphosphonate compositions
WO2007036688A1 (fr) * 2005-09-30 2007-04-05 Pliva Hrvatska D.O.O. Sels et hydrates pharmaceutiquement acceptables de l’acide risédronique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104721165A (zh) * 2015-03-25 2015-06-24 河北仁合益康药业有限公司 一种利塞膦酸钠包衣片组合物及其制备方法
CN104721165B (zh) * 2015-03-25 2017-07-07 河北仁合益康药业有限公司 一种利塞膦酸钠包衣片组合物及其制备方法

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