WO2020240018A1 - Dispositif & régime d'administration - Google Patents

Dispositif & régime d'administration Download PDF

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Publication number
WO2020240018A1
WO2020240018A1 PCT/EP2020/065074 EP2020065074W WO2020240018A1 WO 2020240018 A1 WO2020240018 A1 WO 2020240018A1 EP 2020065074 W EP2020065074 W EP 2020065074W WO 2020240018 A1 WO2020240018 A1 WO 2020240018A1
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WIPO (PCT)
Prior art keywords
injection device
lipid
dose
weight
release formulation
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PCT/EP2020/065074
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English (en)
Inventor
Fredrik Tiberg
Pontus ADLER
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Camurus Ab
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Publication of WO2020240018A1 publication Critical patent/WO2020240018A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases

Definitions

  • the present disclosure relates to injection devices, particularly injection devices suitable for self-administration by a subject, as well as to methods of treatment and dosage regimes utilising such devices.
  • Active pharmaceutical agents or ingredients necessarily generate a biological effect in the subject to whom they are administered. Typically this is an, at least partially, desirable effect and is carried out to counter-act some condition such as an infection, disease, imbalance or other malady from which the subject may be suffering. In many cases such condition may be on-going for a prolonged period such as for months or years or for the remaining lifetime of the subject.
  • administration must be sufficiently simple to be carried out by subjects who are not medically trained and who may have restricted capabilities, due to the condition to be treated, due to advancing age or for any other reason.
  • a pharmaceutically active agent In order to provide its desired function, a pharmaceutically active agent must generally be present within a certain range of concentrations. If the concentration drops below this "functional window" then the agent will provide inadequate effect while if the concentration rises above the window then side effects may result. Many active agents are required for extended periods such as weeks, months or even the remaining lifetime of the subject. In such cases it is desirable to keep the
  • Stable long-term dosing of an API can be achieved in some cases by use of an extended release formulation, e.g. a "depot” formulation.
  • a formulation is designed such that it contains sufficient API for multiple "standard” doses but is administered once and releases the contained active agent over an extended period from a few days to several months.
  • effective depot systems including a highly effective lipid-based extended-release formulation (depot) disclosed in W02005/117830.
  • controlled-release formulations for administration by injection typically have a significantly higher viscosity than simple aqueous solutions. It can therefore be difficult to for untrained subjects to self-administer such formulations without assistance and yet mechanical assistance such as autoinjectors may not generate sufficient force to deliver the formulation in an acceptably short time period.
  • the present disclosure provides an injection device comprising at least one drug compartment containing a lipid controlled-release formulation comprising at least one bioactive agent, at least one expelling mechanism for expelling a dose of said lipid controlled-release formulation, at least one operable portion for operating the expelling mechanism and at least one needle through which the dose of lipid controlled-release formulation is delivered, wherein said device in use delivers a dose of less than 2 cm 3 (e.g. 0.1 to 1.8 2 cm 3 or 0.25 to 1.5 cm 3 ) volume over a period of 1 to 30 seconds (e.g. 2 to 25 or 5 to 20) seconds at 25°C and wherein said expelling mechanism delivers a force of between 5 and 40N.
  • a lipid controlled-release formulation comprising at least one bioactive agent
  • at least one expelling mechanism for expelling a dose of said lipid controlled-release formulation
  • at least one operable portion for operating the expelling mechanism and at least one needle through which the dose of lipid controlled-release formulation is delivered
  • said device in use
  • the injection device may comprise a pre-filled syringe or cartridge as the drug compartment.
  • the device may comprise an expelling mechanism which comprises a spring or other force-generating device.
  • the device may be capable of providing a force of at least 12N, such as between 12N and 35N and may comprise a 22- or 23-gauge needle such as a thin wall or extra-thin wall needle.
  • the disclosure provides a method for treatment of a disease in a human subject comprising providing to said human subject at least one injection device as described herein.
  • Such treatment will particularly be by self-administration (such as by the subject or by a care-giver).
  • the use of the injection device in delivering said active agent and a method of administration of said active agent by means of the device.
  • Figure 1 shows the gliding force for injecting formulations of varying viscosities at various rates through a 22G UTW needle.
  • Figure 2 shows the gliding force for injecting formulations of varying viscosities at various rates through a 23G TW needle.
  • lipid controlled-release formulations have viscosities many times higher than typical aqueous solutions and may be difficult to self-administer without undue discomfort, lengthy injection times, or if the subject (and/or care-giver) has any limitation on manual dexterity, vision or any other limitation.
  • the present disclosure provides a device containing an appropriate formulation which in combination allows for high-performance controlled-release and also reliable self injection without requiring significant medical training and even for those with reduced dexterity or perception.
  • the device further provides for an accurate dosing and may also provide for an appropriate and controlled injection depth and/or duration.
  • the auto-injection device of the present disclosure may contain an injectable pharmaceutical medicament within the drug compartment.
  • a medicament drug product
  • a controlled-release medicament particularly a lipid based "depot” as described herein, particularly one forming a liquid crystalline phase upon
  • controlled-release As used herein the terms controlled-release, extended-release, prolonged release and modified release are used interchangeably. The terms indicate an extended-release product, formulated in such a manner as to make the API available over an extended period of time following administration.
  • a controlled- release formulation will generally, upon administration, release at least one API over a period of no less than 3 days or 5 days, such as 5 to 90 days, preferably 7 to 60 days.
  • Once-weekly controlled-release formulations for dosing every 7 days and maintaining release of an API for at least 7 days are one embodiment.
  • Once-monthly controlled-release formulations for dosing every 28-31 days and maintaining release of an API for at least 31 days form another embodiment.
  • the injection devices of all aspects of the present disclosure include (e.g. contain) at least one API (also termed active agent, active pharmaceutical agent or bioactive agent herein) formulated in at least one controlled-release formulation.
  • API also termed active agent, active pharmaceutical agent or bioactive agent herein
  • Lipid controlled formulations also termed precursor formulations or pre-formulations herein
  • suitable formulations include those described below.
  • Suitable APIs include any of those described herein, particularly peptide or protein APIs.
  • the active agent is selected from the group consisting of an opioid, a prostacyclin or analogues thereof, and a peptide active agent.
  • Particular examples of peptide active agents are selected from the group consisting of constrained and/or cyclised peptides, GnRH analogues, and somatostatin analogues.
  • Peptide active agents are preferably formed of a small number of amino acid units (residues) joined by amide bonds.
  • Peptides of 5 to 50 amino acids are typical, such as 5 to 30 or 6 to 25 amino acids. Shorter peptides of 5 to 15 amino acids may be suitable.
  • Peptide active agents may be formulated solely from the naturally occurring L-amino acids of the genetic code but will commonly include some D-amino acids and/or some modified or synthetic amino acids.
  • modified amino acids may be present at the N- or C- terminal positions and/or in one or more positions within the sequence.
  • the backbone of peptide active agents will be primarily formed of amide bonds between residues but may additionally contain a small number (e.g. up to 1 in 10 or up to 1 in 5) of other backbone bonds. Such other bonds may include ester, ether, thioether, and/or disulphide bonds.
  • peptide active agents may be constrained and/or cyclised.
  • constraint may be by steric hindrance, by polar or non-polar interactions, by hydrogen bonding, by coordination or by covalent bonding.
  • Suitable covalent bonds for cyclic and/or constrained peptides include ester, ether, thioether and disulphide bonds.
  • constraint or cyclisation will occur between side-chains of the amino-acid moieties. This may include interactions including the side chains of synthetic and/or modified amino acids.
  • Peptide and protein based active agents include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptides, bioadhesive peptides, bradykinins and their related peptides, calcitonin peptides including calcitonin and amylin and their related peptides, vasoactive intestinal peptides (VIP) including growth hormone releasing hormone (GHRH), glucagon, and secretin, opioid peptides including proopiomelanocortin (POMC) peptides, enkephalin pentapeptides, prodynorphin peptides and related peptides, pancreatic polypeptide-related peptides like neuropeptide (NPY), peptide YY (PYY), pancreatic poly
  • immunostimulating peptides insulins and insulin-like growth factors, interleukins, luthenizing hormone releasing hormones (LHRH) and their related peptides (which are equivalent to GnRH agonists as described below), melanocortin receptor agonists and antagonists, melanocyte stimulating hormones and their related peptides, nuclear localization signal related peptides, neurotensins and their related peptides, neurotransmitter peptides, opioid peptides, oxytocins, vasopressins and their related peptides, parathyroid hormone and its fragments, protein kinases and their related peptides, somatostatins and their related peptides, substance P and its related peptides, transforming growth factors (TGF) and their related peptides, tumor necrosis factor fragments, toxins and toxoids and functional peptides such as anticancer peptides including angiostatins, antihypertension peptides
  • POMC proopiomelanocortin
  • ACTH adrenocorticotropic hormone
  • the posterior pituitary hormones including vasopressin and oxytocin
  • the growth hormone family including growth hormone (GH), human chorionic somatomammotropin (hCS), prolactin (PRL), the pancreatic polypeptide family including PP, PYY and NPY;
  • MCH melanin-concentrating hormone
  • the orexins include GLP-1 and GIP; ghrelin and obestatin; adipose tissue hormones and cytokines including leptin, adiponectin, and resistin; natriuretic hormones;
  • parathyroid hormone PTH
  • the calcitonin family with calcitonin and amylin the pancreatic hormones including insulin, glucagon and somatostatin, insulin, somatostatins and analogues (e.g. octreotide), GnRH agonists and others indicated herein.
  • All synthetic peptides designed to have similar receptor affinity spectrums as the above mentioned peptides are also very suitable for the disclosure.
  • a further considerable advantage of the depots of the present disclosure is that active agents are released gradually over long periods without the need for repeated dosing.
  • the compositions are thus highly suitable for situations where patient compliance is difficult, unreliable or where a level dosage is highly important, such as mood-altering actives, those actives with a narrow therapeutic window, and those administered to children or to people whose lifestyle is incompatible with a reliable dosing regime and for "lifestyle" actives where the inconvenience of repeated dosing might outweigh the benefit of the active.
  • Active agents which will be routinely required by a subject for extended periods, such as for months or years, are particularly suitable for delivery by depot because this reduces the burden of repeat treatment over an extended period.
  • Cationic peptides and proteins are particularly suitable for use where a portion of the pre-formulation comprises an anionic amphiphile such as a fatty acid or anionic lipid, including phosphatidic acid, phosphatidylglycerol, phosphatidylserine.
  • preferred peptides or proteins include octreotide, lanreotide, calcitonin, oxytocin, interferon-beta and -gamma, interleukins 4, 5, 7 and 8 and other peptides or proteins having an isoelectric point above pH 7, especially above pH 8.
  • the composition of the disclosure is such that a reversed micellar cubic (h) phase, or a mixed phase including h phase is formed upon exposure to aqueous fluids and a polar active agent is included in the composition.
  • a polar active agent include peptide and protein actives, oligo nucleotides, and small water soluble actives, including those listed above.
  • peptide octreotide and other somatostatin related peptides include interferons alpha and beta, glucagon-like peptide 1 and glucagon-like peptide 2 receptor agonists, leuprorelin and other GnRH agonists, abarelix and other GnRH antagonists, granisetron and ondansetron and other 5-H ⁇ 3 receptor antagonists.
  • GnRH analogues form one class of active agents which may be included in formulations of the present disclosure.
  • Gonadotropin-releasing hormone agonists are synthetic peptides modelled after the hypothalamic neurohormone GnRH that interacts with the gonadotropin-releasing hormone receptor to elicit its biologic response, the release of the pituitary hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH).
  • GnRH agonists are useful in treatment of cancers that are hormonally sensitive and where a hypogonadal state decreases the chances of a recurrence. Thus they are commonly employed in the medical management of prostate cancer and have been used in patients with breast cancer. Other indication areas include treatment of delaying puberty in individuals with precocious puberty, management of female disorders that are dependent on estrogen productions.
  • women with menorrhagia, endometriosis, adenomyosis, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.
  • GnRH-RAs Gonadotropin-releasing hormone receptor agonists
  • leuprolide or leuprorelin
  • goserelin histrelin
  • triptorelin buserelin
  • deslorelin nafarelin and related peptides
  • GnRH-RAs form a preferred group of active agents for use in the present disclosure.
  • GnRH itself is a post-translationally modified decapeptide of structure pyro-Glu-His- Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (GnRH-l).
  • GNRH-II having 5-His
  • 7-Trp 7-Trp
  • 8-Tyr substitutions and GnRHJII having 7-Trp, 8-Leu.
  • Several peptide analogues with agonistic properties are known, most of which have the10-Gly-NH 2 replaced with N-Et-Nhh.
  • Fertirelin has 10-Gly to N-Et-NFh substitution only, while analogues having additional substitutions over GnRH-l include Leuprorelin (Leuprolide), (6-D-Leu), Buserelin (6-Ser(Bu‘)), Histrelin (6-d- His(lmbzl)), Deslorelin (6-d-Trp).
  • Another common nona-peptide agonist is Goserelin which is substituted with 6-Ser(Bu‘) and has 10-Gly-NH 2 replaced by AzaGly-NFh.
  • Narafelin (6-d-Nal) and Triptorelin (6-d-Trp) both retain the 10-Gly-NH 2 group.
  • the structures of the two most common GnRH agonists (Leuprolide and Goserelin) are shown below as acetate salts.
  • Leuprolide pyro-Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro- N-Et-NH2 (acetate)
  • Goserelin pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu‘)-Leu-Arg-Pro-Azgly-NH2 (acetate)
  • GnRH antagonists are also known, again based on the GnRH-l structure. These include Abarelix (D-Ala-D-Phe-D-Ala-Ser-Tyr-D-Asp-Leu-Lys('Pr)- Pro-D-Ala), Antarelix (D-Nal-D-Phe-D-Pal-Ser-Phe-D-Hcit-Leu-Lys('Pr)-Pro-D-Ala); Cetrorelix (D-Nal-D-Phe-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala), Ganirelix (D-Nal-D- Phe-D-Pal-Ser-Tyr-D-hArg-Leu-HArg-Pro-D-Ala), Itrelix (D-Nal-D-Phe-D-Pal-Ser- NicLys-D- NicLys -Leu
  • GnRH agonist such as leuprolide
  • LH and FSH gonadotropins
  • ovarian and testicular steroidogenesis a GnRH agonist
  • DHT dihydrotestosterone
  • Leuprolide may also involve inhibition and/or induction of enzymes that control steroidogenesis.
  • Other mechanisms of action may include secretion of an LH molecule with altered biologic activity or impairment of normal pulsatile patterns of LH and FSH secretion.
  • a number of serious medical indications are related to and/or affected by the concentration of gonadal steroid hormones. These include certain neoplastic diseases, including cancers, especially of the breast and prostate, and benign prostatic hypertrophy; premature or delayed puberty in adolescents; hirsuitism; alzheimer’s disease; and certain conditions relating to the reproductive system, such as hypogonadism, anovulation, amenorrhea, oligospermia, endometriosis, leiomyomata (uterine fibroids), premenstrual syndrome, and polycystic ovarian disease. Control of this system is also important in in vitro fertilisation methods.
  • pre-formulations of the present disclosure contain one or more GnRH analogues.
  • GnRH is a peptide hormone
  • typical GnRH analogues will be peptides, especially of 12 or fewer amino acids.
  • Preferably such peptides will be structurally related to GnRH I, II and/or III, and/or one or more of the known analogues, including those listed here.
  • Peptides may contain only amino acids selected from those 20 a-amino acids indicated in the genetic code, or more preferably may contain their isomers and other natural and non-natural amino acids, (generally a, b or g amino acids) and their analogues and derivatives.
  • Preferred amino acids include those listed above as constituents of the known GnRH analogues.
  • Amino acid derivatives are especially useful at the termini of the peptides, where the terminal amino or carboxylate group may be substituted by or with any other functional group such as hydroxy, alkoxy, carboxy, ester, amide, thio, amido, amino, alkyl amino, di- or tri-alkyl amino, alkyl (by which is meant, herein throughout C1-C12 alkyl, preferably C1-C6 alkyl e.g.
  • aryl e.g phenyl, benzyl, napthyl etc
  • other functional groups preferably with at least one heteroatom and preferably having no more than 10 atoms in total, more preferably no more than 6.
  • GnRH analogues are constrained peptides of 6 to 12 alpha- amino acids, of which particular examples include those indicated above, and particularly leuprolide and goserelin, of the sequences indicated above.
  • GnRH analogues any GnRH agonist or antagonist, preferably peptides, peptide derivatives or peptide analogues. Peptide derived GnRH agonists are most preferred, such as those indicated above and especially leuprolide or goserelin.
  • the GnRH analogue will generally be formulated as 0.02 to 12% by weight of the total pre-formulation (based on the amount of free base). Typical values will be 0.1 to 10%, preferably 0.2 to 8% and more preferably 0.5 to 6%. A GnRH analogue content of around 1-5% is most preferable.
  • Doses of the GnRH analogue suitable for inclusion in the pre-formulation, and thus the volume of formulation used will depend upon the release rate (as controlled, for example by the solvent type and amount use) and release duration, as well as the desired therapeutic level, the activity of the specific agent, and the rate of clearance of the particular active chosen.
  • an amount of 0.1 to 500 mg per dose would be suitable for providing a therapeutic level for between 7 and 180 days. This will preferably be 1 to 200 mg.
  • the level will typically be around 1 to 120 mg (e.g. for a 30 to 180 day duration).
  • the amount of leuprolide will be around 0.02 to 1 mg per day between injections, for depots designed for release over 30 days to 1 year, preferably 3 to 6 months.
  • the stability of the active and linearity of the release rate will mean that the loading to duration may not be a linear relationship.
  • a depot administered every 30 days might have, for example 2 to 30 mg or a 90 day depot have 6 to 90 mg of active, such as one of the GnRH analogues indicated herein.
  • Somatostatin analogues form one class of active agents which may be included in formulations of the present disclosure.
  • Somatostatins are natural peptide hormones with a wide distribution in animals, acting as neurotransmitters in the central nervous system, and having diverse paracrine/autocrine regulatory effects on several tissues.
  • SST-14 and SST-28 Two biologically active products are known in higher species, SST-14 and SST-28, the latter being a congener of SST-14 extended at the N-terminus.
  • SST-14 is a 14 residue cyclic peptide hormone having the sequence Ala-Gly-Cys- Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys, where the two cysteine residues are connected by a disulphide bridge to generate a type II b-turn at the key binding sequence of Phe-Trp-Lys-Thr.
  • the biological half-life of natural SST-14 is very short (1-3 minutes) and so it is not, in itself, a viable therapeutic in current formulations, but an increasing number of somatostatin receptor agonists are becoming available with higher activities and/or longer clearance times in vivo.
  • Somatostatin receptor agonists such as SST-14, SST-28, octreotide, lanreotide, vapreotide, pasireotide (SOM 230) and related peptides, are used or indicated in the treatment of a variety of conditions where they are typically administered over an extended period.
  • SRAs form a group of active agents for use in the present disclosure.
  • the SRA is selected from octreotide or SST-14.
  • Octreotide for example, is the synthetic octapeptide with sequence D-Phe-Cys-Phe- D-Trp-Lys-Thr-Cys-Thr-ol (2-7 disulphide bridge) and is typically administered as an acetate salt.
  • This SST-14 derivative retains the key Phe-(D)Trp-Lys-Thr b-turn required for in vivo SST-like activity but, in contrast to the natural hormone, has a terminal half-life of around 1.7 hours.
  • Octreotide is used in treatment of conditions including carcinoid tumours and acromegaly, and is typically administered over a sustained period of weeks, or more commonly many months or years.
  • Somatostatin receptor agonists are of particular interest for the treatment of many different types of cancers since a wide variety of tumours are found to express somatostatin receptors (SSTRs).
  • SSTRs somatostatin receptors
  • SSTR1-SSTR5 The most investigated somatostatin receptor agonists, including octreotide, show high selectivity for SSTR2 and SSTR5; thus, octreotide is of particular interest for the treatment of tumours expressing these types of receptors.
  • the most common "simple" formulation of Octreotide is "Sandostatin” (RTM) from Novartis.
  • the duration of action can be up to 12 hours but s.c. dosing is generally carried out every 8 hours.
  • s.c. injection 3 times daily for periods of months or years is not an ideal dosing regime.
  • Pasireotide LAR is a long acting formulation of pasireotide which addresses some of the above issues.
  • this is a polymer microparticle based system with the inherent limitations of such a system, as are known in the art and described herein above.
  • Carcinoid tumours are intestinal tumour arising from specialised cells with paracrine functions (APUD cells).
  • the primary tumour is commonly in the appendix, where it is clinically benign.
  • Secondary, metastatic, intestinal carcinoid tumours secrete excessive amounts of vasoactive substances, including serotonin, bradykinin, histamine, prostaglandins, and polypeptide hormones.
  • the clinical result is carcinoid syndrome (a syndrome of episodic cutaneous flushing, cyanosis, abdominal cramps, and diarrhea in a patient with valvular heart disease and, less commonly, asthma and arthropathy).
  • These tumours may grow anywhere in the gastrointestinal tract (and in the lungs) with approximately 90% in the appendix.
  • Certain of the pre-formulations of the present disclosure contain salts of one or more somatostatin receptor agonists (which are preferred examples of the peptide actives, which in turn are intended by any reference to active agents herein).
  • SST-14 is a peptide hormone
  • typical somatostatin receptor agonists will be peptides, especially of 14 or fewer amino acids.
  • Preferably such peptides will be structurally constrained such as by being cyclic and/or having at least one intra-molecular cross-link. Amide, ester or particularly disulphide crosslinks are highly suitable.
  • Preferred constrained peptides will exhibit a type-2 b turn. Such a turn is present in the key region of somatostatin.
  • Peptides may contain only amino acids selected from those 20 a- amino acids indicated in the genetic code, or more preferably may contain their isomers and other natural and non-natural amino acids, (generally a, b or y, L- or D- amino acids) and their analogues and derivatives.
  • the term "somatostatin receptor agonist" as used herein may optionally also encompass SST-14 and/or SST-28, since these are viable peptide actives when formulated as salts in the very high performance slow-release formulations described herein.
  • Amino acid derivatives and amino acids not normally used for protein synthesis are especially useful at the termini of the peptides, where the terminal amino or carboxylate group may be substituted by or with any other functional group such as hydroxy, alkoxy, ester, amide, thio, amino, alkyl amino, di- or tri-alkyl amino, alkyl (by which is meant, herein throughout C1-C18 alkyl, preferably C Cs alkyl e.g.
  • aryl e.g phenyl, benzyl, napthyl etc
  • other functional groups preferably with at least one heteroatom and preferably having no more than 10 atoms in total, more preferably no more than 6.
  • somatostatin receptor agonists are constrained peptides of 6 to 10 a-amino acids, of which particular examples include octreotide, lanreotide (of sequence NH2-(D)Naph-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr-CONH2 and its cyclic derivative of sequence NH2-(D)Naph-Cys-Tyr-(D)Phe-Lys-Val-Cys-Thr-CONH2 both having a Cys-Cys intramolecular disulphide crosslink), pasireotide (aka SOM 230) and vapreotide.
  • octreotide of sequence NH2-(D)Naph-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr-CONH2 and its cyclic derivative of sequence NH2-(D)Naph-Cys-T
  • the somatostatin receptor agonist When present, the somatostatin receptor agonist will generally be formulated as 0.1 to 12% by weight of the total formulation (based on the amount of free base). Typical values will be 0.1 to 10%, 0.5 to 9%, preferably 1 to 8% and more preferably 1 to 7%. A somatostatin receptor agonist content of 2-6 % is most preferable.
  • Doses of the somatostatin receptor agonist suitable for inclusion in the formulation, and thus the volume of formulation used, will depend upon the release rate (as controlled, for example by the solvent type and amount use) and release duration, as well as the desired therapeutic level, the activity and the rate of clearance of the particular active chosen.
  • an amount of 1 to 500 mg per dose would be suitable for providing a therapeutic level for between 7 and 90 days. This will preferably be 5 to 300 mg.
  • the level will typically be around 10 to 180 mg (e.g. for a 30 to 90 day duration).
  • the amount of octreotide will be around 0.2 to 3 mg per day between injections.
  • a depot administered every 30 days would have 6 to 90 mg or a 90 day depot have 18 to 270 mg of octreotide.
  • the dosage would typically be an amount of around 0.05 to 40 mg per week of depot duration, preferably 0.1 to 20 mg per week duration (e.g. 1 to 5 mg per week) for a duration of 1 to 24 weeks, preferably 2 to 16 (e.g. 3, 4, 8, 10 or 12) weeks.
  • the pre-formulation may be formulated for dosing weekly (e.g. every 7 ⁇ 1 days).
  • a total dose of 0.05 to 250 mg of Pasireotide per dose would be suitable for providing a therapeutic level for between 7 and 168 days. This will preferably be 0.1 to 200 mg, e.g. 0.2 to 150 mg, 0.1 to 100 mg, 20 to 160 mg etc.
  • a depot administered every 30 days might have, for example 0.2 to 20 mg of Pasireotide, or a 90 day depot might have 30 to 60 mg of Pasireotide.
  • salt of a peptide active agent such as an SRA
  • this will be a biologically tolerable salt.
  • Suitable salts include the acetate, pamoate, chloride or bromide salts. The chloride salt is most preferred.
  • Prostacyclin is an endogenous member of the eicosanoid family and is involved in several processes including platelet activation, vasodilation and blood pressure regulation. Prostacyclin is also known as
  • Epoprostenol was approved for the treatment of pulmonary arterial hypertension (PAH) by the FDA in 1995. PAH is potentially fatal condition characterized by a mean pulmonary artery pressure (mPAP) of >25 mmHg, with normal pulmonary artery wedge pressure (PAWP) ( ⁇ 15 mmHg).
  • mPAP mean pulmonary artery pressure
  • PAWP normal pulmonary artery wedge pressure
  • Epoprostenol sodium for intravenous therapy is marketed as Flolan® (GlaxoSmithKline). Since 2008 a room-temperature stable formulation of epoprostenol (Veletri®, Actelion Pharmaceuticals) has also been available.
  • Remodulin® (United Therapeutics Corporation) is a formulation of treprostinil designed for IV or continuous s.c. injection. Continuous s.c. injection is achieved by means of a microinfusion pump. Although this addresses some of the issues associated with bulky pump equipment, it is still not ideal and furthermore it is recommended that patients have immediate access to a backup infusion pump.
  • Prostacyclin and synthetic analogues such as beraprost, epoprostenol, iloprost and treprostinil are suitable APIs for use in the present disclosure. Some examples are shown below:
  • a prostacyclin analogue will have one or more of the following features. Firstly, it is preferably a synthetic non-peptide. Secondly, it preferably has a molecular weight of below 500 amu, such as below 400 amu (free acid). Thirdly, it may comprise a cyclopentane unit having a 1-hydroxy substituent, a C3-12 alkyl, alkenyl or alkynyl group at the 2- position, and a 3,4-cis fused 5- or 6- membered ring. The numbering used will be readily understood with reference to the structures given herein. Fourthly, a prostacyclin analogue preferably comprises a carboxylic acid and/or an ester unit.
  • a prostacyclin analogue for use in all aspects of the disclosure may be a prostacyclin analogue of formula (I):
  • n 1 or 2;
  • X is O, CH 2 , CHF or CF 2 ;
  • R is H, R10, or is attached by a linking unit to a polyethylene glycol (PEG);
  • PEG polyethylene glycol
  • R1 is H, F or Cl -CIO substituted or unsubstituted alkyl, alkenyl or alkynyl;
  • R2’ is H, F or C1-C6 substituted or unsubstituted alkyl, alkenyl or alkynyl;
  • R2 is a saturated or unsaturated Cl-12 substituted or unsubstituted alkyl, alkenyl or alkynyl group, preferably a saturated or unsaturated Cl-10 group;
  • R5 is X(CH 2 ) a C0 2 R9, wherein X is O or CH 2 , a is 0 to 4, preferably 1 or 2, and wherein R9 is H, C1-C6 substituted or unsubstituted alkyl, alkenyl or alkynyl or a biologically acceptable cation;
  • R8 and R8’ are each independently H, F or C1-C6 alkyl, alkenyl or alkynyl, preferably H;
  • n 1 or 2;
  • All R4 and R4’ groups are each independently H, F or C1-C6 substituted or unsubstituted alkyl, alkenyl or alkynyl ;
  • R5’ is H, F or a C1-C6 substituted or unsubstituted alkyl, alkenyl or alkynyl group, preferably H;
  • R5’ and the neighbouring R4 and/or R4’ groups form a 5, 6 or 7 membered substituted or unsubstituted ring, preferably a 6-membered ring and most preferably a substituted or unsubstituted 6-membered aromatic ring; and any additional R4 and/or R4’ groups are each independently H, F or C1-C6 substituted or unsubstituted alkyl, alkenyl or alkynyl.
  • RIO is a group such a protective or prodrug moiety.
  • Suitable protective and/or prodrug moieties include esters including those defined in subsequent sections.
  • R4 and R4’ are each independently H, F or C1-C6 alkyl, preferably H;
  • R5’ is H, F or a C1-C6 alkyl group, preferably H;
  • R4 and R4’ are each independently H, F or C1-C6 alkyl, preferably H;
  • X may be O or CFh
  • R1 may be H
  • R2 may include an OH group attached to the third carbon atom of R2 from the cyclopentane unit;
  • R2’ may be H
  • R4 and R4’ all may be H or form a phenol ring with R5’;
  • R8 and R8’ may both be H
  • R2 may be an unsaturated C6-C12 group, an unsaturated C8-C10 group, especially including an OH group attached to the third carbon atom of R2 from the cyclopentane unit.
  • R2 may also be
  • R2 is:
  • R2 is:
  • R2 is: or R2 is:
  • R2 is:
  • R5’ may be H
  • X may be O or CH2
  • R5 may be CH2CH2CH2CO2R 9 , where R 9 is as defined above, especially
  • R may be H.
  • the prostacyclin analogue may be iloprost.
  • R2 may be an unsaturated C6-C12 group, an unsaturated C8-C10 group, especially including an OH group attached to the third carbon atom of R2 from the cyclopentane unit.
  • R2 may be
  • R2 is:
  • X may be O
  • R5 may be CH2CH2CH2CO2R 9 , where R 9 is as defined above, especially
  • R may be H.
  • the prostacyclin analogue may be beraprost.
  • X may be CH2;
  • R may be H or attached via a linking group to a PEG
  • R2 may be a saturated C6-C10 group, e.g. a saturated C8 group, especially including an OH group attached to the third carbon atom of R2 from the cyclopentane unit.
  • R2 may be:
  • R2 is:
  • R2 is:
  • R2 is:
  • R5 may be OCH2CO2R 9 , where R 9 is as defined above, e.g. OCH2CO2H.
  • the prostacyclin analogue may be treprostinil.
  • the controlled-release formulation component of the formulation included in the auto injection device of the present disclosure may be any vehicle capable of being injected and forming a depot in vivo which will provide extended-release of the API (active pharmaceutical agent) over a desired period.
  • Various depot systems comprising polymers, such as polylactic acid, polyglycolic acid and/or
  • polylactate/glycolate copolymers are well known in the art.
  • Preferred controlled-release formulations will, however, comprise a lipid-based delivery system, e.g. one forming at least one liquid crystalline phase upon exposure to aqueous fluid.
  • a preferred delivery vehicle for use in the devices of all aspects of the present disclosure is a lipid controlled-release formulation.
  • Suitable formulations include the precursor formulations disclosed, for example in W02005/117830.
  • the injectable lipid controlled-release formulation will be a non-liquid crystalline lipid formulation which forms at least one liquid crystalline phase upon exposure to an aqueous fluid.
  • phase transitions are known from, for example, W02005/117830 and result in the formation of a high-viscosity non-lamellar (especially liquid crystalline) self- assembled monolith when the precursor formulation absorbs water from an aqueous fluid such as a body fluid.
  • the controlled release vehicle of the controlled-release formulation comprises: i) at least one neutral diacyl lipid and/or a tocopherol;
  • the controlled release vehicle of the controlled-release formulation comprises: i) at least one diacyl lipid, such as glycerol dioleate;
  • the at least one neutral diacyl lipid component i) comprises, consists essentially of or consists of glycerol dioleate (GDO).
  • the at least one phospholipid component ii) comprises, consists essentially of or consists of phosphatidyl choline (PC, e.g. dioleyl PC).
  • PC phosphatidyl choline
  • the biocompatible organic solvent component iii) may be at least one oxygen containing organic solvent such as one or more selected from the group consisting of alcohols, such as ethanol, propylene glycol, polyethylene glycol, benzyl alcohol; benzyl benzoate; NMP; dimethylformamide , dimethylacetamide, and DMSO.
  • alcohols such as ethanol, propylene glycol, polyethylene glycol, benzyl alcohol; benzyl benzoate; NMP; dimethylformamide , dimethylacetamide, and DMSO.
  • the lipid controlled-release formulation is a lipid based formulation wherein the lipid components comprises or is essentially consisting of at least one neutral diacyl lipid component which comprises, consists essentially of or consists of glycerol dioleate (GDO); and at least one phospholipid component ii) comprises, consists essentially of or consists of phosphatidyl choline (PC, such as soy PC or dioleyl PC)
  • GDO glycerol dioleate
  • PC phosphatidyl choline
  • Components i) and ii) may be formulated in a wide range of proportions.
  • the weight ratios of components i):ii) may thus be anything from 5:95 right up to 95:5.
  • Preferred ratios would generally be from 90:10 to 20:80 and more preferably from 85:15 to 30:70.
  • a highly suitable range is i):ii) in the ratio 40:60 to 80:20, especially around 50:50, e.g. 45:55 to 60:40.
  • a ratio of 50:50 to 70:30 may also be suitable.
  • the amount of component i) in the controlled-release formulation may be, for example, 10% to 90% (e.g. 18 to 90%) by weight of the total formulation, preferably 10% to 70%, such as 12% to 40% or 12% to 30% by weight of the total formulation.
  • the absolute amount of component i) by weight is no less than the amount of component ii).
  • the amount of component ii) in the precursor formulations may be, for example, 8% to 90% (e.g. 18 to 90%) by weight of the total formulation, preferably 8% to 70%, such as 10% to 40% or 10% to 30% by weight of the total formulation.
  • the amount of total lipid components in the formulation will typically be at least 40% by weight of the total formulation (e.g. 40 to 95%, such as 50 to 90% or 50 to 80%).
  • the amount of component iii) in the controlled-release formulation will be at least sufficient to provide a mixture of injectable viscosity (see below).
  • the phase behaviour of lipid formulations may be analysed by techniques such as visual observation in combination with polarized light microscopy, nuclear magnetic resonance, x-ray or neutron diffraction, and cryo-transmission electron microscopy (cryo-TEM) to look for solutions, L2 or L3 phases, or liquid crystalline phases.
  • Viscosity may be measured directly by standard means. As described above, an appropriate practical viscosity is that which can effectively be syringed and particularly sterile filtered. This will be assessed easily as indicated herein.
  • the weight of solvent component iii) would generally be around 0.5 to 50% of the total weight of the controlled-release formulation. This proportion may be 20 to 40% and more preferably 20 to 38% or 25 to 35% by weight. A highly suitable range is around 30%, e.g. 15 to 45%, especially, 10 to 30% or 10 to 40% by weight of the controlled-release formulation.
  • Component "i)" as indicated herein may comprise a diacyl lipid component comprising a polar "head” group and also two non-polar "tail” groups.
  • the head and tail portions of the lipid will be joined by an ester moiety but this attachment may be by means of an ether, an amide, a carbon-carbon bond or other attachment.
  • Preferred polar head groups are“neutral” head groups, which are non-ionic.
  • Examples include polyols such as glycerol, diglycerol and sugar moieties (such as inositol and glucosyl based moieties); and esters of polyols, such as acetate or succinate esters.
  • Preferred polar groups are glycerol and diglycerol, especially glycerol.
  • “neutral” diacyl lipids are non-ionic lipids with two acyl groups, particularly acyl groups described herein.
  • Diacyl glycerols form exemplary neutral diacyl lipids and include dioleoyl glycerol and di palmitoleoyl glycerol.
  • Dioleoyl glycerol also known as glycerol dioleate (GDO) forms a particular example.
  • Diacyl glycerols of component i) will comprise glycerol and two acyl chains as indicated herein.
  • Component i) may comprise a diacyl lipid, e.g. diacyl glycerol.
  • a diacyl lipid e.g. diacyl glycerol.
  • Such a lipid has two non-polar "tail" groups. This is preferable to the use of mono-acyl (“lyso") lipids because these are typically less well tolerated in vivo.
  • the two non-polar groups may have the same or a differing number of carbon atoms and may each
  • CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations.
  • typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols.
  • Preferable non-polar chains are palmitic, stearic, oleic and linoleic acids, particularly oleic acid.
  • component i) comprises components with C16 to C18 alkyl groups, particularly such groups having zero, one or two unsaturations (e.g. one or two double bonds).
  • component i) may comprise at least 50% of
  • the diacyl lipid when used as all or part of component "i)", may be synthetic or may be derived from a purified and/or chemically modified natural sources such as vegetable oils. Mixtures of any number of diacyl lipids may be used as component i). Most preferably this component will include diacyl glycerol (DAG), especially glycerol dioleate (GDO). In one embodiment, component i) consists of DAGs. These may be a single DAG or a mixture of DAGs.
  • DAG diacyl glycerol
  • GDO glycerol dioleate
  • DAG comprising at least 50%, such as at least 80%, such as at least 90 %, such as at least 93 %, such as such as at least 94 %, such as at least 95 %, such as at least 96 %, such as at least 97 %, and even comprising substantially 100% GDO.
  • An alternative or additional class of compounds for use as all or part of component i) are tocopherols.
  • a tocopherol is used to indicate the non ionic lipid tocopherol, often known as vitamin E, and/or any suitable salts and/or analogues thereof.
  • Suitable analogues will be those providing the phase-behaviour, lack of toxicity, and phase change upon exposure to aqueous fluids, which characterise lipid controlled-release vehicles.
  • the most preferred of the tocopherols is tocopherol itself, having the structure below.
  • a tocopherol will contain no more than 10% of non-tocopherol-analogue compounds, preferably no more than 5% and most preferably no more than 2% by weight.
  • component i) consists essentially of tocopherols, in particular tocopherol as shown above.
  • a preferred combination of constituents for component i) is a mixture of at least one DAG (e.g. at least one C16 to C18 DAG, such as GDO) with at least one tocopherol.
  • DAG e.g. at least one C16 to C18 DAG, such as GDO
  • GDO tocopherol
  • Such mixtures include 2:98 to 98:2 by weight tocopherol:GDO, e.g.10:90 to 90:10 tocopherol:GDO and especially 20:80 to 80:20 of these compounds. Similar mixtures of tocopherol with other DAGs are also suitable.
  • Component "ii)" in preferred lipid controlled-release vehicles is at least one phospholipid.
  • this component comprises a polar head group and at least one non-polar tail group.
  • the difference between components i) and ii) lies principally in the polar group.
  • the non-polar portions may thus suitably be derived from the fatty acids or corresponding alcohols considered above for component i).
  • C16 to C18 acyl groups having zero, one or two unsaturations are highly suitable as moieties forming the non-polar group of the compounds of component ii).
  • the phospholipid will typically be the case that the phospholipid will contain two non-polar groups, although one or more constituents of this component may have one non-polar moiety. Where more than one non-polar group is present these may be the same or different.
  • Preferred phospholipid polar "head” groups include phosphatidylcholine (PC), phosphatidylethanolamine(PE), phosphatidylserine(PS) and phosphatidylinositol(PI).
  • PC and PE are preferred lipids, both individually and as a mixture.
  • component b) may comprise at least 70% PC, PE or mixtures thereof. Most preferred is phosphatidylcholine (PC).
  • component ii) thus comprises at least 50% PC, preferably at least 70% PC and most preferably at least 80% PC.
  • Component ii) may consist essentially of PC.
  • the phospholipid portion may be derived from a natural source.
  • Suitable sources of phospholipids include egg, heart (e.g. bovine), brain, liver (e.g. bovine) and plant sources including soybean. Such sources may provide one or more constituents of component ii), which may comprise any mixture of phospholipids.
  • the components i) and ii), as well as any alternative controlled release matrix are biocompatible.
  • diacyl lipids and phospholipids rather than mono-acyl (lyso) compounds.
  • tocopherol as described above. Although having only one alkyl chain, this is not a“lyso” lipid in the convention sense. The nature of tocopherol as a well tolerated essential vitamin evidently makes it highly suitable in biocompatibility.
  • Two particularly preferred combinations of components i) and ii) are GDO with PC and tocopherol with PC, especially in the region 10-30 wt% GDO/tocopherol (or mixtures), 5-25 wt% PC and 20-40% solvent (especially comprising NMP).
  • lipid-based pre-formulations of the disclosure may also contain additional amphiphilic components at relatively low levels.
  • the pre-formulation contains up to 10% (by weight of components i) and ii)) of a charged amphiphile, particularly an anionic amphiphile such as a fatty acid.
  • Preferred fatty acids for this purpose include caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the
  • fatty acids are palmitic, stearic, oleic and linoleic acids, particularly oleic acid.
  • the formulations of the disclosure comprising diacyl lipids may also contain up to 10% of an optional triacyl glycerol, such as those described herein.
  • Component "iii” of the preferred depot vehicle is a biocompatible (especially oxygen containing) organic solvent. It is desirable that this solvent be tolerable to the subject and be capable of mixing with the aqueous fluid, and/or diffusing or dissolving out of the medicament into the aqueous fluid. Solvents having at least moderate water solubility are thus preferred.
  • Typical solvents suitable for use as component iii) include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides
  • a peptide active agent, component iii) is ethanol and/or a polar solvent such as water and or propylene glycol.
  • ketones include acetone and propylene carbonate.
  • Suitable ethers include diethylether, glycofurol, diethylene glycol monoethyl ether, dimethylisobarbide, and polyethylene glycols.
  • Suitable esters include ethyl acetate, benzyl benzoate and isopropyl acetate and dimethyl sulphide is as suitable sulphide solvent.
  • Suitable amides and sulphoxides include dimethylacetamide (DMA), n- methyl pyrrolidone (NMP), 2-pyrrolidone and dimethylsulphoxide (DMSO). Less preferred solvents include dimethyl isosorbide, tetrahydrofurfuryl alcohol, diglyme and ethyl lactate.
  • NMP is a highly preferred solvent for use in combination with opioid APIs such as buprenorphine.
  • component iii) therefore comprises NMP and may comprise at least 50% or at least 70% NMP.
  • Component iii) may consist essentially of (e.g. >95%) or consist of NMP.
  • NMP and ethanol is a further preferred combination and component iii) may comprise or consist of a mixture of NMP and ethanol.
  • Component iii) as used herein may be a single solvent or a mixture of suitable solvents but will generally be of low viscosity. This is important because one of the controlling issues regarding the ease of injection will be the viscosity of the controlled-release formulation.
  • One primary role of a suitable solvent is to reduce this viscosity. This reduction will be a combination of the effect of the lower viscosity of the solvent and the effect of the molecular interactions between solvent and controlled release formulation, such as the lipid composition.
  • One observation of the present inventors is that the oxygen-containing solvents of low viscosity described herein have highly advantageous and unexpected molecular interactions with the lipid parts of the composition, thereby providing a non-linear reduction in viscosity with the addition of a small volume of solvent.
  • the lipid controlled-release formulation may comprise : a) a lipid controlled-release matrix comprising at least 50% triacyl lipids; and b) at least one oxygen containing organic solvent;
  • Triacyl lipids in this embodiment may be triacyl glycerols (triglycerides).
  • the oxygen containing solvent component b) in this embodiment will typically be as defined herein for component iii) above.
  • the active agent component may be an opioid or opioid salt, particularly buprenorphine or a salt thereof.
  • the lipid controlled-release formulation may thus additionally comprise: c) at least 2% by weight (e.g. at least 10 % or at least 16% or at least 30% or at least 31 % (e.g. 31 to 70%) or at least 45% or at least 50%) of at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base.
  • a key component in the lipid controlled-release formulation of this embodiment is component a).
  • Component a) typically forms 10% to 70% of the total lipid controlled-release formulation in this embodiment. This may be 15% to 64% or 20 to 50% by weight.
  • lipid component a at least 50% of the lipids are formed of triacyl lipids.
  • generally 50% to 100% (such as at least 80%), preferably 60 to 90% or 60% to 95%, more preferably 70 to 90% of said lipid controlled release matrix (component b)) is formed of triacyl lipids.
  • Component a) may consist essentially of triacyl lipids (e.g. be 95% or more triacyl lipids).
  • the triacyl lipids forming part or all of component a) may be any suitable triacyl lipid and will generally have a polar“head” group and three non-polar“tail” groups.
  • Suitable polar head groups will generally be any of those indicated herein for diacyl lipids including non-ionic and include polyols such as glycerol, diglycerol (and oligo/ploy glycerol such as 2 to 10 glycerols) and sugar or carbohydrate moieties (such as mono-, di-, and tri-saccharides including sorbitan, sorbitol, trehalose, inositol, glucose, maltose and sucrose moieties and derivatives thereof) and esters of polyols, such as acetate or succinate esters.
  • Preferred polar groups are glycerol and diglycerol, especially glycerol.
  • Suitable non-polar“tail” groups are those indicated herein for diacyl lipids and/or phospholipids particularly C16 to C20 fatty acyl chains, especially those with one or two unsaturations.
  • Triacyl lipids such as triacyl glycerols, may be synthetic but will typically be derived from natural sources. Many oils of natural products are high in triacyl lipids and these may be used either in their extracted form or in partially or fully purified forms. Animal or preferably vegetable oils are highly suitable sources of triacyl lipids (especially triacyl glycerols) and may include olive oil, corn oil, sunflower oil, rapeseed (canola) oil, palm oil, soybean oil, sesame oil, castor oil and mixtures thereof. Sesame oil, soybean oil, castor oil and mixtures thereof are suitable.
  • the lipid controlled-release formulation may be substantially“water free”.
  • the lipid controlled-release formulation may comprise less than 10% by weight of water, such as less than 5% or less than 2% by weight water.
  • a substantially“water free” lipid controlled-release formulation may be a benefit, and in some cases even a requirement, e.g. as properties of the active agent may benefit from a water free environment.
  • the lipid controlled-release formulations contained in the devices of all aspects and embodiments herein will be flowable, injectable fluids.
  • this non-lamellar formulation will typically be formed upon exposure to an aqueous fluid (e.g. a body fluid).
  • the lipid controlled-release formulation within the device will typically be in a non-liquid crystalline form such as a molecular solution or dilute L2 phase.
  • the lipid controlled-release formulation will typically form a liquid crystalline phase such as a normal or reversed cubic or hexagonal phase upon exposure to an aqueous environment (e.g. to body fluids).
  • the viscosity of the injectable pharmaceutical medicaments used in all embodiments of the present disclosure should be such that they can reasonably be injected using pressures and forces generated by a small injection device, e.g. an auto-injector.
  • the medicaments will be low to moderate viscosity, in the range 100 to 1000 mPas at 25°C (e.g. 200 to 900 mPas, such as 300 to 900, such as 300 to 600, such as 300-500 or 400 to 900 mPas at 25°C).
  • the device of the disclosure e.g. an autoinjector
  • the labelled dose is a dose of an active agent possessing a marketing authorization, i.e. the agent has been approved by a regulatory authority such as FDA (Food and Drug administration and EMA (European Medicine Agency).
  • FDA Food and Drug administration and EMA (European Medicine Agency).
  • the delivery time is e.g. dependent on viscosity of the lipid controlled-release formulation, which is temperature dependent.
  • the precise formulation of the lipid controlled- release formulation may be dependent on the properties of the active agent, and accordingly tuning of the injection device may be required to achieve the desired administration properties, e.g. injection time, for each labelled dose of an active agent.
  • the viscosity of the labelled dose and the force exercised by the expelling mechanism may not be constant throughout the administration of the active agent.
  • the device of the disclosure e.g. an autoinjector, is capable of delivering the labelled dose of an active agent present in a lipid controlled-release formulation in no more than 15 seconds at 25°C where said lipid controlled-release formulation has a viscosity in the range of 300-500 mPas at 25°C.
  • the device of the disclosure e.g. an autoinjector, is capable of delivering the labelled dose of an active agent present in a lipid controlled-release formulation in no more than 12 seconds at 25°C where said lipid controlled-release formulation has a viscosity in the range of 300-500 mPas at 25°C.
  • the device of the disclosure e.g. an autoinjector, is capable of delivering the labelled dose of an active agent present in a lipid controlled-release formulation in no more than 10 seconds at 25°C where said lipid controlled-release formulation has a viscosity in the range of 300-500 mPas at 25°C.
  • the injection device of the disclosure is capable of delivering said dose in no more than 20 seconds at 25°C where said lipid controlled-release formulation has a viscosity of up to 600 mPas at 25°C.
  • the devices of the present invention may be capable of and/or configured to deliver a dose of lipid controlled-release formulation in a period of around 1 to 30 seconds, such as 2 to 25 or 5 to 20 seconds. Since the dose volume may vary, the dosing rate in any aspect or embodiment may be 1 to 40 seconds per cm 3 volume delivered, such as 2 to 20 seconds per cm 3 or 3 to 15 seconds per cm 3 or 5 to 15 seconds per cm 3 , or even 3 to 10 seconds per cm 3 .
  • the injection device In order to deliver the appropriate doses as indicated herein in suitable injection times (e.g. as described in any embodiment herein), the injection device must comprise an expelling mechanism capable of delivering a force sufficient to deliver an appropriate volume through an appropriate needle in a suitable period of time. Each of these and other factors must be appropriately controlled in order to provide a functional and reliable device.
  • the injection device of the disclosure should comprise an expelling mechanism is capable of delivering a force (e.g. average force) of at least 10N, or at least 12N, such as at least 15N, such as at least 20N, such as at least 25N, at least 30N or at least 35N.
  • a force e.g. average force
  • the maximum force provided by the expelling mechanism and/or used in any aspect and embodiment of the present invention may be the greatest force which can safely be provided. This limit will readily be established by the skilled worker on the basis of the materials and configurations used in the devices disclosed herein. For example, the maximum force utilised will respect the risk of breakage of the syringe, cartridge, plunger, expelling mechanism, housing and/or the coupling between any such components. Glass components such as a glass syringe barrel or a glass cartridge may in particular limit the maximum force usable. Maximum forces may typically be less than 100N, such as less than 75N or less than 60N. Less than 50N or less than 45N may be appropriate. This may apply especially where a glass component is used.
  • the expelling mechanism in use will deliver a force (e.g. average force) of at least 5N or at least 10N, or at least 12N, such as at least 15N, such as at least 20N, such as at least 25N, at least 30N or at least 35N.
  • the device will be configured to deliver a force (e.g. average force) of at least 10N, or at least 12N, such as at least 15N, such as at least 20N, such as at least 25N, at least 30N or at least 35N following operation of the operable portion (catch, switch, trigger, release etc).
  • a range of 10N to 40N such as 15N to 30N may be appropriate.
  • the injection device may comprise a needle wherein said needle is a 20-gauge to 28-gauge needle, preferably 22, 23 or 24- gauge needle, such as 22G or 23G, e.g. 22G or 23G thin-walled, extra thin-walled, or ultra thin-walled. Specific examples are 22G ultra thin-walled and 23G thin-walled.
  • the injection device may comprise a needle wherein said needle is thin walled or extra-thin walled or ultra-thin walled.
  • the injection device may comprise a needle having a length of no more than 30mm, such as up to 25mm, such as 5 to 15 mm (e.g. 5 to 25mm or 5 to 15mm).
  • the needle is 12.7 mm (1/2 inch).
  • Such a needle length may be the“effective” needle length, which is used to indicate the length of needle protruding from the surface of the device.
  • Suitable needles may be chosen such that when the device is used, the dose is delivered to a depth of 4 to 12mm under the skin of the subject (e.g. 4 to 10 mm).
  • the injection device disclosed herein comprises at least one drug compartment.
  • the drug compartment may be formed of a pre-filled-syringes (PFS) or cartridge.
  • PFS pre-filled-syringes
  • Such pre-filled-syringes (PFS) or cartridge will contain at least one API formulated in at least one controlled-release formulation.
  • a pre-filled-syringes (PFS) or cartridge may be formed of any suitable material but will typically be a transparent or semi transparent material such as a polymer material or glass. Pre-filled glass syringes or pre-filled glass cartridges form one embodiment of the drug compartment.
  • Suitable syringes for forming the drug compartment of the device are pre-filled- syringes (PFS) including at least one API formulated in at least one controlled- release formulation.
  • PFS pre-filled- syringes
  • Such pre-filled syringes may be incorporated (permanently or replacably) into an auto-injector device.
  • Such an auto-injector device may thus provide the expelling mechanism of the device of the disclosure (e.g. by any of the means discussed herein)
  • Suitable syringes for use in the device of all aspects herein are marketed by Schott and Gerresheimer e.g. Schott syriQ sterile syringe, and Gerresheimer Gx® Glass Needle Syringes.
  • the drug compartment is a PFS as described herein.
  • a PFS is assembled in a suitable auto-injector arrangement to make up an auto-injector device.
  • a needle as discussed herein, and conforms to suitable parameters then an injection device of the present disclosure will be formed.
  • An alternative embodiment for forming the drug compartment of the present device relates to a cartridge, pre-filled with at least one API formulated in at least one controlled-release formulation.
  • a cartridge may be incorporated into a suitable auto-injector device.
  • Such an auto-injector device may thus provide the expelling mechanism of the device of the disclosure (e.g. by any of the means discussed herein)
  • Suitable cartridges for use in the device of all aspects here are marketed by Gerresheimer e.g. Gerresheimer Gx® Glass Cartridges and Schott Cartridges for Injectables.
  • the device of all aspects herein comprises at least one expelling mechanism for expelling a dose of said lipid controlled-release formulation and further comprises at least one operable portion for operating the expelling mechanism.
  • the expelling mechanism will provide a suitable force (as discussed herein) for dispensing the dose of lipid controlled-release formulation.
  • suitable expelling mechanisms include a spring or other elastic material (under tension or compression), a pressurized compartments, e.g. pressurized using a gas such as CO2, combustion of a fuel, an motor, e.g. an electric motor (e.g. battery powered), or alternative mechanisms.
  • a spring e.g. under
  • the injection device in use may deliver said dose to a depth of 4-12 mm below the surface of the skin such as 4 to 10mm or 5 to 8 mm.
  • the injection device may comprise a drug compartment, such as the part of a pre-filled syringe (PFS) or a cartridge containing the API, having a capacity of 0.25 to 5ml, preferably 0.5 to 2ml, especially around 1 ml.
  • a drug compartment such as the part of a pre-filled syringe (PFS) or a cartridge containing the API, having a capacity of 0.25 to 5ml, preferably 0.5 to 2ml, especially around 1 ml.
  • the injection device of the present disclosure may be a multiple-dose (e.g. 2- to 12- dose) injection device but will typically be a single-dose injection device.
  • the injection device may be configured to“lock” and become inoperable once delivery of a dose (or all doses) is complete such that no further dosing is possible.
  • the injection device may also be configured to become inoperable once the expelling mechanisms has been engage, even if the device is failing.
  • Such a lock will typically be mechanical, such as by a barb or catch but may also be electrical, such as by the breaking of a circuit.
  • the operable portion of the device in all aspects herein may be any suitable catch, switch, latch or trigger mechanism which is capable of triggering the expelling mechanism.
  • the injection device of the present disclosure may be a fixed-dose or a variable-dose injection device. Typically the device will be a fixed-dose injection device.
  • the volume of the dose delivered may be at least 40% (e.g. 40-95%) or at least 80% of the capacity of said drug compartment.
  • the volume of the dose will typically be around of 0.25 to 1.5 cm 3 , such as 0.25 to 1.0 cm 3 or 0.5 to 1.0 cm 3 .
  • a typical dose may be around 0.60 to 0.70 cm 3 , such as around 0.64 cm 3 .
  • the device of the disclosure may be configured such that the needle is protected from contact prior to use.
  • the injection device may be configured such that upon use a permanent change to said injection device takes place.
  • a permanent change may be a visible change (e.g. a change in colour, connection or integrity), an audible change (e.g. a change in structure or connection resulting in a rattle when shaken), a change of structure (e.g. loss or disconnection of a part or increased or decreased freedom of movement of a part) and/or a change of conductivity (e.g. electrical disconnection or change in resistance between two parts that were previously connected or change in electronic memory corresponding to a change detected electronically).
  • a visible change e.g. a change in colour, connection or integrity
  • an audible change e.g. a change in structure or connection resulting in a rattle when shaken
  • a change of structure e.g. loss or disconnection of a part or increased or decreased freedom of movement of a part
  • a change of conductivity e.g. electrical disconnection or change in resistance between two parts that were previously connected or
  • An example of a visible change may be that the injection device of the disclosure is formed with at least one frangible part wherein said permanent change is a visible change brought about by the breakage or disconnection of at least one said frangible part.
  • the injection device of the disclosure may comprise at least one microcontroller.
  • a microcontroller may have the facility to signal (for example by wired or wireless internet, by a radio telephone network or otherwise) that delivery of said dose has or has not been made.
  • signal may be used by the subject to track administration (e.g. by means of a suitably configured electronic device such as a mobile telephone or tablet) or may be used by medical professionals to monitor compliance with a set dosing schedule. The level of such compliance may be used when determining whether continuing self-administration is appropriate.
  • the injection device of the disclosure may generate an audible, visual and/or tactile signal is generated when delivery of said dose begins. Audible signals are typical.
  • the injection device of the disclosure may generate an audible, visual and/or tactile signal is generated when delivery of said dose ends.
  • Audible signals are typical.
  • the administration device may further be tamper resistant. Tamper resistance will typically be implemented by provision of a resilient outer layer such as an outer casing which cannot easily be opened. In particular such opening can be made difficult or impossible without breakage of the device.
  • a tamper resistant outer layer may be constructed of any suitable resilient material such as a polymeric material and/or a metal. Polymeric materials may be readily fabricated into structures which "snap" together irreversibly or substantially irreversibly and thus form the preferred material.
  • Tamper resistant devices include tamper-proof or tamper-evident devices. These are designed to discourage interference with the device and in particular to discourage attempts to access the lipid controlled-release formulation other than by
  • Such tamper resistance may include a device of the present disclosure comprising at least one microcontroller wherein such a microcontroller may have the facility to send and/or receive a signal (for example by wired or wireless internet, by a radio telephone network or otherwise).
  • the device of any aspect of the present disclosure may be locked such that the expelling mechanism will not operate until a signal is received by said
  • Such“unlock” signal will typically be sent around (e.g. within one day of, or within one hour of) the time that the lipid controlled-release formulation contained in the device is due to be administered. Receipt of an“unlock” signal by the device may result in the permanent unlocking of the device such that
  • administration may be made at any time after such a signal is received or may trigger the start of an“unlocked window” of time during which administration may be made (e.g. the expelling mechanism may be triggered) before the device will re-lock. After any re-lock, the device may become permanently inoperable or may be unlocked again on receipt of a further unlock signal.
  • Any“unlocked window” may be of a duration of a few hours (e.g. 1 to 6 hours) or of a longer period such as 12 or 24 hours or 1 to 7 days, such as 1 to 3 days. During an unlocked window, the operable portion with function to operate the expelling mechanism.
  • the operable portion will not function and may generate a signal, such as a visible or audible signal to indicate that the device is not within an unlocked window.
  • the device will typically include a visible signal indicating that the device is or is not unlocked (or within an unlocked window). Where the device is within an unlocked window the device may include a display indicating the remaining duration of the unlocked window. Where the device is locked, the device may include a display indicating the remaining time until the device will unlock, or unlock is expected.
  • self-administration is used to indicate administration by a subject or by a caregiver (e.g. spouse, partner, friend or family member). Typically self- administration is used to indicate administration that is not given by a medical professional in their capacity as such. Similarly, self-administration can indicate administration which does not take place at a medical care establishment.
  • the injection device of all aspects of the present disclosure is suitable for self
  • the device is suitable for operation by a patient or carer.
  • the term“about”,“around”,“substantially” or“approximately” in relation to a number or a range of numbers will generally indicate that the number or range specified is preferred but that such a number may be varied to a certain extend without materially affecting the properties of the relevant material, composition or similar product.
  • the skilled worker will typically be able to readily establish the extent by which such numbers may be varied without prejudicing the key advantages of the present disclosure.
  • such numbers or the ends of such ranges may be varied by ⁇ 10%, preferably ⁇ 5% and more preferably ⁇ 1%.
  • compositions“consisting essentially of” certain components may include up to 10%, preferably up to 5% and most preferably up to 1 % of other components in addition to those specified.
  • the term“labelled dose” indicates the dose which a device is designed and/or configured to deliver.
  • the dose will typically not be user adjustable and is termed“labelled dose” since the device will typically carry a marking (label) indicating the dose which will be delivered when the device is actuated.
  • “average force” or“glide force” or“gliding force” are used to indicate the average of the force used or required for delivery of a dose, averaging that force over the period beginning after the initial movement of the expelling mechanism (after break-loose) and ending immediately before the force rises sharply at the end of travel of the expelling mechanism (e.g. immediately before the plunger reaches the shoulder of a syringe).
  • the term“subject” will generally be a human or animal subject, particularly a human subject. Such a subject will typically be a patient such as a patient in need of treatment with the bioactive agent.
  • Auto-injectors are well known in the art in various forms.
  • Such an autoinjector may, for example, comprise: a housing; a cartridge or syringe receiver; a drive module; and a processing unit.
  • the cartridge receiver receives a cartridge or a syringe, which may comprise a stopper and a compartment containing a
  • the devices of the present disclosure may comprise an autoinjector, in which embodiment, the cartridge or syringe, when present in the housing, will form the drug compartment, and the drive module will form the expelling mechanism.
  • expelling mechanisms are springs, pressurized gas, or an electric motor.
  • a drive module typically configured to move a plunger rod between a retracted plunger rod position and an extended plunger rod position.
  • the plunger rod is configured to move the first stopper.
  • the drive module moves a plunger rod between a retracted plunger rod position and an extended plunger rod position.
  • the plunger rod in turn moves the first stopper which serves to deliver a dose of medicament.
  • a processing unit may be coupled to the drive module. Such a processing unit controls the drive module to move the plunger rod as appropriate.
  • An autoinjector may be used in a method comprising receiving a trigger event and moving the plunger rod to an injection plunger rod position following reception of the trigger event.
  • the trigger event in the present disclosure may be operation of the operable portion.
  • the trigger event may, for example, be a push of a button, a pull of a trigger, release of a catch, a turn of a releasing ring or any other
  • the trigger event may be indicative of the auto injector being pressed against the injection site. Examples
  • Typical injection devices deliver a force up to around 20-25N.
  • needle, volume, injection mechanism and injection time studies may be carried out using appropriate samples. Methods based upon ISO 11040 are appropriate (e.g. IS011040-4:2015). Needle
  • a pre-filled syringe containing 1ml of lipid controlled-release formulation (placebo or containing active agent) is placed in a material tester having a 100N load cell.
  • the plunger rod is mounted without moving the plunger stopper to avoid compromising the“break-loose force” measurement.
  • the test is run at a speed chosen to provide delivery of the correct dose in a specified period. The necessary load is measured over time until the plunger stopper comes into contact with the shoulder of the syringe barrel, at which point the test is halted.
  • Break-loose force is determined using the maximum force in the force chart in the travel range of 0 mm to £ 5 mmand the glide-force is calculated from the average force between the end of the break-loose period until just before the end of the plunger travel, alternatively the maximum force from just after the end of the break- loose period until just before the end of the plunger travel is used to calculate the glide force.
  • injection time is linearly dependent upon viscosity, needle length and fill volume; injection time is dependent upon the fourth power of the internal syringe diameter and is inversely dependent on the residual force and on the internal diameter of the needle to the fourth power.
  • Samples were prepared by weighing the appropriate amounts of EDTA or EDTA(Na) and alkylamine into glass vials, e.g. 15R vials, followed by addition of organic solvent or solvent mixture (e.g EtOH/PG (50/50 w/w)). Vials were sealed and placed on either a roller mixer by end-over-end rotation at ambient RT or magnetic stirrer.
  • organic solvent or solvent mixture e.g EtOH/PG (50/50 w/w
  • Lipid placebo formulations were prepared by weighing appropriate amounts of SPC, GDO, (and appropriate additives such as EDTA/alkylamine solution when needed) and solvent(s) into sterilized glass vials. The sealed vials were then placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution ( ⁇ 24 hours).
  • API-containing formulations were prepared by adding appropriate amounts of API powder to the lipid placebo formulations in sterilized glass vials. The vials were sealed and placed on a roller mixer at room temperature until mixed completely into clear homogeneous liquid solution (ca. 24 hours).
  • EDTA and ETA at EDTA:ETA molar ratio 1 :4 were dissolved in EtOH/PG (50/50 w/w) mixture. Then, appropriate amounts of SPC, GDO (at
  • lipid peptide (e.g. octreotide) formulations as above were divided into sterilized 2R glass vials (0.5 g of formulation per vial).
  • the head space of the vials was ambient air, i.e. , no inert atmosphere such as nitrogen was introduced in the head space.
  • Vials were sealed and placed in controlled environment storage cabinets at 25°C/60% RH and 40°C/75% RH. At predefined sampling points (up to three months of storage) two vials of each formulation and storage cabinet were withdrawn, equilibrated to room temperature for 1 hour and analyzed for peptide content (assay) using gradient HPLC with UV detection.
  • the filling procedure and storage conditions ensured forced degradation conditions as the head space was composed of air rather than inert atmosphere such as nitrogen.
  • peptide e.g. octreotide, such as octreotide chloride
  • lipid formulations were carried out by gradient HPLC with UV detection.
  • the HILIC analytical column used was a HALO Penta-HILIC 2.7 pm, 150x3.0 mm.
  • Quantification was carried out by interpolating the peptide (e.g. octreotide) peak area obtained in lipid formulation samples (prepared by dissolving the lipid formulation in a sample solvent at the required target peptide concentration) into the calibration curves generated from standard solutions containing known concentrations of the corresponding peptide.
  • a typical mobile phases used (for example with octreotide) consisted of water: 2M sodium chloride: acetonitrile: trifluoroacetic acid 384:16:400:1 (v/v) (mobile phase A) and water: methanol: acetonitrile: trifluoroacetic acid 20:30:950:1 (v/v) (mobile phase B).
  • the detection was carried out at 220 nm.
  • the sample solvent used was acetonitrile: methanol (1 :1 , v/v); octreotide eluted after approximately 25.2 min.
  • Lipid formulations containing 2.34 wt% of OCT(CI) in the presence and absence of 100 ppm of EDTA were prepared according to the compositions given in Table 2 and the general methods described above. Further details can be found in WO
  • Lipid formulations containing 2.27 wt% of OCT(CI) and different concentrations of EDTA were prepared according to the compositions given in Table 3 using the methods decribed herein. Further details can be found in WO 2018/060213 Example 8.
  • Lipid formulations containing OCT(CI) in the absence and presence of 100 ppm EDTA were prepared according to the compositions given in Table 4 and the general methods described above. Further details can be found in WO 2018/060213
  • the octreotide content corresponds to 20 mg/mL octreotide free base when corrected for peptide content, purity and formulation density.
  • Example 9 and Figure 3 presents the octreotide assay at different storage time points. As shown, the presence of 0.01 wt% (100 ppm) of EDTA solubilized in the lipid formulation with the help of ETA significantly enhanced the long-term peptide stability in pre-filled syringes at the long-term 25°C/60% RH storage condition.
  • Lipid formulations containing SOM(CI) in the absence and presence of 100 ppm EDTA using EtOH/PG were prepared according to the compositions given in Table 5 and the general methods described above. Further details can be found in WO 2018/060213 Example 13.
  • Example 13 and Figure 9 presents the SOM assay at different storage time points and storage conditions. As shown, independently of solvent mixture used to prepare the lipid formulations, the presence of 100 ppm of EDTA solubilized in the lipid formulation by the use of ETA dramatically enhanced the peptide stability at both 40°C/75% RH and 25°C/60% RH storage conditions.
  • TPN(Na) The solubility was assessed by adding TPN(Na) to respective lipid stock mixtures followed by mixing on a roller mixer at room temperature (RT) until mixed completely into clear homogeneous liquid solution. During preparation samples were visually inspected. Results showed that TPN(Na) has good solubility in a variety of pre formulations and that a drug load of at least 7 wt% ( ⁇ 78 mg TPN(0)/ml_) is feasible. As shown in Table 6, measured viscosities of the formulations range between 185- 628 mPas depending on co-solvent type, concentration and composition.
  • Example 6 Ready-to-administer lipid formulations of buprenorphine
  • formulations indicated in Table 7 below comprising buprenorphine, lipids and solvent were generated by adding the respective component in the required proportions to sterile injection glass vials followed by capping with sterile rubber stoppers and aluminium crimp caps.
  • Mixing of the formulations (sample sizes 5-10 g) was performed by placing the vials on a roller mixer at ambient room temperature until liquid and homogenous formulations were obtained.
  • the formulations were finally sterile filtered through 0.22 mhi PVDF membrane filters using ca 2.5 bar nitrogen pressure.
  • the lipids used were Lipoid S100 (SPC) from Lipoid, Germany, and Rylo DG19 Pharma (GDO) from Danisco, Denmark.
  • the formulations are filled into glass syringes, which are incorporated into auto injector devices.
  • Example 7 Compositions comprising buprenorphine base, triglycerides and solvents
  • compositions according to Table 8 are prepared by weighing the required amounts of buprenorphine base, triglyceride and solvent in 4 ml_ injection glass vials.
  • the vials are closed with Flurotec®-coated rubber stoppers and aluminum crimp caps followed by end-over-end rotation mixing at ambient room temperature.
  • NMP N-methyl pyrrolidone
  • MCT Medium Chain Triglycerides (e.g. Labrafac Lipophile WL 1349, Gattefosse, France)

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Abstract

L'invention concerne des dispositifs d'injection appropriés pour des formulations à libération contrôlée à base de lipides, en particulier des dispositifs d'injection automatique appropriés pour une auto-administration par un sujet, ainsi que des procédés de traitement et des régimes posologiques faisant appel à de tels dispositifs
PCT/EP2020/065074 2019-05-29 2020-05-29 Dispositif & régime d'administration WO2020240018A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2022235186A1 (fr) * 2021-05-04 2022-11-10 Camurus Ab Compositions et méthodes de traitement de tumeurs neuroendocrines

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WO2005117830A1 (fr) 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique
US20060161111A1 (en) * 2002-08-05 2006-07-20 Potter David S Drug delivery system
WO2012160212A1 (fr) * 2011-05-25 2012-11-29 Camurus Ab Formulation de peptides à libération contrôlée
JP2015522649A (ja) * 2012-07-26 2015-08-06 カムルス エービー オピオイド製剤
WO2018050864A1 (fr) 2016-09-15 2018-03-22 Camurus Ab Formulations d'analogues de prostacycline
WO2018060213A1 (fr) 2016-09-27 2018-04-05 Camurus Ab Formulations contenant un agoniste du récepteur de la somatostatine

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Publication number Priority date Publication date Assignee Title
US20060161111A1 (en) * 2002-08-05 2006-07-20 Potter David S Drug delivery system
WO2005117830A1 (fr) 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique
WO2012160212A1 (fr) * 2011-05-25 2012-11-29 Camurus Ab Formulation de peptides à libération contrôlée
JP2015522649A (ja) * 2012-07-26 2015-08-06 カムルス エービー オピオイド製剤
WO2018050864A1 (fr) 2016-09-15 2018-03-22 Camurus Ab Formulations d'analogues de prostacycline
WO2018060213A1 (fr) 2016-09-27 2018-04-05 Camurus Ab Formulations contenant un agoniste du récepteur de la somatostatine

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Publication number Priority date Publication date Assignee Title
WO2022235186A1 (fr) * 2021-05-04 2022-11-10 Camurus Ab Compositions et méthodes de traitement de tumeurs neuroendocrines

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