WO2022029430A1 - Nouvelles formulations injectables comprenant un médicament immunomodulateur - Google Patents

Nouvelles formulations injectables comprenant un médicament immunomodulateur Download PDF

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Publication number
WO2022029430A1
WO2022029430A1 PCT/GB2021/052015 GB2021052015W WO2022029430A1 WO 2022029430 A1 WO2022029430 A1 WO 2022029430A1 GB 2021052015 W GB2021052015 W GB 2021052015W WO 2022029430 A1 WO2022029430 A1 WO 2022029430A1
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Prior art keywords
formulation
thalidomide
injection
pharmaceutically
kit
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PCT/GB2021/052015
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English (en)
Inventor
Johan Raud
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Vicore Pharma Ab
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Publication of WO2022029430A1 publication Critical patent/WO2022029430A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • ILDs Interstitial lung diseases
  • COPDs chronic obstructive airway disease
  • asthma obstructive airway diseases
  • ILDs may be caused by injury to the lungs, which triggers an abnormal healing response but, in some cases, these diseases have no known cause. ILDs can be triggered by chemicals (silicosis, asbestosis, certain drugs), infection (e.g. pneumonia) or other diseases (e.g. rheumatoid arthritis, systemic sclerosis, myositis, hypersensitivity pneumonitis or systemic lupus erythematosus (lupus)). The most common ILDs are idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both of which are characterised by chronic inflammation and reduced lung function.
  • IPF idiopathic pulmonary fibrosis
  • sarcoidosis both of which are characterised by chronic inflammation and reduced lung function.
  • Sarcoidosis is a disease of unknown cause that is characterised by collections of inflammatory cells that form lumps (granulomas), often beginning in the lungs (as well as the skin and/or lymph nodes, although any organ can be affected).
  • symptoms include coughing, wheezing, shortness of breath, and/or chest pain.
  • Treatments for sarcoidosis are patient-specific. In most cases, symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is possible, but for those presenting lung symptoms, glucocorticoids (e.g. prednisone or prednisolone), antimetabolites and/or monoclonal anti-tumor necrosis factor antibodies are often employed.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • IPF in the other hand is a chronic lung disease characterized by a progressive and irreversible decline in lung function caused by scarring of the lungs. Symptoms typically include cough and shortness of breath. Although less prevalent than asthma and COPD, mortality rates from IPF are much higher (e.g. 5 times higher than that of asthma, despite asthma being 100 times more prevalent). Current treatment of IPF includes oxygen supplementation. Medications that are used include pirfenidone or nintedanib, but with only limited success in slowing the progression of the disease. Further, both of these drugs commonly cause (predominantly gastrointestinal) side-effects. IPF affects about 5 million people globally. Average life expectancy after diagnosis is around four years.
  • Immunomodulatory imide drugs are a class of immunomodulatory drugs that contain an imide group.
  • the drug class includes thalidomide and analogues thereof, such as lenalidomide and pomalidomide.
  • Primary medical uses of IMIDs include the treatment of cancers, such as multiple myeloma and myelodysplastic syndrome (a precursor condition to acute myeloid leukaemia), as well as certain autoimmune diseases (including erythema nodosum leprosum, a painful vasculitic complication of leprosy).
  • Off- label uses include other forms of cancer, such as Hodgkin's lymphoma and prostate cancer, as well as other conditions like primary myelofibrosis.
  • Cyclodextrin-based thalidomide formulations for the local treatment of nosebleeds in hereditary hemorrhagic telangiectasia are also known (see Colombo et al, Int. J. Pharm., 514, 229 (2016)).
  • thalidomide potential use as a systemic treatment of ILDs, such as IPF, including IPF cough (see Zhao et al, Clin. Exp.
  • Thalidomide s infamous history of causing birth defects (teratogenicity) following its use as an antiemetic during pregnancy is well known and, whilst still its most feared adverse effect, can be completely avoided by taking appropriate precautions.
  • the most common adverse effects seen in current clinical practice include somnolence, fatigue, peripheral neuropathy, constipation and skin rash.
  • thalidomide since thalidomide’s discovery, many modes and means of administration have been reported, including, for example, as a topical gel (see e.g. St. John et al, Bone Marrow Transplant, 48, 610 (2013)), as a nasal powder (see e.g. Colombo supra) and, more recently, embedding the drug in mesoporous silica particles for pulmonary delivery (see international patent application WO 2019/211624).
  • thalidomide is presently only available commercially for peroral administration in the form of a capsule, with a typical initial dosage of 200 mg/day. Due to its sedative properties, thalidomide is usually taken once a day at bedtime.
  • a pharmaceutical formulation (which can also be referred to as a ‘pharmaceutical composition’) in the form of an injectable suspension of particles consisting essentially of thalidomide, or a pharmaceutically-acceptable salt thereof, suspended in a pharmaceutically- acceptable, and injectable, vehicle, for use in the treatment of a medical condition by injection, which formulations and/or compositions are referred to hereinafter as ‘the formulations of the invention’.
  • the formulations of the invention comprise, and are injected in the form of, particles that consist essentially of thalidomide or a pharmaceutically- acceptable salt thereof suspended in a pharmaceutically-acceptable vehicle.
  • the pharmaceutically-acceptable vehicle should in the main part comprise a solvent system that is chemically inert to the active ingredient, has no detrimental side effects or toxicity under the conditions of use, and is one that is capable of suspending thalidomide or salt thereof prior to injection.
  • the vehicle should be one in which the solubility of thalidomide or salt thereof is low, by which we mean a solubility of less than about 5 mg/mL, such as less than about 2 mg/mL, preferably less than about 1 mg/mL, more preferably less than about 0.5 mg/mL, especially less than about 0.1 mg/mL and particularly less than about 0.05 mg/mL, all at about neutral pH value, at about room temperature (e.g. about 20°C) and at or around atmospheric pressure.
  • the solubility of thalidomide or salt thereof is low, by which we mean a solubility of less than about 5 mg/mL, such as less than about 2 mg/mL, preferably less than about 1 mg/mL, more preferably less than about 0.5 mg/mL, especially less than about 0.1 mg/mL and particularly less than about 0.05 mg/mL, all at about neutral pH value, at about room temperature (e.g. about 20°C) and at or around atmospheric pressure.
  • non-polar oils in which thalidomide is poorly soluble may be employed as the main component of the vehicle of a composition of the invention, including non-polar oils, including vegetable oils, such as olive oil, castor oil, safflower oil, coconut oil, corn oil, peanut oil, cottonseed oil and, particularly, sesame oil and soybean oil
  • the pharmaceutically-acceptable vehicle comprises an aqueous solvent system, by which we mean a solvent system that comprises water.
  • the vehicle may, particularly when it is essentially aqueous, include other ingredients/excipients, such as isotonicity- modifying agents (e.g.
  • pH adjusting and/or buffering agents e.g. disodium hydrogen phosphate dihydrate, anhydrous citric acid, sodium citrate, sodium hydroxide and combinations thereof
  • polar co-solvents e.g. ethanol, glycerol, propylene glycol, polyethylene glycols of various molecular weights and tetraglyol
  • non- polar co-solvents e.g. triglycerides, such as Miglyol, sesame oil, peanut oil and soybean oil
  • viscosity-increasing, or thickening, agents to avoid particle aggregation and/or sedimentation e.g.
  • carboxymethylcellulose and derivatives thereof such as sodium carboxymethylcellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, Poloxamers, such as Poloxamer 407, polyvinylpyrrolidone, cyclodextrins, such as hydroxypropyl- ⁇ -cyclodextrin, and polyethylene glycols of various molecular weights); surfactant/wetting agents to achieve a homogeneous suspension (e.g.
  • sorbitan esters sodium lauryl sulfate; monoglycerides, polyoxyethylene esters, polyoxyethylene alkyl ethers, polyoxylglycerides and, preferably, Tweens (Polysorbates), such Tween 80 and Tween 20); and other ingredients, such as mannitol, croscaramellose sodium and hyaluronic acid.
  • a co-solvent is non-polar, formulations of the invention may be presented as a two-phase system such as an emulsion.
  • excipients may be commercially-available or are otherwise described in the literature, for example in Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference.
  • vehicles comprising mixtures of certain solvents (e.g. oils) in which thalidomide is essentially insoluble as hereinbefore defined may be employed, we prefer that the vehicle consists essentially of a single solvent in which thalidomide is essentially insoluble.
  • the vehicle/solvent system comprises one or more of the oil-based solvents as mentioned herein, by which we mean that the vehicle/solvent system comprises mainly one or more of such oils, or that it is an essentially aqueous solvent system, by which we mean that the vehicle/solvent system comprises mainly water.
  • the vehicle/solvent system comprises mainly one or more of the aforementioned oils, or that the vehicle/solvent system comprises mainly water.
  • the vehicle/solvent system may comprise at least about 50% of the one or more oils, or of water, by weight, including at least about 60%, such as at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 82%, at least about 84%, at least about 86%, at least about 88% or at least about 90%, such as at least about 92%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% and at least about 99%, of the one or more oils, or of water, by weight, based on the total weight of the solvent system (and/or the pharmaceutically-acceptable vehicle) of a formulation of the invention.
  • total amounts of the aforementioned ‘other’ ingredients, and particularly other solvents, whether polar or non-polar may be up to about 50%, such as up to about 40%, such as up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 18%, up to about 16%, up to about 14%, up to about 12% or up to about 10%, such as up to about 8%, up to about 6%, up to about 5%, up to about 4%, up to about 3%, up to about 2% and up to about 1%, by weight, based on the total weight of the solvent system (and/or the pharmaceutically-acceptable vehicle) of a formulation of the invention.
  • the pharmaceutically-acceptable vehicle must allow for the injection of the formulation of the invention at an appropriate injection site.
  • the vehicle may be in the form of a liquid of varying viscosities at standard temperatures, including a sol or a gel, provided that the physical and chemical properties of the vehicle: x enable the formation of a stable, homogeneous suspension of individual particles consisting essentially of thalidomide or pharmaceutically- acceptable salt thereof; and yet x allow for both withdrawal of that formulation from a container, such as a vial, and injection of that formulation to the relevant administration site, through an appropriate delivery means, such as a needle or a catheter.
  • a stable suspension will thus be one in which particles do not settle and/or agglomerate irreversibly.
  • the pharmaceutically-acceptable vehicle of the formulation of the invention should enable to formation of a uniform suspension when a receptacle, such as a vial or a syringe, in which the formulation is contained is tapped and/or shaken for an appropriate length of time (e.g. several seconds), in order to dislodge any solid material that may have settled and to ensure a uniform suspension after such agitation and prior to injection.
  • a receptacle such as a vial or a syringe
  • an appropriate length of time e.g. several seconds
  • formulations of the invention need to be capable of passing through an appropriate delivery means, such as a hypodermic needle or a catheter, from a vial prior to an injection (avoiding clogging and foaming tendencies, and enabling accurate dose measurements), and during injection (allowing for ease of injectability and avoiding the need for excessive force, enabling evenness of flow and freedom from clogging).
  • an appropriate delivery means such as a hypodermic needle or a catheter
  • the vehicle may be modified by the use of excipients (including co-solvents, more preferably surfactants and, particularly, viscosity modifiers) to create a formulation of the invention that exhibits such properties.
  • surfactant/wetting agents such as those listed above and particularly sorbitol derivatives, such as sorbitan and Polysorbates, such Tween 80 and Tween 20); and/or, more preferably, viscosity-increasing, or thickening, agents such as those listed above and particularly cellulose derivatives, such as microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose and, especially, carboxymethylcellulose and/or sodium carboxymethylcellulose, may be employed alone or in combination, along with the solvent system of the vehicle, to achieve a stable, homogeneous suspension.
  • surfactant/wetting agents such as those listed above and particularly sorbitol derivatives, such as sorbitan and Polysorbates, such Tween 80 and Tween 20
  • viscosity-increasing, or thickening, agents such as those listed above and particularly cellulose derivatives, such as microcrystalline cellulose, hydroxypropylmethyl
  • homogeneous and ‘distributed homogeneously’ in the context of the present invention mean that there is a substantially uniform content of thalidomide or salt thereof throughout the vehicle of a formulation of the invention.
  • the measured content of active ingredient that is present as between such samples gives rise to a standard deviation from the mean amount (i.e. the coefficient of variation and/or relative standard deviation) of less than about 8%, such as less than about 6%, for example less than about 5%, particularly less than about 4%, e.g. less than about 3% and preferably less than about 2%.
  • formulations of the invention form a de facto ‘depot’ comprising active ingredient following injection. That is, whatever is formed following injection of a formulation of the invention (whether a reservoir comprising a localized mass of active ingredient, crystalline particles of thalidomide deposited in tissue, a monolithic structure (as is often the case for pharmaceutical depots), or otherwise), a controlled and/or sustained release of thalidomide into plasma takes place at a steady rate.
  • Such behaviour is observed following injection of formulations of the invention in spite of the substantial absence of other, standard depot-forming excipients that are known to those skilled in the art, such as biodegradable (e.g. PLGA) microparticles or lipid liquid crystals.
  • formulations of the invention are preferably essentially free of functional pharmaceutically-acceptable excipients.
  • ‘Functional’ pharmaceutically-acceptable excipients in this context includes excipients that are normally employed in the pharmaceutical arts to have an effect on the release and/or the dissolution rate of an active ingredient, particularly those that might be expected to give rise to a delayed release of active ingredients following injection, and/or depot-forming excipients such as those mentioned above.
  • formulations of the invention and pharmaceutically- acceptable vehicles included therein comprise less than about 10%, such as less than about 5%, including less than about 2% and preferably less than about 1% of such excipients.
  • Thalidomide and pharmaceutically-acceptable salts are presented in formulations of the invention in the form of particles that consist essentially of thalidomide or salt thereof.
  • particles consisting essentially of thalidomide/salt we mean particles that are essentially free of functional pharmaceutically-acceptable excipients employed in the pharmaceutical arts to have an effect on the release or the dissolution of an active ingredient as defined above.
  • core particles comprising thalidomide that are coated with any sort of organic or inorganic sustained- release coating. What are not necessarily excluded however are particles comprising thalidomide that include, for example, other active ingredients and/or inert, non-functional, pharmaceutically-acceptable excipients.
  • Non- functional pharmaceutically-acceptable excipients include those that would not normally be expected to have an effect on the release or the dissolution rate of thalidomide or salt thereof (i.e. the opposite of above-described ‘functional’ pharmaceutically-acceptable excipients).
  • particles consisting essentially of thalidomide/salt thereof comprise less than about 50%, such as less than about 40%, including less than about 30%, for example less than about 20%, less than about 10%, or less than about 5%, by weight, based on the total weight of the thalidomide particles that are, or are to be suspended, in a formulation of the invention, of either: x non-functional pharmaceutically-acceptable excipients as defined above, and/or x more preferably, other active ingredients.
  • particles consisting essentially of thalidomide/salt thereof comprise less than about 20%, such as less than about 10%, including less than about 5%, for example less than about 4%, less than about 3%, less than about 2%, or less than about 1%, by weight, based on the total weight of the thalidomide particles that are, or are to be suspended, in a formulation of the invention, of functional pharmaceutically-acceptable excipients as defined above.
  • particles may consist entirely of thalidomide or a pharmaceutically-acceptable salt thereof (i.e. comprise no further added ingredients, and/or ingredients other than trace amounts of water or impurities).
  • the particles consisting essentially of thalidomide or pharmaceutically- acceptable salt thereof are preferably presented in the form of microparticles.
  • active ingredient is preferably presented as a plurality of primary (i.e. non-agglomerated) particles consisting essentially of thalidomide or salt thereof as defined above, typically having a weight- and/or a volume-based mean diameter of no more than about 1,000 ⁇ m, such as no more than about 500 ⁇ m, including no more than about 250 ⁇ m, preferably no more than about 100 ⁇ m, including no more than about 50 ⁇ m, such as no more than about 20 ⁇ m, or no more than about 10 ⁇ m.
  • primary particles of thalidomide or salt thereof have weight- and/or volume-based mean diameter of no less than about 0.2 ⁇ m, such as no less than about 0.5 ⁇ m, including no less than about 1 ⁇ m.
  • weight based mean diameter will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by weight, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained by e.g. sieving (e.g. wet sieving).
  • volume based mean diameter is similar in its meaning to weight based mean diameter, but will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by volume, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the volume fraction, as measured by e.g. laser diffraction.
  • Particle sizes may also be measured by standard equipment, such as a dry particle size measurement technique, including dry dispersion technologies available from manufacturers such as Sympatec GmbH (Clausthal-Zellerfeld, Germany). Other instruments that are well known in the field may be employed to measure particle size, such as equipment sold by e.g.
  • particles having weight- and/or volume-based mean diameters within the above limits we include mean diameters of particles when prepared and/or prior to suspension in the vehicle of a formulation of the invention, when so suspended and/or at any time prior to being injected. It will be appreciated that some aggregation of primary particles to form secondary particles may occur during handling and/or processing of active ingredient. This can and should nevertheless be minimised.
  • Primary particles of thalidomide/salt thereof may be prepared by an appropriate technique, such as precipitation, cutting (e.g.
  • Formulations of the invention are administered parenterally/systemically by injection.
  • injection may also include administration by infusion.
  • Injection may take place intravenously or intraarterially (including by intravascular or other perivascular devices/dosing means), intramuscularly, intraosseously, intracerebrally, intracerebroventricularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, intratumorally, cutaneously, intracutaneously, subcutaneously or transdermally, via a pharmaceutically-acceptable dosing means.
  • formulations of the invention are administered subcutaneously and/or, more particularly, intramuscularly.
  • Formulations of the invention may comprise between about 1% and about 50%, such as between about 5% (such as about 10%) and about 30% (such as about 25%) by weight of the particles consisting essentially of thalidomide or salt thereof, with the remainder made up by the pharmaceutically-acceptable vehicle.
  • Preparation of formulations of the invention may be achieved non-inventively by the skilled person using routine techniques, and essentially comprises incorporation of particles consisting essentially of thalidomide or salt thereof as described herein into the pharmaceutically-acceptable vehicle as described herein. Such a process may be achieved with due regard to the intended route of administration and standard pharmaceutical practice.
  • a formulation of the invention may be contained within a reservoir, such as a syringe, that is connected to, and/or is in association with, a surgical administration apparatus, such as a needle, a catheter or the like, for injection (and/or infusion) as needed.
  • a surgical administration apparatus such as a needle, a catheter or the like
  • an injectable dosing means comprising a formulation of the invention contained within a reservoir, and an injection means. The formulations of the invention are injected by applying some kind of physical force, pushing the formulation within the reservoir so that it passes through the surgical administration apparatus.
  • the physical force may be applied mechanically, either automatically or manually (for example by pushing the plunger of a syringe).
  • the surgical administration apparatus will have appropriate dimensions to allow the delivery of a formulation of the invention to the intended site of administration. This will likely depend upon factors including the age and/or the BMI of the subject in question.
  • a needle with a length of about 5/8” (16 mm) to about 3” (75 mm) or 2” (50 mm), for example about 7/8” (22 mm) to about 11 ⁇ 2” (40 mm) is preferred.
  • needle gauges of between 18 and 31 may be employed, with a gauge of between 22 (e.g. 24) and 27 (e.g. 25) being preferred for subcutaneous injection, and a gauge of between 19 (e.g. 20) and 25 (e.g. 24) being preferred for intramuscular injection.
  • Formulations of the invention and dosing means containing them should be presented in a form that complies with regulatory standards for injectable formulations and devices related to the functionality and/or performance of the parenteral drug delivery system (see e.g.
  • EMEA, ICH Q6A Note for Guidance Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96), May 2000, and FDA, CDER, Guidance for Industry Container Closure System for Packaging Human Drugs and Biologics, May 1999). Such requirements include the force required to initiate and maintain plunger movement down the barrel, and the capability of a syringe to deliver the labelled amount of drug product.
  • Formulations of the invention may be stored (e.g. in an appropriate sterile vial) prior to being loaded into a suitable injectable dosing means, or may be prepared immediately (i.e. within an hour down to a few minutes) within an appropriate sterile receptacle, such as a vial, prior to loading into such a dosing means and then administering it by injection.
  • a pre-loaded injectable dosing means as described above, but modified to comprise at least two chambers, one of which comprises particles consisting essentially of thalidomide or salt thereof as defined herein, and the other of which comprises a pharmaceutically-acceptable vehicle as defined herein, wherein admixing to make a formulation of the invention occurs prior to and/or during injection.
  • formulations of the invention are capable of maintaining physical and chemical integrity under normal storage conditions. That is, formulations of the invention are capable of delivering a consistent and/or uniform, steady state dose of active ingredient when injected, at any time after manufacture, including after storing under normal storage conditions.
  • formulations of the invention may be stored under normal storage conditions, with an insignificant degree of changes in physical and/or chemical properties of the formulation per se, any component thereof, and/or, most importantly, active ingredient, over time.
  • An ‘insignificant degree of changes in physical and/or chemical properties’ thus includes that, both before, and after, having been loaded into a dosing means for injection as described herein, formulations of the invention possess both physical stability and chemical stability.
  • formulations of the invention may be stored (with or without appropriate pharmaceutical packaging), under normal storage conditions, with an insignificant degree of chemical degradation or decomposition of the components of the formulation and, particularly, the active ingredient.
  • physical stability we include that formulations of the invention may be stored (with or without appropriate pharmaceutical packaging), under normal storage conditions, with an insignificant degree of physical transformation, such as aggregation or sedimentation, or changes in the nature and/or integrity of the formulation and, particularly, the active ingredient, including dissolution, solvatization, solid state phase transition, etc.
  • ‘normal storage conditions’ include temperatures of between minus 80 and plus 50°C (preferably between 0 and 40°C and more preferably ambient temperature, such as between 15 and 30°C), pressures of between 0.1 and 2 bars (preferably atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 60%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months).
  • formulations of the invention and/or active ingredients contained therein may be found to be less than about 15%, more preferably less than about 10%, and especially less than about 5%, chemically degraded/decomposed, and/or physically transformed, as appropriate.
  • Formulations of the invention are useful as medicaments/pharmaceuticals and in particular in any condition that thalidomide is known to be of potential use in.
  • Such conditions include the treatment of cancers, such as multiple myeloma and myelodysplastic syndrome, as well as Hodgkin's lymphoma, prostate cancer, primary myelofibrosis, renal-cell carcinoma, glioma, colorectal cancer, melanoma, Kaposi’s sarcoma, Waldenström’s macroglobulinaemia, in addition to anorexia and cachexia in late stage cancers; autoimmune diseases, such as rheumatoid arthritis, erythema nodosum leprosum, sarcoidosis, Still’s disease, Sjögren’s syndrome, Crohn’s disease, Behçet’s disease, discoid lupus erythematosus and ankylosing spondylitis, as well as common symptoms of such disorders, including granulomatous skin lesions of sarcoidosis, cutaneous lesions of lupus, oral and genital lesions of Behçet’
  • Formulations of the invention find particular utility however in the treatment of ILDs.
  • a formulation of the invention for use in the treatment of an ILD by injection as well as the use of a formulation of the invention for the manufacture of a medicament for the treatment of an ILD by injection.
  • ILDs include autoimmune diseases (in which the immune system attacks the body), such as lupus, rheumatoid arthritis, sarcoidosis and scleroderma/systemic scelorosis, lung inflammation due to breathing in a foreign substance such as dust, fungus or mould (hypersensitivity pneumonitis), side effects of medicines (such as nitrofurantoin, sulfonamides, bleomycin, amiodarone, methotrexate, gold, infliximab, etanercept, and other chemotherapy medicines) or radiation treatment to the chest, or occupational lung disease, brought on by working with or around asbestos, coal dust, cotton dust, and silica dust.
  • autoimmune diseases in which the immune system attacks the body
  • lupus rheumatoid arthritis
  • lung inflammation due to breathing in a foreign substance such as dust, fungus or mould (hyp
  • ILD may in addition and/or in the alternative be understood by those skilled in the art to include any pulmonary condition characterized by an abnormal healing response, including chronic inflammation, reduced lung function and/or scarring, irrespective of the cause, such as sarcoidosis, and PF, especially IPF.
  • the term may also include diseases and/or conditions that are known to lead to, and/or be causes of, such pulmonary conditions, such as systemic sclerosis.
  • a formulation of the invention for use in a condition that leads to and/or is a cause of an ILD, such as PF or IPF, including systemic sclerosis.
  • Formulations of the invention may also be useful not only in treating underlying conditions, such as ILDs, but also treating, preventing and/or alleviating specific symptoms of those diseases, including wheezing, tiredness, weight loss/cachexia, chest pain and especially cough and shortness of breath.
  • treatment of an ILD includes treatment of the symptoms of an ILD, such as IPF cough.
  • a method of treatment of an ILD comprises the injection of a pharmacologically-effective amount of thalidomide in the form of a formulation of the invention to a patient in need of such treatment.
  • formulations of the invention may also be useful in the treatment or prevention of any fibrotic condition of one or more internal organs characterised by the excessive accumulation of fibrous connective tissue, and/or in the treatment or prevention of fibrogenesis and the morbidity and mortality that may be associated therewith.
  • fibrosis may be associated with an acute inflammatory condition, such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multiple- organ inflammation, injury and/or failure, which may be caused by internal or external trauma (e.g. injury), or by an infection.
  • ARDS acute respiratory distress syndrome
  • SARS severe acute respiratory syndrome
  • multiple- organ inflammation, injury and/or failure which may be caused by internal or external trauma (e.g. injury), or by an infection.
  • Such conditions may thus result from sepsis or septic shock caused by a viral, bacterial or fungal infection.
  • acute lung injury ARDS and, particularly, SARS may be caused by viruses, such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2), which may result in internal tissue damage and/or dysfunction of relevant internal (e.g. mucosal) tissues, such as the respiratory epithelium.
  • SARS-CoV-2 novel SARS coronavirus 2
  • tissue damage may in turn give rise to severe fibrosis.
  • SARS disease 2019 or COVID-19 coronavirus disease 2019 or COVID-19
  • a formulation of the invention for use in the treatment of a ‘precursor’ condition that may lead to fibrosis, and/or in the treatment of a fibrotic condition, such as an ILD (e.g. PF or IPF), that is caused by such a precursor condition.
  • a fibrotic condition such as an ILD (e.g. PF or IPF)
  • ILD e.g. PF or IPF
  • precursor conditions may include systemic sclerosis, acute injury or a relevant (e.g. viral) infection, including those mentioned above (such as SARS-CoV-2).
  • ‘Patients’ include mammalian (particularly human) patients. Human patients include both adult patients as well as paedeatric patients, the latter including patients up to about 24 months of age, patients between about 2 to about 12 years of age, and patients between about 12 to about 16 years of age.
  • Thalidomide and pharmaceutically-acceptable salts thereof may be administered in the form of racemates, single enantiomers and/or pharmaceutically-acceptable salts.
  • Pharmaceutically-acceptable salts of thalidomide include base addition salts and, preferably, acid addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or, preferably, free base form of an active ingredient with one or more equivalents of an appropriate acid or base as appropriate, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g.
  • Salts may also be prepared by exchanging a counter-ion of an active ingredient in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • thalidomide is employed in formulations of the invention in its free form (i.e. not in the form of a pharmaceutically-acceptable salt).
  • Administration of formulations of the invention may be continuous (e.g. by infusion), but is preferably intermittent (e.g. by single and/or multiple injections, which may be at regular intervals). The mode of administration may be dependent on the severity of that condition, or otherwise on the need for treatment.
  • a controlled and sustained release of thalidomide into plasma takes place.
  • the formulations of the invention may thus allow for the steady state release of thalidomide into plasma over a period of at least about 3 days and up to about a month (e.g. up to about 30 days) after administration.
  • a formulation of the invention provides for such a release over a period of at least about 5 days, such as at least about 7 days, including at least about 10 (e.g. at least about 14 days, at least about 21 days or at least about 28 days), following administration by injection.
  • regular intermittent doses of formulations of the invention are at about 2 or, more preferably, about 3 or about 4 week intervals. It may also be preferable, at least at the outset, to give doses every few days (e.g. about once a week) to reach a steady state concentration of active ingredient in plasma.
  • thalidomide or salt thereof that are included in formulations of the invention may be determined by the skilled person, and, depending on the disorder to be treated, should preferably be sufficient to give a concentration in plasma that is at least about 10 ng/mL, such as at least about 20 ng/mL, for example at least about 50 ng/mL, including at least about 100 ng/mL and at least about 200 ng/mL, such as at least about 300 mg, including at least about 400 ng/mL, at least about 500 ng/mL, and at least about 600 ng/mL, including at least about 750 mg/mL.
  • suitable doses of thalidomide or salt thereof in formulations of the invention in adult patients (average weight e.g.
  • about 70 kg may be sufficient, depending on the disorder to be treated, to provide between about 1 mg, such as about 2 mg, including about 5 mg, such as about 10 mg, including about 25 mg, of thalidomide (calculated as the free base) per day of treatment, up to about 1 g, including up to about 800 mg, such as up to about 600 mg or about 500 mg, including up to about 400 mg, up to about 300 mg and up to about 250 mg, more preferably up to about 200 mg, including about 100 mg, such as about 75 mg, or about 50 mg, of thalidomide (calculated as the free base) per day of treatment.
  • 1 mg such as about 2 mg, including about 5 mg, such as about 10 mg, including about 25 mg, of thalidomide (calculated as the free base) per day of treatment
  • up to about 1 g including up to about 800 mg, such as up to about 600 mg or about 500 mg, including up to about 400 mg, up to about 300 mg and up to about 250 mg, more preferably up to about 200 mg,
  • thalidomide and salts thereof in the treatment of IPF should preferably not exceed about 150 mg/day, and preferably not be more than about 100 mg per day of treatment.
  • suitable injected doses of thalidomide are those that will release about 100 mg of thalidomide per day following injection until thalidomide concentrations in plasma fall below clinically effective concentrations or until the next dose is injected.
  • the daily dose of thalidomide or salt thereof should preferably not exceed about 400 mg (e.g. up to about 300 mg or up to about 200 mg), and for certain other disorders, such as erythema nodosum leprosum, the daily dose should preferably not exceed about 800 mg (e.g. up to about 500 mg or to about 400 mg).
  • the daily dose should preferably not exceed about 800 mg (e.g. up to about 500 mg or to about 400 mg).
  • this would mean injecting no more than about 2 g, or 4 g, respectively at the outset.
  • it may not be possible or desirable to administer certain amounts e.g.
  • thalidomide may be cleared for a relevant period of time (e.g. one to two weeks or so) between separate doses. This is because the effect on symptoms such as cough appears to continue even after plasma levels of thalidomide have reduced to levels that are well below those mentioned above.
  • dosing regimens may be tailored depending on the stage of treatment of any particular disorder with thalidomide.
  • formulations of the invention may be used to administer thalidomide or salt thereof at an appropriate dose as part of an induction phase (i.e.
  • the induction dose that is administered will depend on the condition to be treated and may, for example, be one or more of the higher dosing levels mentioned above.
  • formulations of the invention may be used to administer thalidomide or salt thereof at an appropriate dose (for example at lower level than in the induction phase), as part of a maintenance treatment of that disorder.
  • the medical practitioner, or other skilled person will be able to determine routinely the actual dosage, which will be most suitable for an individual patient, depending on the severity of the condition, as well as the mode and/or the frequency of administration of injections.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect an appropriate response (e.g. a reduction in symptoms such as, in the case of IPF, cough) in the mammal (e.g. human) over a reasonable timeframe (as described hereinbefore).
  • an appropriate response e.g. a reduction in symptoms such as, in the case of IPF, cough
  • the selection of the exact dose and formulation/composition and/or the most appropriate delivery regimen will thus be influenced by inter alia the pharmacological properties of the formulation, the nature, stage and severity of the condition being treated, in addition to the physical condition, mental acuity, age, condition, body weight, sex and response of the patient to be treated, as well as genetic differences between patients.
  • Formulations of the invention may be co-administered with other pharmaceutical formulations comprising different (or the same) active ingredients that are intended for the treatment of one of more of the conditions mentioned hereinbefore, such as ILDs (whether administered by parenterally, perorally, or otherwise).
  • ILDs whether administered by parenterally, perorally, or otherwise.
  • uses and methods that involve administration of formulations of the invention may be combined with one or more treatments comprising other active ingredients that are useful in the treatment of one or more such condition (or a peroral treatment comprising thalidomide).
  • IPF anti-fibrotics
  • IMIDs such as pomalidomide or lenalidomide
  • corticosteroids such as cortisone, dexamethasone and prednisone
  • inflammation suppressants such as cyclophosphamide
  • other immunosuppressants such as azathioprine and mycophenolate mofetil
  • antioxidants such as N-acetylcysteine
  • AT2 receptor agonists such as C21 (N- butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2- sulfonamide)
  • TNF inhibitors such as etanercept
  • painkillers such as ibuprofen and paracetamol
  • cough suppressants and/or expectorants such as ibuprofen and paracetamol
  • sarcoidosis include, for example, corticosteroids, such as dexamethasone, cortisone, prednisone and prednisolone; antimetabolites; immune system suppressants, such as methotrexate, azathioprine, leflunomide, mycophenoic acid/mycophenolate mofetil, cyclophosphamide; other IMIDs, such as pomalidomide or lenalidomide; aminoquinolines; monoclonal anti-tumor necrosis factor antibodies, such as infliximab and adalimumab; AT2 receptor agonists, such as C21 (N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5- iso-butylthioph-ene-2-sulfonamide); TNF inhibitors such as etanercept; and painkillers, such as ibupro
  • corticosteroids such as dexamethasone, cor
  • IMIDs such as lenalidomide and pomalidomide
  • corticosteroids such as dexamethasone
  • proteasome inhibitors such as bortezomib, ixazomib and carfilzomib
  • monoclonal antibodies such as include isatuximab, elotuzumab, daratumumab
  • cyctotoxic drugs such as etopside, cisplatin, cyclophosphamide, vincristine, doxorubicin, melphalan or melflufen (melphalan flufenamide), panobinostat and/or selinexor.
  • Formulations of the invention may also be combined in such treatment with cell (e.g. T-cell) therapies, gene therapies, autologous stem cell transplantation and/or radiation therapy.
  • Formulations of the invention may also be used for maintenance therapy following stem cell transplantation, and/or after induction therapy in patients who do not receive stem cell transplantation.
  • DMARDs disease-modifying antirheumatic drugs
  • DMARDs disease-modifying antirheumatic drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Relevant patients may thus also (and/or may be already) be receiving such therapy for the treatment of their condition based upon administration of one or more of such active ingredients, by which we mean receiving a prescribed dose of one or more of those active ingredients mentioned above, prior to, in addition to, and/or following, treatment with thalidomide.
  • Pharmaceutically-acceptable salts, and doses, of other active ingredients useful in the treatment of relevant conditions include those that are known in the art and described for the drugs in question to in the medical literature, such as Martindale – The Complete Drug Reference (35 th Edition) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference. Wherever the word ‘about’ is employed herein, for example in the context of absolute numbers (e.g.
  • amounts i.e. absolute amounts, such as sizes (particle sizes, dimensions), doses, solubilities, weights or concentrations of (e.g. active) ingredients in solvents including plasma, temperatures, time periods or frequencies, or relative amounts including percentages, it will be appreciated that such variables are approximate and as such may vary by ⁇ 10%, for example ⁇ 5% and preferably ⁇ 2% (e.g. ⁇ 1%) from the actual numbers specified.
  • the term ‘about’ 10% means e.g. ⁇ 10% about the number 10, i.e. between 9% and 11%.
  • formulations of the invention provide a controlled and/or sustained release of thalidomide into plasma at a steady rate.
  • formulations of the invention are capable of controlling thalidomide’s dissolution rate following administration, and provide for a more favourable pharmacokinetic profile by greatly reducing the fluctuations in plasma concentrations of active ingredient in plasma that are observed when the drug is administered perorally, and as mentioned hereinbefore.
  • formulations of the invention may provide stable plasma concentrations that are within the relevant therapeutic window for a condition for a prolonged period, which can retain or even improve efficacy at the same time as reducing levels of the adverse effects of thalidomide mentioned hereinbefore.
  • This reduction in side effects may give rise to a broader range of possible therapeutic applications, enabling an effective drug to be administered to patients for use in conditions for which thalidomide is not presently approved, due to those side effects.
  • allowing thalidomide to be cleared for relevant period of time as described hereinbefore may further reduce the risk of side effects.
  • formulations of the invention enable the provision of a dosage form that is administered much less frequently and in a controlled, clinical environment, which provides the additional advantages of improved compliance and also lower quantities of a drug (that also acts as a sedative) in general circulation.
  • the uses/methods described herein may otherwise have the advantage that, in the treatment of the relevant conditions mentioned herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, similar methods (treatments) known in the prior art, whether for the treatment of those conditions or otherwise.
  • Figure 4 shows time-course of thalidomide plasma concentrations in rats after subcutaneous injections of suspensions of thalidomide in a phosphate buffered aqueous vehicle and in different oil vehicles
  • Example 1 Comparison of Pharmacokinetics of Aqueous and Oil suspensions of Thalidomide, Lenalidomide and/or Pomalidomide after Oral and Subcutaneous Administration in vivo Approximately 10 week old male RccHan:WIST rats (Envigo, Venray, Netherlands) weighing approximately 315-330 g at the start of the study (Day 1) were used. The animals were housed 3-6 per cage and were acclimatized for at least 14 days before the start of dosing. Nesting material, chew sticks and tunnels were provided to the animals. During the acclimatization, the animals were handled and trained in procedures that they were later exposed to. Each animal was uniquely identified within the study by an animal reference number and tail pen marking.
  • the IMIDs thalidomide (Combi-Blocks, Inc., San Diego, CA, USA), pomalidomide (Ambeed, Inc., Arlington Hts, IL, USA) and lenalidomide (Ambeed, Inc., Arlington Hts, IL, USA) were micronized using a Fritsch premium line Pulverisette mill (FRITSCH GmbH, Idar-Oberstein, Germany) with a 20 mL zirconium oxide grinding bowl and 32 g of 5 mm zirconium oxide grinding balls.
  • Fritsch premium line Pulverisette mill FRITSCH GmbH, Idar-Oberstein, Germany
  • each IMID was milled with 1.5 g of 0.5% Tween 80 as milling medium for 4 x 15 min at 150 rpm with 5 minute pauses (lenalidomide and pomalidomide) or 6 x 15 min at 150 rpm with 5 minute pauses (thalidomide).
  • the IMIDs were then washed with water using suction filtration and dried overnight at 50°C in a vacuum oven. After milling, the particle sizes were analyzed using a Shimadzu SALD-7500nano particle size analyzer (Shimadzu Corporation, Kyoto, Japan).
  • each milled IMID suspension was dispersed using a Sonoplus HD3200 ultrasonic homogeniser equipped with a MS73 probe (Bandelin Electronic GmbH & Co. KG, Berlin, Germany) and 2 mL 0.5% Tween 80 as dispersion medium (30 s, 0.2 s to 0.1s pulse, 10% amplitude).
  • the particle sizes were measured in the 0.2-800 ⁇ m range with water as measurement medium (signal averaging count of one measurement: 256; signal accumulation count: 10; interval: 3s; stirrer speed: fast; refractive index for thalidomide and lenalidomide: 1.65_0.00i; refractive index for pomalidomide: 1.70_0.00i).
  • micronized IMIDs were suspended in: (a) a 100 mM phosphate buffer at pH 7.4 (made by mixing 8.02 mL of 1 M K2HPO4 (Sigma-Aldrich) and 1.98 mL of 1M KH2PO4 (Sigma-Aldrich) stock solutions in Milli-Q H2O and adding Milli-Q H2O to approximately to 90 mL, followed by stirring and adjustment of pH to 7.4 with KH 2 PO 4 , filling up to 100 mL with Milli-Q H2O and filtering 50 mL in a 0.2 ⁇ m filter (Sarstedt AG & Co.
  • Miglyol 812 N (IOI Oleochemical, Hamburg, Germany), a medium-chain triglyceride oil on FDA’s inactive ingredient list for subcutaneous administration.
  • concentrations of thalidomide, pomalidomide and lenalidomide in the dosing formulations were 10 mg/mL phosphate buffer (for peroral administration by gavage), and 50 mg/mL phosphate buffer or Miglyol (for subcutaneous administration by injection).
  • the suspensions were vortexed for 3 minutes followed by sonication for 3 minutes.
  • the IMIDs were then kept in suspension by magnetic stirring until administration to the animals. The animals were dosed once with 50 mg/kg of each IMID.
  • the day of dosing was designated Day 1.
  • Body weights were recorded before dosing on Day 1, and once a week during the study.
  • animals were bled from a peripheral vein after warming, or from the orbital plexus at termination.
  • HAD Day 20, last measurement after s.c. administration
  • Acceptable sampling time deviations were: 30 MAD +/- 2 minutes, 2-8 HAD +/- 5 minutes, 24-48 HAD +/- 30 minutes, 72-288 HAD +/- 120 minutes.
  • Blood samples were placed on water ice immediately after collection. Blood samples were then centrifuged (approximately 2000xG, 5 minutes, 4°C) and at least 30
  • ⁇ L of plasma was transferred into a separate polypropylene tube, immediately frozen upright at approximately -20°C within 30 minutes of collection. All plasma samples were labelled with study number, sample number, animal number, and time point. At the end of the experiments, animals were killed by exsanguination from a common carotid artery under isoflurane and oxygen anesthesia. The skin at and around the injection site was fixed in buffered 4% formaldehyde, processed, sectioned (4-6 ⁇ m), stained with haematoxylin-eosin and examined by light microscopy. Histological changes in the skin samples from the injection site were described by a pathologist, wherever possible, according to distribution, severity and morphologic character.
  • Severity scores used were graded 1-5 (minimal, slight, moderate, marked and severe, respectively) or P (present). The microscopic evaluation was partially blinded as the group number was known to the pathologist, but not the treatment for each group.
  • the amounts of thalidomide, lenalidomide and pomalidomide were measured in rat plasma samples using positive electrospray ionization on triple-quadruple mass spectrometer and operating multiple reaction monitoring (MRM) mode.
  • MRM multiple reaction monitoring
  • stock solutions of thalidomide, lenalidomide and pomalidomide were prepared at the concentration of 1.00 mg/mL in DMSO, which were used for the preparation of the calibration samples in rat plasma.
  • the supernatant was analysed. Two sets of calibration samples were prepared. 30 Blank samples were prepared by pipetting 20 NjL of blank rat plasma and 50 NjL of acetonitrile with 0.1% FA in a 384 well plate. Blank samples with IS were prepared by pipetting 20 NjL of rat plasma and 50 NjL of acetonitrile with 0.1% FA and IS in a 384 well plate. After mixing, the samples were centrifuged for 10 minutes (4000 RPM) at room temperature. The supernatant was analysed. Two sets of blank samples were prepared. Plasma study samples were prepared by pipetting 20 NjL of sample and 50 NjL of acetonitrile with 0.1% FA and IS into a 384 well plate.
  • the instrumental conditions used were as follows: The mass spectrometer instrument used was a Xevo TQ-S Micro (Waters) in ES+ mode, using multiple reaction monitoring (MRM) of the transitions m/z 259.0 to 84.0 (thalidomide); m/z 263.0 to 84.0 (thalidomide-d4, IS); m/z 273.9 to 200.9 (pomalidomide); m/z 260.0 to 149.0 (lenalidomide). During the analysis a capillary voltage of 5.0 kV was applied, and cone voltages of 40 V for thalidomide, lenalidomide and thalidomide-d4,35 V for pomalidomide were used.
  • the source temperature was set to 150°C and the desolvation temperature to 350°C.
  • a desolvation Gas Flow of 650 L/hr and a collision gas pressure of 2.6 x 10-3 mbar was used in combination with a collision energy of 10 V for thalidomide and thalidomide-d4, 20 V for pomalidomide and 17 V for lenalidomide using a 0.015 s dwell time.
  • the LC- instrumentation consisted of a Binary Solvent manager and Sample Manager(Waters).
  • the analytical runs were accepted based on the results of the back-calculated calibration samples. Outliers were excluded from calculations. Calibration samples with a deviation from the nominal concentration larger than 20 % were considered outliers and excluded from the calibration curve. A calibration curve had to consist of 12 accepted calibration samples to be accepted for quantification. Study sample concentrations were calculated using the ratio of the analyte peak area and the IS peak area for each sample against the established calibration curve. Integrations, calibrations and calculations were performed using MassLynx as well as Office 365. The IMID plasma concentration data were analysed by non-compartmental methodology/analysis, using Phoenix® WinNonlin TM 6.4, build 8.2.0.4383, from Certara (Princeton, NJ, USA).
  • the maximal concentration (C max ) was a direct observation from the concentration versus time data.
  • the area under the concentration versus time curve from time 0 to the time point at the last measurable concentration was calculated using linear trapezoidal linear interpolation.
  • the pharmacokinetic parameters and equations used for calculations are given in Table 3 below.
  • Table 3 As shown in Figure 1, the time courses of thalidomide plasma concentrations after subcutaneous administration compared to peroral administration (50 mg/kg of thalidomide in the phosphate buffered aqueous suspension) were strikingly different.
  • the C max after peroral administration was more than 8 times higher than after subcutaneous administration, and while the thalidomide concentration fell off relatively quickly after peroral administration, subcutaneous administration led to a relatively stable plasma concentration for approximately two weeks.
  • AUClast The total thalidomide exposure (AUClast), on the other hand, was very similar in the two groups (see Table 4 below).
  • the time-course of the thalidomide plasma concentration after subcutaneous administration (50 mg/kg of thalidomide in the phosphate buffered aqueous suspension) was surprisingly different from those of the other two, chemically very similar IMIDs, pomalidomide and lenalidomide given subcutaneously at the same dose and in the same aqueous vehicle.
  • lenalidomide subcutaneously administered led to a high peak and short duration of active ingredient in plasma.
  • pomalidomide subcutaneously administered led to a very long duration of active ingredient in plasma with significant drug levels even at the last sampling timepoint almost 3 weeks after drug administration.
  • the plasma concentration curve after subcutaneous pomalidomide administration was unstable with the plasma concentration between 144 to 288 hours being more than twice as high compared to the plasma concentration between 24 to 48 hours.
  • thalidomide was administered subcutaneously in the oil suspension, it was found that, compared to subcutaneous administration in the aqueous vehicle, the plasma concentration declined much faster.
  • the total exposure (AUClast) was only 37% of that of thalidomide in the aqueous vehicle.
  • mice and subcutis Microscopic changes (histological findings) at the subcutaneous injection sites (skin and subcutis) are described in Table 5 below.
  • Table 5 e r g Inflammatory cells: mainly lymphocytes, scattered macrophages and neutrophilic granulocytes
  • x slight granuloma formation was observed in one of three animals receiving the thalidomide aqueous suspension
  • x moderate to marked granuloma formation and haemorrhage was observed in all three animals receiving the pomalidomide aqueous suspension
  • x some perivascular to multifocal inflammatory cell infiltration was observed in: o two of three animals receiving the lenalidomide aqueous suspension, o one animal receiving pomalidomide aqueous suspension, o none of the animals receiving thalidomide aqueous suspension
  • subcutaneous injection of thalidomide in oil caused formation of empty capsules lined by fibrotic tissue in all three animals, slight inflammatory cell infiltration in one of
  • Example 2 Comparison of Pharmacokinetics of Aqueous and Oil Suspensions of Thalidomide after Subcutaneous Administration in vivo Thalidomide (Chemtronica AB, Sweden) was micronized using a Fritsch premium line Pulverisette mill (FRITSCH GmbH, Idar-Oberstein, Germany) with two 80 mL zirconium oxide grinding bowls and 100 g of 3 mm zirconium oxide grinding balls in each.
  • thalidomide was milled with approximately 21 g of 0.5% Tween 80 water solution as a milling medium in each bowl for 2 x 10 min at 300 rpm with a 5 minute pause. Everything was repeated once with equal amounts of thalidomide and the milling medium. The four suspensions were then filtered using vacuum filtration and the solid was then washed several times with small portions of water. Finally the solid was vacuum dried at 50°C to constant weight (approximately 5 hours). The micronization resulted in the following particle sizes: Dv10 – 2.1 ⁇ m; Dv50 – 3.4 ⁇ m; Dv90 – 8.8 ⁇ m.
  • Example 3 Comparison of Pharmacokinetics of Aqueous Suspensions of Thalidomide after Subcutaneous and Intramuscular Administration in vivo Essentially the same procedures as those described in Examples 1 and 2 were followed to inject micronized thalidomide in aqueous media via two different administration routes intramuscular (i.m.) injection and s.c. injection. Prior to injection, the thalidomide was suspended in the following media: phosphate buffer (PB), PB with 0.25% carboxymethylcellulose sodium (Na- CMC; Sigma-Aldrich) or PB with 0.1% Tween 80 (Sigma-Aldrich), at concentrations of 50 mg/mL (for subcutaneous injection) and 250 mg/mL (for intramuscular injection).
  • PB phosphate buffer
  • Na- CMC carboxymethylcellulose sodium
  • Sigma-Aldrich Sigma-Aldrich
  • Tween 80 Sigma-Aldrich

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Abstract

L'invention concerne une formulation pharmaceutique sous la forme d'une suspension injectable de particules constituée essentiellement de thalidomide ou un sel pharmaceutiquement acceptable correspondant en suspension dans un excipient pharmaceutiquement acceptable et injectable pour une utilisation dans le traitement d'une pathologie médicale par injection. Des excipients aqueux sont préférés. Les formulations forment un dépôt après injection et sont utiles dans le traitement de pneumopathies interstitielles. Les pneumopathies interstitielles qui peuvent être mentionnées comprennent la fibrose pulmonaire idiopathique et la sarcoïdose.
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