WO2008040993A1 - Pharmaceutical formulation of risedronate - Google Patents

Pharmaceutical formulation of risedronate 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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Prior art keywords
formulation
risedronate
weight
sodium
following
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PCT/GB2007/003784
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French (fr)
Inventor
Snejezana Miric
Marija Ribic
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Pliva Hrvatska D.O.O.
Bucks, Teresa Anne
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Application filed by Pliva Hrvatska D.O.O., Bucks, Teresa Anne filed Critical Pliva Hrvatska D.O.O.
Publication of WO2008040993A1 publication Critical patent/WO2008040993A1/en

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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
    • A61K31/66—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

The present invention relates to an oral pharmaceutical dosage formulation comprising [1-hydroxy-2-(3-piridinyl)ethylidene]bisphosphonic acid, herein after referred to as risedronate for treating of osteoporosis. The present invention also relates to a manufacturing process for the preparation of risedronate tablets. This formulation also discloses a use of risedronate having a specifically selected particle size range and use of the excipients that ensure adequate flowability of a dry blend as well as required content uniformity and drug release rate of the final product.

Description

PHARMACEUTICAL FORMULATION OF R1SEDRQNATE
Field of invention
The present invention relates to 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.
Background of the invention:
Polyphosphonic acids and their pharmaceutically-acceptable salts have been proposed for use in the treatment and prophylaxis of a number of pathological conditions which can affect humans or other mammals and involve calcium and phosphate metabolism. Such conditions may be divided into two broad categories:
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). In this disease, dissolution of normal bone occurs which is then haphazardly replaced by soft, poorly mineralized tissue such that the bone becomes deformed from pressures of weight bearing, particularly in the tibia and femur. Hyperparathyroidism, hypocalcaemia of malignancy, and osteolytic bone metastases are conditions also included in the first category. 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. In particular 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. However, 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
Figure imgf000003_0001
When formed as an acid addition salt it is referred to as risedronate. As used herein the term risedronate refers to the sodium salt of risedronic acid, preferably in the form of the tri-sodium salt.
Processes of preparing risedronic acid, and salts thereof, are known in the art, and some examples thereof are as follows.
EP 1243592B describes a process of preparing risedronic acid by reacting 3- pyridylacetic acid with phosphorous acid and phosphorous trichloride in a solvent. In the case where the solvent is chlorobenzene, the reaction is carried out at a temperature in the range of 85-1000C. In the case where 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
Figure imgf000004_0001
where n is 2 to 8. 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. Specifically, there is disclosed (i) 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, (ii) the trihydrate of the trisodium salt, which contains from 19 to 21 weight % of sodium and 12 to 14 weight % of crystalline water and (iii) 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.
There are a few patents and applications about pharmaceutical formulations comprising risedronic acid or a pharmaceutically acceptable salt thereof but none of them discuss the particle size of the active pharmaceutical ingredient. 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.
Pharmaceutical formulation comprising risedronic acid or a pharmaceutically acceptable salt thereof with a particle size larger then 350 μm (d90 > 350 μm) 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). Tablets obtained with such particle sized risedronic acid, or a pharmaceutically acceptable salt thereof, tend to break up into a number of layers, generally in the middle of a tablet. Using risedronic acid, or a pharmaceutically acceptable salt thereof, with particle size of about 50 μm or less successfully solves said problems that occur during manufacturing of the formulation.
Description of the invention:
During research and development of the formulation the inventors have, unexpectedly, found that management of the particle size can solve the problems described above. Primarily 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 μm. It is preferred that the risedronate in the formulation, has a (dgo) of 50 μm or less, more preferably of 40 μm or less and even more preferably of 30 μm or less. It is further preferred that risedronate in the formulation, has a (dso) of 15 μm or less, more preferably of 10 μm or less and even more preferably of 7 μm or less. It is further preferred that risedronate in the formulation has a (di0) of 3 μm or less, more preferably of 2 μm or less.
A preferred mean particle size of risedronate in the formulation is equal to or less than 40 μm and more preferred the mean particle size of risedronate is equal to or less than 30 μm. The range of mean particle size preferred for use in the invention is 1 to 40 μm, more preferably 5 to 30 μm, and even more preferably 5 to 20 μm.
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. Using risedronate with a mean particle size of less than 50 μm 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. Preferably it is prepared by means of direct compression; a process that includes blending of risedronate with excipients without the addition of water. According to the direct compression method a manufacturing process includes following steps:
1. mixing and homogenization of risedronate and excipients to obtain a tableting blend
2. compression of the tableting blend into tablet core and 3. film coating of the tablet core
There are several advantages of the direct compression technology: savings on time and energy, required less sophisticated equipment and production facilities, lower number of processing parameters, therefore simplified validation process. However, there are also several disadvantages: it is hard to obtain good compressibility of non-processed substances so the amount of the drug per tablet is limited, and the differences in particle size of the substances used in pharmaceutical formulation can cause segregation during processing and non-uniform drug content in the tablet. A procedure of obtaining a tableting blend is performed in a specific way that gives adequate quality of the final product in terms of homogeneity and uniformity of tableting blend by mixing under the specified process parameters.
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 μm and one of the excipients functioning as a filler. During the first step of the direct compression method (homogenization of risedronate and excipients to obtain tableting blend) it can be difficult to achieve required content uniformity (distribution of the risedronate) due to some of the excipients having particle size larger than risedronate and, therefore, prevent it from dispersing evenly through entire tableting blend. This is successfully solved by performing said step of premixing risedronate with mean particle size less than 50 μm and one of the excipients functioning as a filler before first step of standard and above described direct compression method said filler having particle size similar to used risedronate mean particle size less than 50 μm.
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.
The term "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, according to this invention, are mean particle size [which means the value (d4,3) the volume moment mean of the particles], (dgo), the diameter of which 90% by weight of the particles are smaller than and (d5o), 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.
The phrase "safe and effective amount", as used herein, 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.
The term "pharmaceutically acceptable excipients" as used herein and above 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 500C to 8O0C, preferably in the range of about 6O0C to 700C, followed by the addition of a hydroxide of the pharmaceutically acceptable alkali metal, in particular sodium hydroxide, to form a solution. Suitably 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 1000C, and preferably a Ci-4alcohol, 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. Suitably the lactose may be spray-dried (eg spray dried lactose anhydrate, eg Pharmatose™ DCL 11). Starch may for example be corn starch
(eg unmodified com starch or alternatively pre-gelatinized 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 Aerosil™ 200) or talc. Preferably the antiadherent is colloidal silicon dioxide. 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. 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. Preferably 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 μP 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.
Brief Description of the Drawings
Figure 1: Particle size analysis results determined by low angle laser light scattering on Mastersizer 2000 (Malvern) with Hydro μP sample dispersion unit
Examples The present invention can be further illustrated by the following non-limiting examples.
Example 1
Figure imgf000013_0001
Preparation of tablet core:
Risedronate in the form of tri-sodium salt was mixed with lactose monohydrate, microcrystalline cellulose and croscarmelose sodium and homogenized for 20 minutes. 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. Coating:
The tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
Example 2
Figure imgf000014_0001
Risedronate in the form of tri-sodium salt was mixed with lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose and croscarmelose sodium and homogenized for 20 minutes.
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.
Coating:
The tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry) Example 3
Figure imgf000015_0001
Preparation of tablet core:
Risedronate in the form of tri-sodium salt was mixed with starch, lactose monohydrate, sodium starch glycolate and colloidal silicon dioxide and homogenized for 15 minutes.
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.
Coating:
The tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
Example 4
Figure imgf000016_0001
Preparation of tablet core:
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. 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.
Coating:
The tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)
Example 5
Figure imgf000017_0001
Risedronate in the form of tri-sodium salt was mixed with lactose monohydrate, microcrystalline cellulose and crospovidone and homogenized for 15 minutes. 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.
Coating:
The tablets were coated with aqueous suspension of lactose monohydrate, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and iron oxide yellow (Opadry)

Claims

Claims:
1. An oral pharmaceutical dosage formulation comprising risedronate in the form of tri-sodium salt, and suitable pharmaceutical excipients, wherein the mean particle size of risedronate is less than 50 μm.
2. A formulation as claimed in claim 1 as claimed in claim, wherein said mean particle size is from 1 to 40 μm.
3. A formulation claimed in claim 1 , wherein said mean particle size is from 5 to 30 μm.
4. A formulation claimed in claim 1 , wherein said mean particle size is from 5 to 20 μm.
5. A formulation as claimed in claims 1 to 4 comprising from 0.5 to 40 percent by weight of risedronate.
6. A formulation as claimed in claims 1 to 4 comprising from 1 to 30 percent by weight of risedronate.
7. A formulation as claimed in claims 1 to 4 comprising from 5 to 30 percent by weight of risedronate.
8. A formulation as claimed in claims 1 to 7 wherein the tri-sodium salt is risedronate tri-sodium salt dihydrate.
9. A formulation as claimed in claims 1 to 8 wherein said suitable pharmaceutical excipients comprise one or more of the following; antiadherent, binder, filler, disintegrant and lubricant
10. A formulation as claimed in claim 9 wherein the antiadherent is selected from one or more of the following; colloidal silicon dioxide and talc. o
11. A formulation as claimed in claim 10 comprising from 0.1 to 5% by weight of antiadherent
12. A formulation as claimed in claims 10 and 11 wherein antiadherent is colloidal silicon dioxide
13. A formulation as claimed in claim 9 wherein the filler is selected from one or more of the following; lactose monohydrate, lactose anhydrate and starch.
14. A formulation as claimed in claim 13 comprising from 50 to 90% by weight of filler.
15. A formulation as claimed in claim 9 wherein the binder is selected from one or more of the following; microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, vinylpyrrolidone containing polymers and starch.
16. A formulation as claimed in claim 15 comprising from 10 to 30 % by weight of binder
17. A formulation as claimed in claims 15 and 16 wherein binder is microcrystalline cellulose
18. A formulation as claimed in claim 9 comprising a disintegrant selected from one or more of the following; crospovidone (cross linked polyvinylpyrrollidone), sodium starch glycolate, croscarmellose sodium, powdered cellulose, microcrystalline cellulose or carboxymethylcellulose calcium.
19. A formulation as claimed in claim 18 comprising from 1 to 10% by weight of disintegrant 9
20. A formulation as claimed in claims 18 and 19 wherein disintegrant is sodium starch glycolate
21. A formulation as claimed in claim 9 comprising lubricant 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.
22. A formulation as claimed in claim 21 comprising from 0.1 to 5% by weight of lubricant
23. A formulation as claimed in claims 21 and 22 wherein lubricant is magnesium stearate
24. A formulation as claimed in claims 1 to 23 formulated in one of following forms; a tablet, a film-coated tablet, a capsule, pellets or mini tablets filled in capsule.
25. A formulation as claimed in claims 1 to 24 in the form of a film-coated tablet.
26. A formulation as claimed in claim 25 comprising from 2 to 5% by weight of film coating material.
27. A process for preparation of the formulation claimed in claims 1 to 26 comprising following steps: 1. mixing and homogenization of risedronate and excipients to obtain a tableting blend
2. compression of the tableting blend into tablet core and
3. film coating of the tablet core
8. A process for preparation of the formulation claimed in claim 27 wherein said step 1 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
PCT/GB2007/003784 2006-10-07 2007-10-05 Pharmaceutical formulation of risedronate WO2008040993A1 (en)

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