AU4161900A - A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate - Google Patents

A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate Download PDF

Info

Publication number
AU4161900A
AU4161900A AU41619/00A AU4161900A AU4161900A AU 4161900 A AU4161900 A AU 4161900A AU 41619/00 A AU41619/00 A AU 41619/00A AU 4161900 A AU4161900 A AU 4161900A AU 4161900 A AU4161900 A AU 4161900A
Authority
AU
Australia
Prior art keywords
pharmaceutical formulation
formulation according
additive
bisphosphonate
lipid
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.)
Abandoned
Application number
AU41619/00A
Inventor
Lennart Lindfors
Jan-Erik Lofroth
Sven Sjogren
Anna-Lena Ungell
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.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of AU4161900A publication Critical patent/AU4161900A/en
Abandoned legal-status Critical Current

Links

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
    • A61K31/662—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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

Description

WO 00/61111 PCT/SEOO/00664 A PHARMACEUTICAL FORMULATION COMPRISING AN BISPHOSPHONATE AND AN ADDITIVE AGENT PRO VIDING AN ENHANCED ABSORPTION OF THE BISPHOSPHONATE TECHNICAL FIELD The present invention relates to pharmaceutical formulations comprising bisphosphonates. The invention also relates to a process for preparing such pharmaceutical formulations, to the use of such pharmaceutical formulations for inhibition of bone resorption and for the treatment and prevention of osteoporosis. 10 BACKGROUND ART Bisphosphonates 15 Bisphosphonates are carbon-substituted pyrophosphate analogues that include potent inhibitors of bone resorption, such as alendronate (4-amino-I -hydroxybutvlidene- 1,1 biphosphonic acid) (Sato et al. (1991) J. Clin. Invest. 88, 2095-2105). OH O=P-OH
H
2 N OH O=P-OH OH alendronate 20 The oral bioavailability of bisphosphonates (etidronate; clodronate; pamidronate; alendronate) in humans lies between 1% and 10% according to Lin (Bone 18, 75-85, 1996) and absorption is diminished when given with meals, especially in the presence of calcium. Therefore bisphosphonates should never be given at mealtime and never together :5 with milk or diary products according to Fleisch (Bisphosphonates in bone disease. Stampli & Co., Bern 1993, p.50, and references cited therein). In Dowty M.E. et al, Pharm. Sci. Suppl., Vol 1, No 1: 448 (1998) the low permeability of risedronate is disclosed.
WO 00/61111 PCT/SEOO/00664 2 The oral bioavailability of alendronate has been studied by Gertz et al. (Clinical Pharmacology & Therapeutics, vol. 58, pp. 288-298. 1995). It was found that taking alendronate either 60 or 30 minutes before breakfast reduced bioavailability by 40% relative to a 2-hour wait before a meal. Taking alendronate either concurrently with or 2 5 hours after breakfast drastically (>85%) impaired availability. A practical dosing recommendation, derived from these findings was that patients should take the drug with water after an overnight fast and at least 30 min before any other food or beverage. Moreover, the labeling information on an existing commercial formulation of alendronate 10 (FOSAMAX ) contains a warning that the formulation, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa. This clearly shows that a solution to the problems associated with the poor and variable absorption of orally administered bisphosphonates known for a long time has not yet been found. 15 Consequently, there is a need for pharmaceutical formulations comprising bisphosphonates, such as alendronate, which reduces the above mentioned drawbacks and allows the patient to take the medicament more conveniently, e.g. together with food intake. 20 Absorption enhancers Pharmaceutical excipients may be classified as functional or not-functional (M E Aulton: Pharmaceutics - The science of dosage form design, Churchill Livingstone 1988, Hong Kong). Non-functional excipients are, e g, binders, fillers, dryers etc and are used to fulfill 25 pharmaceutical technology aspects of the formulation as size, hardness, appearence (e g colour) etc. Functional excipients on the other hand are utilized, e g to achieve certain types of release profiles such as immediate release, extended release, controlled release etc by the use of rapidly or slowly hydrating, swelling, eroding, etc polymer materials; to achieve fast dissolution of the drug by incorporating surface active substances; to achieve 30 control of the pH in the formulation or in the immediate environment of the drug by the usage of buffers in the formulation; etc.
WO 00/61111 PCT/SEOO/00664 3 Another important aspect of excipients is the influence from functional excipients on the biological environment that can be obtained with certain substances, often called enhancers in the literature, by for example changing the permeability of the biological membrane, to 5 inhibit complex formation with biological substances present (e g proteins, lipids, bile salt, ions), etc. The rational for the use of such excipients is then to achieve, e g higher availability, less variation in absorption due to, e g food interactions (Charman WN et al. J Pharm Res 86 (3): 269-282 (1997)) avoidance of instability in GI-environment, to diminish drug influence on membrane integrity etc. Comprehensive reviews on the effect of 10 enhancer agents and their use in pharmaceutical formulations have been presented by E J van Hoogdalem et al (Pharm Theor vol 44, 407-443 (1989)); by S Muranishi et al (Crit Rev Ther Drug Carrier Syst vol 7, 1-33 (1990)); by E S Swenson and W J Curatolo (Adv Drug Deliv Rev vol 8, 39-92 (1998)); in drug Absorption Enhancement (Ed: A B G de Boer, Harwood Academic Publishers 1994); in Baughman RA et al Circulation 98 (16): is 1610-1615 (1998); in Bai JP et al, Crit Rev Therap Drug Carrier Syst 12(4): 339-371 (1995); in Bowe CL et al, Proc Nat Acad Sci 94 (22): 12218-23 (1997); in Chao AC et al, J Pharm Sci 87(11): 1395-1399 (1998); in Chao AC et al, J Drug Targeting 6(1): 37-43 (1998); and in Fix JA. J Pharm Sci 85(12) 1282-1285 (1996). 20 In many circumstances the enhancers combine several different effects. However, the degree of influence on the biological environment is seldom known i prior, and mechanisms behind the effects are obscure and difficult to ascertain in-vivo. The different types of such functional excipients includes e g lipids, chelators, and polymers which all may act, e g by preventing or enhancing complexation with species from the biological 2+ 25 environment (e g proteins, bile salts, lipids, ions like Ca etc), by influencing the membrane permeability in a reversible or irreversible manner, by presenting the drug in small particulate form and thereby avoiding high local concentrations that might be irritating near the membranes of the drug, etc. 30 WO 00/61111 PCT/SEOO/00664 4 DISCLOSURE OF THE INVENTION It has surprisingly been found that the absorption of bisphosphonates can be substantially improved by incorporating one or more additives in pharmaceutical formulations 5 containing bisphosphonates. The use of additives as enhancers will result in positive advantageous effects, such as enhanced and/or less variable absorption when bisphosphonates, e.g. alendronate, is given by different administration routes, such as the oral, the rectal, the buccal, the nasal and the pulmonary route. It will allow the patient to take the medicament more conveniently, e.g. together with food intake. It will also reduce 10 side-effects as local irritation of, e g the upper gastrointestinal mucosa. Therefore, the present invention provides a pharmaceutical formulation comprising at least one bisphosphonate and one or more additives selected from the group consisting of - a surfactant, such as a nonionic surfactant, e.g., a sorbitan ester (Span series), a 15 polysorbate (Tween series), a poloxyethylated glycol monoether (like the Brij series), a polyoxylated alkyl ester (Myrj series), a polyoxyethylated alkyl phenol (like the Triton series), an alkyl glucoside, like sugar glycosides, e.g., dodecylmaltoside, sugar fatty acid esters, e.g. sucrose laurate, sucrose monostearate and saponins; - an ampholytic surfactant, e.g., a betaine; 20 - an anionic surfactant, e.g., a sulphated fatty alcohol, a sulphated polyoxyethylated alcohol, others like dioctyl sulphosuccinate; - a cationic surfactant, e.g., an ammonium compound; - a bile salt, such as a dihydroxy bile salt like sodium deoxycholate, a trihydroxy bile salt like sodium glycocholate and fusidates, e.g., sodium dihydrofusidate; 25 - a soap and a fatty acid, and a salt thereof, e.g. octanoic acid, decanoic acid and sodium decanoate; - a lipid (with the exception of those dislosed in PCT application no. SE98/01790), such as a phospholipid, e.g., DPPC and DMPC; - an oil, e.g., soy bean oil and sunflower oil; so - an enamine, such as DL-phenylanaline and ethylacetoacetate enamine; - a chelating agent, e.g., EDTA, EGTA, and citric acid; - a phenothiazine, such as chlorpromazine; WO 00/61111 PCT/SEOO/00664 5 - a fatty acid derivative of carnitine and peptides, e.g., palmitoyl-DL-carnitine; - a substance selected from the group consisting of azone, concanavalin A. a phosphate and a phosphonate derivative, such as DL -a-glycerophosphate and 3-amino-i hydroxypropylidene- 1,1 -diphosphonate, diethyl maleate and diethylethoxymethylene malonate; - a product from Maillard reactions, i.e. a product obtained by reacting sugars with amino acids, e.g., a compound from a glucoselysine reaction; - a polymer, such as a polyacrylic acid, e.g., Carbopol", polycarbophil; - a chitosan and a chitosan derivative; and 10 - a block copolymer, e.g., a poloxamer, poloxamine, and meroxapol. - a biodegradable polymer, e g polyactic acid, polyglycolic acid, and copolymers of these. Suitable intended combinations of the enhancing agents are, but are not limited to: 15 Lipids (also those disclosed in PCT application no. SE 98/01790) and surfactants, eg monoolein and sodium taurocholate, monoolein and Tween 80 (polyoxyethylene (20) sorbitan mono-oleate, also namned polysorbate 80); Lipids of non-phospholipids character (also those disclosed in SE 98/01790) and 20 phospholipids, e g medium chain glycerides and lecithins; Lipids (also those disclosed in SE 98/01790) and block copolymers, e g monoolein and Pluronic F 127 (which is the triblock copolymer poloxamer 407 of polyoxyethylene/polyoxypropylene/polyoxyehylene); 25 Surfactants and oils, e g sucrose fatty acid esters and soy bean oil; and Polymers and lipids, e g polycarbophil and monoolein. 30 The combinations might be in the form of emulsions and microemulsions comprising e g monoolein/triglyceride/water or isopropyl mynistate/lecithin/water.
WO 00/61111 PCT/SEOO/00664 6 Preferred additives of the invention are - nonionic surfactants, such as sugar glycosides and sugar fatty acid esters; - lipids, such as a phospholipid e g DPPC and DMPC; - an oil, such as soy bean oil and sunflower oil; - a chelating agent, e g EDTA, EGTA, citric acid; - a fatty acid derivative of carnitine or a peptide; e.g. palmitoyl-DL-camitine; - polymer, such as polyacrylic acid, e g Carbopol, polycarbophil - a block copolymer, e g a poloxamer, poloxamine and meroxapol; - a saponin; 10 - the combinations listed above. Lipids referred to above as disclosed in PCT application no. SE 98/01790 are a medium chain glyceride or a mixture of medium chain glycerides, particularly those having the formula 15
H
2 C-O-R H C-O-R2 1 2 3 wherein R , R and R are the same or different and each represent a hydrogen atom or an alkanoyl chain having 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, provided that 1 2 3 at least one or R , R and R is an alkanoyl group. 20 The dosage form used may be a solid, semisolid or liquid preparation prepared by techniques which are known per se. Usually the active substance will constitute between 0.001% and 99% by weight of the preparation, preferably 0.003 to 1.3 % by weight, most preferably 0.1 to 1%. -5 Preferably, the bisphosphonate has the general formula Il WO 00/61111 PCT/SEOO/00664 7 0 R4 O \P, O=P-O 0II wherein 5 R 4 is H, OH or Cl; and R5 is (a) alkyl with I to 6 carbon atoms, optionally substituted with amino, alkylamino. dialkylamino or heterocyclyl; 10 (b) halogen; (c) arylthio, preferably chlorosubstituted; (d) cycloalkylamino with 5 to 7 carbons; or (e) saturated five or six membered nitrogen containing heterocyclyl with I or 2 heteroatoms. Alkyl groups in alkylamino and dialkylamino may have 1 to 5 carbon atoms and may be combined independently in the dialkylamino group. The term "heterocyclyl" means a saturated or unsaturated 5 to 7- membered heterocyclic 20 group with one or two rings and I to 3 heteroatoms, independently chosen from N, 0 and S. Unless otherwise stated or indicated, the term "aryl" denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such 25 as naphtyl.
WO 00/61111 PCT/SEOO/00664 8 The term "substituted aryl" denotes an aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl. aryl or cyano groups. Compounds of the formula II include: 4-amino-i -hydroxybutylidene- 1,1 -bisphosphonic acid (alendronate), N,N-dimethyl-3 -amino-i -hydroxypropylidene- 1,1 -bisphosphonic acid (mildronate,olpadronate), I -hydroxy-3-(N-methyl-N-pentylamino)propylidene- 1,1 -bisphosphonic acid (ibandronate), 10 1 -hydroxy-2-(3-pyridyl)ethylidene- 1,1 -bisphosphonic acid (risedronate), 1 -hydroxyethylidene- 1,1 -bisphosphonic acid (etidronate), 1 -hydroxy-3-(1 -pyrrolidinyl)propylidene- 1,1 -bisphosphonic acid, 1 -hydroxy-2-(1-imidazolyl)etylidene- 1,1 -bisphosphonic acid (zoledronate), 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene-1,1-bisphosphonic acid 15 (minodronate), 1-(4-chlorophenylthio)methylidene-1,1- bisphosphonic acid ( tiludronate), 1 -(cycloheptylamino)methylidene- 1,1 -bisphosphonic acid (cimadronate, incadronate), 6-amino-i -hydroxyhexylidene- 1,1 -bisphosphonic acid (neridronate) and pharmaceutically acceptable salts there of. 20 The most preferred compounds of the formula II are 4-amino-i -hydroxybutylidene- 1,1 bisphosphonic acid (alendronate) and its pharmaceutically acceptable salts. In a preferred form, the pharmaceutical formulation according to the invention is adapted 25 for oral administration and may be given during fasted or fed conditions. In the preparation of pharmaceutical formulations according to the invention in the form of dosage units for oral administration, the bisphosphonate and the absorption enhancing agent may be filled into soft or hard gelatine or cellulose capsules; mixed with solid, 30 powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient; with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate WO 00/61111 PCT/SEOO/00664 9 and polyethylene glycol waxes. The mixture is then processed into particulate forms. granules or pressed into tablets. In one embodiment of the invention the bisphosphonate and the additive is mixed into a s suitable form considering that a particulate (solid, semisolid or liquid) form might be preferably chosen to avoid the presentation of the drug in high local concentrations that might be irritating at the mucosal membranes. Such particulate forms can be obtained by well known procedures, such as dispersing the bisphosphonate as a micronised powder (< 10 im) in a suitable medium like sesam oil, soya oil etc, or by forming a carrier/drug 1o system in particulate form. Micronised bisphosphonates or carrier/drug systems can be prepared by techniques such as but not limited to dry or wet milling, freeze milling, air-jet micronisation, spray drying, spray chilling, spray freeze drying, electrospraying, supercritical crystallisation (RESS or GAS methods), emulsion solvent evaporation, emulsion solvent extraction and emulsion solvent diffusion. 1s This suspension of the bisphosphonate in oil or the carrier/bisphosphonate system is then administered orally as a suspension or in capsules. Suitable daily doses of bisphosphonates in therapeutic treatment of humans are about 0.001 20 to 100 mg/kg body weight at peroral administration, preferably 0.001 to 10 mg/kg, most preferably 0.005 to 0.3 mg/kg. The enhancing agent, or the combination of enhancing agents, and a suitable carrier or non-functional excipients when needed will constitute between 0.1 to 99.9% by weight of 25 the preparation, preferably between 80% to 99.9% by weight. The pharmaceutical formulations according to the invention are useful for inhibiting bone resorption and thus for the treatment or prevention of bone loss related to osteoporosis, age, steroid therapy, rheumatism, Paget's disease or cancer. The pharmaceutical so formulation according to the invention are also useful in the prevention and/or treatment of secondary osteoporosis except steroid induced osteoporosis, periodontitis, osteoarthritis. The pharmaceutical formulations according to the invention are further useful for the WO 00/61111 PCT/SEOO/00664 10 treatment of hypercalcaemia. Consequently, the use of the said pharmaceutical formulations for treating these conditions are additional aspects of the invention. In another aspect the invention provides a process for the preparation of a pharmaceutical 5 formulation according to the invention, said process comprising forming a mixture of (i) bisphosphonate, (ii) an additive, and (iii) a pharmaceutically acceptable carrier. In a further aspect the invention provides the use of bisphosphonate in conjunction with an absorption enhancing agent for the manufacture of a medicament for the inhibition of bone 10 resorption, or thus for the treatment or prevention of bone loss related to osteoporosis., age, steroid therapy, rheumatism, Paget's disease or cancer. The pharmaceutical formulation according to the invention are also useful in the prevention and/or treatment of secondary osteoporosis except steroid induced osteoporosis, periodontitis, osteoarthritis. Preferably, the said medicament is adapted for oral administration. 15 In yet a further aspect the invention provides a method for the inhibition of bone resorption, or thus for the treatment or prevention of bone loss related to osteoporosis, age, steroid therapy, rheumatism, Paget's disease or cancer. The pharmaceutical formulation according to the invention are also useful in the prevention and/or treatment of secondary 20 osteoporosis except steroid induced osteoporosis, periodontitis, osteoarthritis, which method comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical formulation according to the invention. Preferably, the said pharmaceutical formulation is administered orally. 25 Biological evaluation The effectiveness of formulations according to the present invention to prevent bone loss has been analyzed in studies using intact young growing rat model, developed and well established to predict the effectiveness of bisphosphonates in later clinical practise. 30 Results WO 00/61111 PCT/SEOO/00664 l1 ED4 0 values obtained in the intact rat model show that orally administered formulations according to the invention that have been tested are more potent than equimolar bisphosphonate alone. In a 14-day study of intact young growing rats a clear dose-response effect of enhancer was found. No effects were found for bisphosphonate in saline and given per os. The effects on bone density obtained with enhancer/bisphosphonate was similar to what was obtained with bisphosphonate given subcutaneously, while no effect was found for bisphosphonate in saline given per os. All rats appeared normal and gained normal weight. 10 Conclusions The rat studies strongly support the concept that enhancers as suggested in the present specification can increase the oral bioavailability of a bisphosphonate as disclosed in the present specification even in the presence of food. 15 WO 00/61111 PCT/SEOO/00664 12 Examples Examples of pharmaceutical formulations according to the invention: 5 Formulation 1 Alendronate 2.3 mg Caprylic acid, sodium salt 11.5 mg 50 mM Tris with 100 mM NaCI (buffer) 1.0 g 10 Approx. 2.3 mg alendronate and 11.5 mg caprylic acid was dissolved in buffer and pH adjusted to 7.5 using sodium hydroxide. Formulation 2 Alendronate 2.3 mg 15 Monoolein 11.5 mg Tween 80 11.5 mg 50 mM Tris with 100 mM NaCI (buffer) 1.0 g Approx. 2.3 mg alendronate and 11.5 mg monoolein was dissolved in buffer containing 20 Tween 80 and pH adjusted to 7.5 using sodium hydroxide. Formulation 3 Alendronate 2.3 mg Quil A 11.5 mg 2; 50 mM Tris with 100 mM NaCI (buffer) 1.0 g Approx. 2.3 mg alendronate and 50 mg Quil A was dissolved in buffer and pH adjusted to 7.5 using sodium hydroxide.
WO 00/61111 PCT/SEOO/00664 13 Formulation 4 Alendronate 2.3 mg Carbopol 934P 5.0 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approx. 2.3 mg alendronate and 5.0 mg Carbopol was mixed with buffer to form a dispersion and pH adjusted to 7.5 using sodium hydroxide. Formulation 5 10 Alendronate 2.3 mg Carbopol 934P 15.0 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approx. 2.3 mg alendronate and 15.0 mg Carbopol was mixed with buffer to form a is dispersion and pH adjusted to 7.5 using sodium hydroxide. Formulation 6 Alendronate 2.3 mg Isopropylmyristate 630 mg 20 Lecithin (Epicuron 200) 270 mg 50 mM Tris with 100 mM NaCl (buffer) 100 mg Approx. 23 mg alendronate was dissolved in buffer and pH adjusted to pH 7.5 using sodium hydroxide and added to a mixture of isopropylmyristate and lecithin (70/30 w/w) 25 while vortexing. Formulation 7 Alendronate 2.3 mg Isopropylmyristate 450 mg 3o Tween 21 450 mg WO 00/61111 PCT/SEOO/00664 14 50 mM Tris with 100 mM NaCl (buffer) 100 mg Approx. 23 mg alendronate was dissolved in buffer and pH adjusted to pH 7.5 using sodium hydroxide and added to a mixture of isopropylmyristate and Tween 21 (50/50 w/w) 5 while vortexing. Formulation 8 Alendronate 2.3 mg Monoolein 630 mg 10 Soybean triglycerides 270 mg 50 mM Tris with 100 m-M NaCI (buffer) 100 mg Approx. 23 mg alendronate was dissolved in buffer and pH adjusted to pH 7.5 using sodium hydroxide and added to a mixture of monoolein and soybean triglycerides (70/30 is w/w) while vortexing. Formulation 9 Alendronate 2.3 mg Soybean triglycerides 1.0 g 20 2.3 mg alendronate was added to soybean triglycerides and micronized using ultrasonication while cooling on ice.

Claims (46)

1. A pharmaceutical formulation comprising at least one bisphosphonate and one or more of an additive agent, said additive agent being present in an amount sufficient to provide an enhanced absorption of the bisphosphonate, and said additive being a substance selected from the group consisting of - a surfactant; - an ampholytic surfactant; - an anionic surfactant; 10 - a cationic surfactant; - a bile salt; - a soap and a fatty acid, and a salt thereof; - a lipid with the exception of a medium chain glyceride or a mixture of medium chain glycerides having the formula H 2C-O-R
2 HC -O-R 2 H 2C-O-R 3 12 3 wherein R , R and R are the same or different and each represent a hydrogen atom or an alkanoyl chain having 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, provided that 1 2 3. at least one or R , R and R is an alkanoyl group. - an oil; 20 - an enamine; - a chelating agent; - a phenothiazine; - a fatty acid derivative of carnitine or a peptide; - a substance selected from the group consisting of azone, concanavalin A, a phosphate and 25 a phosphonate derivative, such as DL -a-glycerophosphate and 3-amino-I hydroxypropylidene-1,1-diphosphonate, diethyl maleate and diethylethoxymethylene malonate; WO 00/61111 PCT/SE0O/00664 16 - a product from Maillard reactions; - a polymer, such as a block copolymer and a biodegradable polymer; - a chitosan and a chitosan derivative; 5 2. A pharmaceutical formulation according to claim 1, wherein the additive is a nonionic surfactant.
3. A pharmaceutical formulation according to claim 2, wherein the nonionic surfactant is a sugar glycoside or a sugar fatty acid ester. 10
4. A pharmaceutical formulation according to claim 1, wherein the additive is a lipid.
5. A pharmaceutical formulation according to claim 4, wherein the lipid is a phospholipid. 15
6. A pharmaceutical formulation according to claim 1, wherein the additive is an oil.
7. A pharmaceutical formulation according to claim 6, wherein the oil is soy bean oil or sunflower oil. 20
8. A pharmaceutical formulation according to claim 1, wherein the additive is a chelating agent.
9. A pharmaceutical formulation according to claim 8, wherein the chelating agent is 25 EDTA, EGTA or citric acid.
10. A pharmaceutical formulation according to claim 1, wherein the additive is a fatty acid derivative of carnitine or a peptide. 30
11. A pharmaceutical formulation according to claim 10, wherein the additive of the fatty acid derivative of carnitine or a peptide is palmitoyl-DL-carnitine. WO 00/61111 PCT/SEO0/00664 17
12. A pharmaceutical formulation according to claim 1, wherein the additive is a polymer.
13. A pharmaceutical formulation according to claim 12, wherein the polymer is a polyacrylic acid.
14. A pharmaceutical formulation according to claim 1, wherein the additive is a block copolymer.
15. A pharmaceutical formulation according to claim 14, wherein the block copolymer is a 10 poloxamer, a poloxamine or meroxapol.
16. A pharmaceutical formulation according to claim 1, wherein the additive is a saponin.
17. A pharmaceutical formulation according to claim 1, wherein the additive is a is biodegradable polymer.
18. A pharmaceutical formulation according to claim 17, wherein the biodegradable polymer is polyactid acid or polyglycolic acid. 20
19. A pharmaceutical formulation according to claim 1, wherein the additive is a combination of a lipid and a surfactant.
20. A pharmaceutical formulation according to claim 19, wherein the combination of the lipid and the surfactant is monoolein and sodium taurocholate, or monoolein and 25 Tween 80.
21. A pharmaceutical formulation according to claim 1, wherein the additive is a combination of a lipid of non-phospholipid character and a phospholipid. '0
22. A pharmaceutical formulation according to claim 21, wherein the combination of the lipid of non-phospholipid character and the phospholipid is a medium chain glyceride and a lecithin. WO 00/61111 PCT/SEOO/00664 18
23. A pharmaceutical formulation according to claim 1, wherein the additive is a combination of a lipid and a block copolymer. s
24. A pharmaceutical formulation according to claim 23, wherein the combination of the lipid and the block copolymer is monoolein and Pluronic F 127.
25. A pharmaceutical formulation according to claim 1, wherein the additive is a combination of a surfactant and an oil. 10
26. A pharmaceutical formulation according to claim 25, wherein the combination of the surfactant and the oil is a sucrose fatty acid ester and soy bean oil.
27. A pharmaceutical formulation according to claim 1, wherein the additive is a is combination of a polymer and a lipid.
28. A pharmaceutical formulation according to claim 27, wherein the combination of the polymer and the lipid is polycarbophil and monoolein. 20
29. A pharmaceutical formulation according to claim 1, wherein the combination of additives is chosen to form an emulsion or a microemulsion.
30. A pharmaceutical formulation according to any one of claims 1 to 29 wherein the said bisphosphonate has the formula II 25 4 O \ R_ where0 0II wherein WO 00/61111 PCT/SEOO/00664 19 R 4 is H, OH or Cl, and R5 is (a) alkyl with 1 to 6 carbon atoms, optionally substituted with amino, alkylamino. dialkylamino or heterocyclyl; 5 (b) halogen; (c) arylthio or chlorosubstituted arylthio; (d) cycloalkylamino with 5 to 7 carbons; or (e) saturated five or six membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. 10
31. A pharmaceutical formulation according to claim 30 wherein the bisphosphonate has the formula II wherein R4 is H or OH and 15 R is (a) alkyl with I to 6 carbon atoms, optionally substituted with amino, alkylamino, dialkylamino or heterocyclyl; (d) cycloalkylamino with 5 to 7 carbons; or (e) saturated five or six membered nitrogen containing heterocyclyl with 1 or 2 20 heteroatoms.
32. A pharmaceutical formulation according to claim 30 wherein the bisphosphonate has the formula II wherein 25 R4 is OH and R is (a) alkyl with 1 to 6 carbon atoms, optionally substituted with amino, alkylamino, dialkvlamino or heterocyclyl; (d) cycloalkylamino with 5 to 7 carbons; or so (e) saturated five or six membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. WO 00/61111 PCT/SEOO/00664 20
33. A pharmaceutical formulation according to claim 30 wherein the bisphosphonate is 4-amino-I -hydroxybutylidene- 1,1 -bisphosphonic acid (alendronate), N,N-dimethyl-3-amino- 1 -hydroxypropylidene- 1,1 -bisphosphonic acid s (mildronate,olpadronate), 1 -hydroxy-3-(N-methyl-N-pentylamino)propylidene- 1,1 -bisphosphonic acid (ibandronate), 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid (risedronate), I -hydroxyethylidene- 1,1 -bisphosphonic acid (etidronate), 10 1 -hydroxy-3-(1 -pyrrolidinyl)propylidene- 1,1 -bisphosphonic acid, 1 -hydroxy-2-(1 -imidazolyl)etylidene- 1,1 -bisphosphonic acid (zoledronate), 1 -hydroxy-2-(imidazo[ 1,2-a]pyridin-3-yl)ethylidene- 1,1 -bisphosphonic acid (minodronate), 1-(4-chlorophenylthio)methylidene-1,1- bisphosphonic acid ( tiludronate), 15 1-(cycloheptylamino)methylidene-1,1-bisphosphonic acid (cimadronate, incadronate), 6-amino-i -hydroxyhexylidene- 1,1 -bisphosphonic acid ( neridronate) and pharmaceutically acceptable salts there of.
34. A pharmaceutical formulation according to claim 33 wherein the bisphosphonate is 20 alendronate (4-amino-1 -hydroxybutylidene- 1,1 -biphosphonic acid) or pharmaceutically acceptable salts there of.
35. A pharmaceutical formulation according to any one of claims 1 to 34 which is adapted for oral administration. 25
36. A pharmaceutical formulation according to any one of claims 1-35 which is adapted for non colonic delivery.
37. A pharmaceutical formulation according to any one of claims I to 36 for inhibiting 30 bone resorption. WO 00/61111 PCT/SE00/00664 21
38. A pharmaceutical formulation according to any one of claims 1 to 36 for the treatment and prevention of osteoporosis and bone loss related to age, steroid therapy, rheumatism, Paget's disease, cancer, secondary osteoporosis except steroid induced osteoporosis, periodontitis or osteoarthritis.
39. A pharmaceutical formulation according to any of the preceeding claims wherein the formulation is in particulate form.
40. A pharmaceutical formulation according to claim 39 wherein the particulate form is 10 solid or semisolid.
41. A pharmaceutical formulation according to any of claims 39 and 40 wherein the bisphosphone is in the form of micronized powder. is
42. A process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 40, comprising forming a mixture of (i) at least one bisphosphonate, (ii) an additive and (iii) a pharmaceutically acceptable carrier.
43. The use of a pharmaceutical formulation according to any one of claims 1 to 41 for the 20 manufacture of a medicament for the inhibition of bone resorption.
44. The use of a pharmaceutical formulation according to any one of claims 1 to 41 for the manufacture of a medicament for the treatment and prevention of osteoporosis and bone loss related to age, steroid therapy, rheumatism, Paget's disease, or cancer, 25 secondary osteoporosis except steroid induced osteoporosis, periodontitis or osteoarthritis.
45. A method for inhibition of bone resorption which comprises administering to a mammal, including man, in need of such treatment an effective amount of a 30 pharmaceutical formulation according to any one of claims I to 41. WO 00/61111 PCT/SEOO/00664
46. A method for the treatment and prevention of osteoporosis and bone loss related to age, steroid therapy, rheumatism, Paget's disease, cancer, secondary osteoporosis except steroid induced osteoporosis, periodontitis or osteoarthritis,which comprises administering to a mammal, including man, in need of such treatment an effective 5 amount of a pharmaceutical formulation according to any one of claims 1 to 41.
AU41619/00A 1999-04-09 2000-04-06 A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate Abandoned AU4161900A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9901272 1999-04-09
SE9901272A SE9901272D0 (en) 1999-04-09 1999-04-09 New improved formulation
PCT/SE2000/000664 WO2000061111A1 (en) 1999-04-09 2000-04-06 A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate

Publications (1)

Publication Number Publication Date
AU4161900A true AU4161900A (en) 2000-11-14

Family

ID=20415159

Family Applications (1)

Application Number Title Priority Date Filing Date
AU41619/00A Abandoned AU4161900A (en) 1999-04-09 2000-04-06 A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate

Country Status (11)

Country Link
EP (1) EP1171097A1 (en)
JP (1) JP2002541185A (en)
KR (1) KR20010104389A (en)
AU (1) AU4161900A (en)
CA (1) CA2364659A1 (en)
IL (1) IL145506A0 (en)
NO (1) NO20014895L (en)
NZ (1) NZ514478A (en)
SE (1) SE9901272D0 (en)
WO (1) WO2000061111A1 (en)
ZA (1) ZA200108260B (en)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8119159B2 (en) 1999-02-22 2012-02-21 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
US7658938B2 (en) 1999-02-22 2010-02-09 Merrion Reasearch III Limited Solid oral dosage form containing an enhancer
US6943155B2 (en) 2000-04-07 2005-09-13 Lenard M. Lichtenberger Unique compositions of zwitterionic phospholipids and bisphosphonates and use of the compositions as bisphosphate delivery systems with reduced GI toxicity
DE60116483T2 (en) * 2000-05-05 2006-09-07 F. Hoffmann-La Roche Ag GEL PHARMACEUTICAL COMPOSITION FOR SUBCUTANEOUS APPLICATIONS CONTAINING BISPHOSPHONIC ACIDS OR THEIR SALTS
MXPA03007837A (en) 2001-03-01 2004-03-16 Emisphere Techonologies Inc Compositions for delivering bisphosphonates.
JP4381805B2 (en) 2001-07-02 2009-12-09 メリオン リサーチ スリー リミテッド Delivery of bioactive materials
SI1506041T1 (en) 2002-05-10 2008-02-29 Hoffmann La Roche Ibandronic acid for the treatment and prevention of osteoporosis
BR0309691A (en) 2002-12-20 2005-08-02 Hoffmann La Roche High dose ibandronate formulation
US7358360B2 (en) * 2003-01-17 2008-04-15 Teva Pharmaceutical Industries Ltd. Risedronate sodium having a very low content of iron
GB0310919D0 (en) * 2003-05-13 2003-06-18 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
US8637503B2 (en) 2003-05-16 2014-01-28 Board Of Regents, The University Of Texas System Phenothiazine enantiomers as agents for the prevention of bone loss
US7645459B2 (en) 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of bisphosphonates
US20080287400A1 (en) 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
KR20130063041A (en) * 2004-05-24 2013-06-13 워너 칠콧 컴퍼니 엘엘씨 Enteric solid oral dosage form of bisphosphonate containing a chelating agent
US7645460B2 (en) 2004-05-24 2010-01-12 The Procter & Gamble Company Dosage forms of risedronate
US20080286359A1 (en) 2004-05-24 2008-11-20 Richard John Dansereau Low Dosage Forms Of Risedronate Or Its Salts
WO2006020009A1 (en) * 2004-07-23 2006-02-23 The Procter & Gamble Company Solid oral dosage form of a bisphosphonate containing a chelating agent
KR100815040B1 (en) * 2005-01-31 2008-03-18 주식회사종근당 Pharmaceutical compositions containing bisphosphonate for improving oral absorption
NO20053519L (en) * 2005-07-18 2007-01-19 Thia Medica As Use of compounds comprising fatty acids
MX2008012678A (en) * 2006-04-07 2008-12-17 Merrion Res Iii Ltd Solid oral dosage form containing an enhancer.
GB0616794D0 (en) 2006-08-24 2006-10-04 Arrow Int Ltd Solid dosage form
RU2517135C2 (en) 2008-05-07 2014-05-27 Меррион Рисерч Iii Лимитед Peptide compositions and methods for production thereof
US10092580B2 (en) 2008-07-21 2018-10-09 Otonomy, Inc. Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders
KR101631243B1 (en) * 2009-05-13 2016-06-17 신일제약주식회사 Method for preparing novel alendronate emulsion dried product and pharmaceutical composition containing the same
EP2459176B1 (en) 2009-07-31 2017-09-27 Grünenthal GmbH Crystallization method and bioavailability
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
FR2954320B1 (en) 2009-12-17 2012-06-15 Cll Pharma SUPPLEMENTALLY AVAILABLE ORAL PHARMACEUTICAL COMPOSITION CONTAINING BIPHOSPHONIC ACID OR ONE OF ITS SALTS
US9089484B2 (en) 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration
WO2012071517A2 (en) 2010-11-24 2012-05-31 Thar Pharmaceuticals, Inc. Novel crystalline forms
KR20140026354A (en) 2011-01-07 2014-03-05 메리온 리서치 Ⅲ 리미티드 Pharmaceutical compositions of iron for oral administration
KR20120105738A (en) * 2011-03-16 2012-09-26 현대약품 주식회사 An enteric-coated oral formulation
JP5874545B2 (en) * 2011-06-20 2016-03-02 アステラス製薬株式会社 Pharmaceutical composition for oral administration
WO2016120378A1 (en) 2015-01-29 2016-08-04 Novo Nordisk A/S Tablets comprising glp-1 agonist and enteric coating
CN108025042A (en) * 2015-07-06 2018-05-11 董正欣 The new formulation of PTHrP analogs
EP3455229B1 (en) * 2016-05-13 2021-03-24 Thar Pharma LLC Novel crystalline forms
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
CN112972400A (en) * 2021-03-09 2021-06-18 华侨大学 Rapidly disintegrable minodronic acid granules and preparation method thereof
KR20240013402A (en) * 2022-07-22 2024-01-30 주식회사 아이큐어비앤피 Oral pharmaceutical composition comprising teriparatide for preventing or treating osteoporosis and method for preparing the same

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8618259D0 (en) * 1986-07-25 1986-09-03 Leo Pharm Prod Ltd Pharmaceutical compositions
EP0550385A1 (en) * 1991-12-19 1993-07-07 Ciba-Geigy Ag Oral pharmaceutical compositions containing derivatives of methane-diphosphonic acid and 18-crown-6 ethers
TW237386B (en) * 1992-04-15 1995-01-01 Ciba Geigy
SE501389C2 (en) * 1992-04-24 1995-01-30 Leiras Oy Pharmaceutical preparation and process for its preparation
AU687744B2 (en) * 1993-05-15 1998-03-05 Riemser Arzneimittel Ag More easily biologically absorbed tablet containing dichloromethylene diphosphonic acid as the active agent
IL118422A0 (en) * 1995-06-02 1996-09-12 Merck & Co Inc Use of alendronate for the prevention of osteoporosis
GB9516268D0 (en) * 1995-08-08 1995-10-11 Danbiosyst Uk Compositiion for enhanced uptake of polar drugs from the colon
GB9710699D0 (en) * 1997-05-24 1997-07-16 Danbiosyst Uk Gastro-retentive controlled release system
FI109088B (en) * 1997-09-19 2002-05-31 Leiras Oy Tablet and process for its preparation
SE9703691D0 (en) * 1997-10-10 1997-10-10 Astra Ab Pharmaceutical compositions

Also Published As

Publication number Publication date
CA2364659A1 (en) 2000-10-19
JP2002541185A (en) 2002-12-03
IL145506A0 (en) 2002-06-30
WO2000061111A1 (en) 2000-10-19
SE9901272D0 (en) 1999-04-09
ZA200108260B (en) 2003-03-26
NO20014895D0 (en) 2001-10-08
NO20014895L (en) 2001-12-10
NZ514478A (en) 2004-01-30
KR20010104389A (en) 2001-11-24
EP1171097A1 (en) 2002-01-16

Similar Documents

Publication Publication Date Title
AU4161900A (en) A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate
EP1021194B1 (en) New improved formulation for treatment of osteoporosis
US7354912B2 (en) Unique compositions of zwitterionic phospholipids and bisphosphonates and use of the compositions as bisphosphate delivery systems with reduced GI toxicity
JP3933933B2 (en) Parenteral pharmaceutical composition containing biphosphonate
AU2004308644B2 (en) Pharmaceutical formulations of bisphosphonates
CZ297341B6 (en) Coated peroral tablet for treating bone diseases and containing ibandronate as active substance
CA2378521A1 (en) Pharmaceutical tablets
US10093691B2 (en) Crystallization method and bioavailability
WO2014088385A1 (en) Stable pharmaceutical composition for treating osteoporosis
MXPA01010085A (en) A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate
KR102158375B1 (en) Complex liquid fomulation comprising vitamin D emulsion and bisphosphonate and use for preventing or treating osteoporosis
KR20130014376A (en) Pharmaceutical composition for oral administration comprising bisphosphonic acid or its salt
MXPA06007307A (en) Pharmaceutical formulations of bisphosphonates
WO2008020305A2 (en) Solid dosage forms of bisphosphonic acids