WO2016066611A1 - Compositions pharmaceutiques contenant du cinacalcet et procédés pour leur préparation et leur utilisation - Google Patents

Compositions pharmaceutiques contenant du cinacalcet et procédés pour leur préparation et leur utilisation Download PDF

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Publication number
WO2016066611A1
WO2016066611A1 PCT/EP2015/074808 EP2015074808W WO2016066611A1 WO 2016066611 A1 WO2016066611 A1 WO 2016066611A1 EP 2015074808 W EP2015074808 W EP 2015074808W WO 2016066611 A1 WO2016066611 A1 WO 2016066611A1
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Prior art keywords
pharmaceutical composition
cinacalcet
formulation
propylene glycol
lipid component
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PCT/EP2015/074808
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English (en)
Inventor
Pietro TREVISO
Prashant Agarwal
Hywel Williams
Eduardo JULE
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Capsugel Belgium N.V.
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Publication of WO2016066611A1 publication Critical patent/WO2016066611A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/44—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

Definitions

  • the present disclosure relates to oral pharmaceutical compositions containing the drug cinacalcet, or acceptable salts thereof, and methods for their preparation and use.
  • Cinacalcet is a drug designed to lower parathyroid hormone levels (PTH) in the body. It works directly at the parathyroid gland by increasing the sensitivity of calcium-sensing receptors to extracellular calcium, which, in turn, suppresses PTH secretion.
  • the drug cinacalcet has the following chemical structure:
  • Sensipar® tablets containing the hydrochloride salt form of cinacalcet base was developed by Amgen, and approved in 2004 by the FDA for the treatment of secondary Hyperparathyroidism (HPT), hypercalcemia in patients with parathyroid carcinoma, and severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.
  • HPT Hyperparathyroidism
  • cinacalcet works in the parathyroid gland (Kruse AE et al. Nephrol. Dial. Transplant. (2005) 20 (7): 131 1 -1314), it needs to be absorbed from the
  • Gl gastrointestinal tract following oral administration in order to be effective.
  • a critical step in drug absorption from the small intestine (often the primary site of drug
  • the presence of food can improve drug absorption by several different mechanisms, such as improving drug solubilization by promoting the release of natural solubilizers in the small intestine (i.e., bile salts and phospholipids) and by slowing Gl transit time, which results in greater time for a drug to dissolve in the stomach.
  • improving drug solubilization by promoting the release of natural solubilizers in the small intestine (i.e., bile salts and phospholipids) and by slowing Gl transit time, which results in greater time for a drug to dissolve in the stomach.
  • cinacalcet Due to its relatively low solubility ( ⁇ 1 ⁇ g/mL in water), cinacalcet suffers from a sub-linear increase in absorption with increasing dose and increased absorption when administered with meals (Padhi D & Harris R Clin Pharmacokinet 2009; 48 (5): 303-31 1 ). Specifically, it has been found that when Sensipar® is coadministered with a high fat meal in healthy subjects, cinacalcet Cmax and AUC°° values increase by 82% and 68%, respectively, when compared to fasted state values. Also, when administered with a low fat meal, Cmax and AUC°° values increased by 65% and 50%, respectively.
  • Sensipar® should be taken with food or shortly after a meal, to achieve a maximal level of drug absorption using this tablet dosage form (Sensipar®
  • the present disclosure generally relates to oral pharmaceutical compositions containing cinacalcet or an acceptable salt form thereof, and methods for their preparation and use. More specifically, formulation approaches to address solubility limited absorption of cinacalcet are disclosed.
  • the pharmaceutical compositions described herein comprise cinacalcet, a lipid component of either a medium-chain glyceride (MCG) or long-chain glyceride (LCG), or a propylene glycol fatty acid ester, or a suitable blend of these lipid
  • non-ionic surfactant having a HLB of at least 6.
  • the lipid component is chosen from the group consisting of mono-, di- and triglycerides of 6-12 carbon fatty acids, and blends thereof.
  • the lipid component is chosen from the group consisting of mono-, di- and tri caprylic and capric glycerides, and blends thereof.
  • the lipid component is chosen from the group consisting of mono-, di- and triglycerides of 14 - 22 carbon fatty acids, and blends thereof.
  • the lipid component is chosen from the group consisting of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprate, propylene glycol dilaurate or propylene glycol heptanoate.
  • the non-ionic surfactant has a HLB of at least 8.
  • the non-ionic surfactant is chosen from the group consisting of polyoxyethylated mono- and di-fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylated mono- and di-fatty acid esters, glycerol macrogolglycerides, DL-a-tocopheryl polyethylene glycol succinate, polyoxyethylene-polyoxypropylene copolymers, polyglycerol esters of fatty acids, and ethoxylated fatty alcohols.
  • the non-ionic surfactant is selected from the group consisting of polyoxyethylated mono- and di-fatty acid esters of castor oil or hydrogenated castor oil, and polyethylene glycol ester of caprylic/capric glycerides, and sorbitan monolaurate, and blends thereof.
  • the ratio of lipid component to non-ionic surfactant is at least 0.25:1.
  • the ratio of lipid component to non-ionic surfactant is at least 0.5: 1.
  • the ratio of lipid component to non-ionic surfactant is at least 1 :1.
  • the cinacalcet is completely dissolved in the formulation.
  • the cinacalcet is partly dispersed in the
  • the cinacalcet is present in an amount of at least 27.2 mg/g (2.72% w/w).
  • the cinacalcet is present in an amount of at least 54.4 mg/g (5.44 % w/w).
  • the cinacalcet is present in the formulation in an amount of at least 108.8 mg/g (10.8% w/w).
  • the cinacalcet is in the form of a hydrochloride salt, or another pharmaceutically acceptable salt form.
  • the cinacalcet is in the form of a free base.
  • the formulation contains between 5-75% w/w lipid component and 25-75% non-ionic surfactant. [0031] In another embodiment, the formulation contains between 20-75% w/w lipid component and 20-50% non-ionic surfactant.
  • the formulation optionally contains a
  • cosolvent is propylene glycol, polyethylene glycol, isorpropyl myristate, triacetin, glycerol, ethanol, or diethylene glycol monoethyl ether.
  • the formulation containing cinacalcet is delivered in pharmaceutically acceptable dosage form including capsules, sachets and bottles.
  • the formulation containing cinacalcet is delivered in the form of a capsule.
  • One advantage of the instant disclosure is to provide a formulation that has a reduced food effect relative to prior art cinacalcet formulations, by improving compound solubility and dissolution rate in the Gl tract, and / or by enhancing uptake of the compound into the lymphatic system following oral administration.
  • w/w % and wt% means by weight as a percentage of the total weight of the composition.
  • compositions here are lipid-based formulations intended to be administered orally either in a hard capsule or soft gelatin capsule.
  • the lipid-based formulations comprise cinacalcet, a lipid component, a nonionic surfactant and optionally a cosolvent in which the drug is completely or partly dissolved.
  • the formulation may either be in the form of a solution or a
  • formulations may be administered as single unit dosage forms (i.e., liquid or semi-solid fills) filled into hard or soft capsules, sachets or bottles.
  • the compound cinacalcet means both the free base form of the drug as well as pharmaceutically acceptable salts, including acid addition salts such as those containing sulfate, hydrochloride, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, hydrochloride, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • Cinacalcet has the following properties:
  • the instant disclosure provides a lipid formulation comprising a lipid component and a non-ionic surfactant.
  • the lipid component may consist of a medium-chain glyceride, a long-chain glyceride, a propylene glycol fatty acid ester or a mixture of these excipients.
  • MCGs Medium-chain glycerides
  • the MCG may be a mono-, di- or triglyceride.
  • Preferred MCGs are caprylic and capric mono- and diglycerides, and blends thereof, including glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate. Examples are sold under the trade names Imwitor® and Capmul®.
  • MCGs include caprylic/capric triglycerides, sold under trade names such as MiglyolTM, Labrafac® and Captex®, glycerol esters of lauric acid, such as glyceryl monolaurate, glyceryl dilaurate and glycerol trilaurate, and polyglycerol esters of caprylic acid, sold under the trade names such as Caprol®.
  • LCGs Long-chain glycerides
  • the LCG may be a mono-, di- or triglyceride.
  • LCGs include glyceryl behenate, glyceryl monolinoleate, glycerol monooleate, glycerol monostearate, glycerol monopalmitate, glyceryl dilinoleate, glycerol diooleate, glycerol distearate, glycerol dipalmitate, glyceryl trilinoleate, glyceryl triolein, glyceryl tristearate, glyceryl tripalmitate, sold under trade names such as PeceolTM, MaisineTM 35-1 , GeleolTM and Capmul®.
  • LCGs include simple oils including, but not limited to the following: almond oil, canola oil, castor oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil and hydrogenated vegetable oil.
  • Example propylene glycol fatty acid esters that may be used in the formulation as the lipid phase include propylene glycol monocaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol dilaurate , and propylene glycol heptanoate . Examples are sold under the trade names Capmul®, Capryol®, Lauroglycol® and Labrafac® PG. These propylene glycol fatty acid esters may also be used in the formulations as surfactants when a more lipophilic excipient is included.
  • preferred lipid components in the present invention are those that can dissolve the compound at concentrations greater than 25 mg active (free base equivalent) per gram of excipient ("mg/g" hereinafter), and more preferably, above 50 mg/g, and more preferably, above 100 mg/g, which may be determined via solubility assays.
  • preferred lipid components include LCGs, namely glycerol monooleate (Peceol®) or glycerol monolinoleate (MaisineTM 35-1 ), and more preferably, MCGs such as glycerol monocaprylate (e.g., Capmul® MCM EP or Imwitor® 308) or propylene glycol fatty acid esters such as propylene glycol monocaprylate (Capryol® 90 or Capryol® PGMC).
  • LCGs namely glycerol monooleate (Peceol®) or glycerol monolinoleate (MaisineTM 35-1 )
  • MCGs such as glycerol monocaprylate (e.g., Capmul® MCM EP or Imwitor® 308) or propylene glycol fatty acid esters such as propylene glycol monocaprylate (Capryol® 90 or Capryol® PGMC).
  • the non-ionic surfactant has a capacity to emulsify the lipid component of the formulation and has a hydrophilic-lipophilic balance ("HLB") of at least 6.
  • the hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule.
  • An HLB value of 0 corresponds to a completely lipophilic/hydrophobic molecule, and a value of 20 corresponds to a completely hydrophilic/lipophobic molecule.
  • HLB values for various surfactants are well known in the art.
  • the non-ionic surfactant may be selected from propylene glycol mono- or diesters of 8 - 22 carbon fatty acids, sorbitan fatty acid esters including sorbitan monolaurate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, polysorbate 85; polyoxyethylated mono- and di-fatty acid esters such as esters of castor oil (Kolliphor® EL), hydrogenated castor oil (Kolliphor® RH40), hydroxystearic acid (Kolliphor® HS-15); glycerol macrogolglycerides such as Labrasol®, Gelucire® 44/14, Gelucire® 50/13, Labrafil®; DL-a-tocopheryl polyethylene glycol succinate; polyoxyethylene- polyoxypropylene copolymers such as poloxamer 124, poloxamer 188, poloxamer 407; polyglycerol esters of
  • the preferred surfactants in the present invention are those with a capacity to emulsify the lipid component of the formulation, namely those surfactants with a HLB greater than 8 for example Span 20 and polysorbate 85 (Tween 85), or, more preferably, a HLB greater than 12, for example, Kolliphor RH40, Kolliphor EL, Solutol HS-15, polysorbate 20, polysorbate 60, polysorbate 80, , Gelucire® 44/14, Labrasol®, Gelucire® 50/13 or DL-a-tocopheryl polyethylene glycol succinate.
  • a HLB greater than 8 for example Span 20 and polysorbate 85 (Tween 85), or, more preferably, a HLB greater than 12, for example, Kolliphor RH40, Kolliphor EL, Solutol HS-15, polysorbate 20, polysorbate 60, polysorbate 80, , Gelucire® 44/14, Labrasol®, Gelucire® 50/13 or DL-a-to
  • the non-ionic surfactant is selected from the group consisting of polyoxyethylated mono- and di-fatty acid esters of castor oil or hydrogenated castor oil, and polyethylene glycol ester of caprylic/capric glycerides, and sorbitan monolaurate, and blends thereof. It is also possible to utilize a single non-ionic surfactant or a combination of non-ionic surfactants in a cinacalcet lipid formulation.
  • the amount of lipid and non-ionic surfactant in the lipid-based formulation are chosen so as to enable relatively high compound loadings of cinacalcet with optimal formulation dispersibility.
  • the formulation contains between 5-75% w/w, typically 6-70% w/w, typically 7-65% w/w, typically 8-60% w/w, lipid component and 25- 75% w/w non-ionic surfactant.
  • the ratio of lipid component to non-ionic surfactant is at least 0.25:1.
  • the ratio may be at least 0.5:1 , may be at least 1 :1 , may be at least 1.5:1 , may be at least 2:1 , or may be at least 3:1.
  • the amount of cinacalcet in the lipid formulations is preferably at least 27.2 mg/g (27.2 mg cinacalcet free base equivalent per g of lipid formulation), may be at least 40.8 mg/g, or may be at least 54.4 mg/g.
  • other lipids such as LCG and propylene glycol fatty acid esters
  • similar lipid:surfactant ratios are employed, though when developing a lipid solution it is generally found that stable cinacalcet loadings in the formulation are lower when compared to equivalent formulations containing MCG or propylene glycol fatty acid esters.
  • the amount of cinacalcet in suspension-type lipid formulations can be higher than that of lipid solutions, preferably at least 108.8 mg/g.
  • the lipid formulation may contain other optional excipients to improve emulsification of the lipid component in the formulation and overall drug solubility, and may include phospholipids, free fatty acids, fatty acid alcohols or synthetic fatty acid derivatives including isopropyl myristate and isopropyl palmitate. Isopropyl myristate and isopropyl palmitate may also be added to the lipid formulation as a cosolvent, for the purpose of improving drug solubility in the formulation.
  • cosolvents may include propylene glycol, polyethylene glycol, triacetin, glycerol, ethanol and diethylene glycol monoethyl ether, or other pharmaceutically acceptable cosolvents.
  • Example Formulations 1 , 2 and 3 were prepared as follows. The target compound mass was initially weighed into a glass vial before the addition of compound- free formulation, followed by mixing at 30°C until the compound was completely dissolved, which was confirmed by the absence of any drug crystals in the formulation using a polarized light microscope.
  • Dispersion of the formulation into aqueous solution was evaluated as follows: 1 g of compound containing formulation was added directly to a glass beaker followed by 250 mL aqueous medium (pre-equilibrated to 37°C) under constant stirring. Samples were periodically analyzed over a 24 hour period by polarized light microscopy to detect potential compound precipitation. Since cinacalcet is a poorly water-soluble compound, precipitation to form crystals following dispersion in an aqueous medium was considered an indicator of poor lipid formulation performance.
  • Examples 1 , 2, 3 formed homogenous dispersions in water with no evidence of compound precipitation over 24 hours. Following HPLC analysis, the amount of compound solubilized within the aqueous-rich colloidal phase was 93.5%, 103.3% and 98.3% for Examples 1 , 2 and 3, respectively.
  • Examples 1 , 2 and 3 described above all contain a notable amount of a high HLB non-ionic surfactant which was included to facilitate dispersion of the lipid formulation oil phase.
  • Additional cinacalcet lipid formulations were prepared and tested to explore the importance of including a surfactant and surfactant type, and were as follows:
  • a MCG glycerol monocaprylate
  • Capmul® MCM glycerol monocaprylate
  • Example 5 Capryol® 90, which consists of propylene glycol fatty acid esters of caprylic acid, is used as the lipid component. On dispersion, Example 5 showed no evidence of precipitation over 24 hours and provided a high level (>94.1 %) of cinacalcet solubilization in the aqueous-rich colloidal phase. The performance of Example 5 containing a propylene glycol fatty acid ester as the lipid component was therefore consistent with Examples 1-4 described above that contained MCG.
  • Peceol® was investigated as an example LCG. It consists of a mono, di and triester mixture of oleic acid. In Example 6 containing Peceol®, it was necessary to lower the compound loading to 40.8 mg/g to produce stable lipid solutions due to a decrease in cinacalcet solubility in this lipid component relative to MCG and propylene glycol fatty acid esters. On dispersion of Example 6 in water, there was no evidence of compound precipitation over 24 hours. Example 6 also provided substantial
  • solubilization of the compound in the aqueous-rich colloidal phase (>75%).
  • lipid component including MCG, LCG and propylene glycol fatty acid esters.
  • MCG MCG
  • LCG propylene glycol fatty acid esters
  • glycerol monocaprylate e.g., Imwitor® 308, Capmul® MCM
  • propylene glycol fatty acid esters e.g., Capryol® 90
  • Example 7 was prepared as follows: Example Isopropyl 108.8 Compound was mixed Lipid formulation
  • Example 7 is an example of a lipid suspension for the compound cinacalcet.
  • Example 7 is consistent in composition to Example 1 described earlier, but differing in the compound/formulation ratio, and differing in terms of the physical form of the compound in the formulation.
  • Example 7 was tested on dispersion similarly to the Example 1 described above, both in water and in pH 6.5 phosphate buffered saline (PBS), but where the mass of formulation was reduced to 0.5 g to deliver the same cinacalcet dose in 250 ml dispersion medium.
  • the pH of the PBS medium mimics that of the pH of the small intestine, the primary site of drug absorption.
  • cinacalcet is weakly basic with an apparent pKa of 8.72, it will show decreasing aqueous solubility with increasing pH, thus higher solubility in the acidic stomach compared to the more neutral small intestine.
  • Dispersion testing of cinacalcet formulations in pH 6.5 PBS will therefore be more stressful to solubilization in comparison to water (where an acidic salt counterion can shift pH to a more acidic value) and in an acidic simulated gastric fluid.
  • Example 7 offered complete (>95%) cinacalcet solubilization in both water and in PBS.
  • This example lipid suspension therefore provides similar performance to Example 1 , despite it containing cinacalcet dispersed in a crystalline form in the formulation. Since it was not possible to completely solubilize the same dose of cinacalcet in PBS in the absence of lipid formulation, it is apparent that the dispersed lipid formulation is able to increase cinacalcet solubility in the dispersed state.
  • Example cinacalcet formulations were tested for their ability to solubilize the compound at 54.4 mg/g, and then placed on storage at ICH conditions

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Abstract

La présente invention concerne des compositions pharmaceutiques contenant du cinacalcet et des procédés pour leur préparation et leur utilisation.
PCT/EP2015/074808 2014-10-31 2015-10-27 Compositions pharmaceutiques contenant du cinacalcet et procédés pour leur préparation et leur utilisation WO2016066611A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019186516A1 (fr) 2018-03-30 2019-10-03 Ftf Pharma Private Limited Formes posologiques liquides de cinacalcet ou d'un sel de celui-ci

Citations (4)

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US6267985B1 (en) * 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US20130303495A1 (en) * 2009-12-31 2013-11-14 Sov Therapeutics Emulsion formulations
US9203736B2 (en) 2008-03-31 2015-12-01 Ericsson Ab Method and apparatus for providing resiliency in multicast networks
WO2015193380A2 (fr) * 2014-06-19 2015-12-23 Solural Pharma ApS Forme pharmaceutique orale solide de composés lipophiles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6267985B1 (en) * 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US9203736B2 (en) 2008-03-31 2015-12-01 Ericsson Ab Method and apparatus for providing resiliency in multicast networks
US20130303495A1 (en) * 2009-12-31 2013-11-14 Sov Therapeutics Emulsion formulations
WO2015193380A2 (fr) * 2014-06-19 2015-12-23 Solural Pharma ApS Forme pharmaceutique orale solide de composés lipophiles

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Title
KRUSE AE ET AL., NEPHROL. DIAL. TRANSPLANT., vol. 20, no. 7, 2005, pages 1311 - 1314
PADHI D; HARRIS R, CLIN PHARMACOKINET, vol. 48, no. 5, 2009, pages 303 - 311
WILLIAMS, HD. ET AL., J. PHARM. SCI., vol. 101, 2012, pages 3360 - 3380

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019186516A1 (fr) 2018-03-30 2019-10-03 Ftf Pharma Private Limited Formes posologiques liquides de cinacalcet ou d'un sel de celui-ci

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