WO2016044902A1 - Composition pharmaceutique de 15-desoxy-delta-12,14-prostaglandine j2 dans un systeme micellaire a base de poloxamere et son utilisation dans le traitement d'etats inflammatoires - Google Patents

Composition pharmaceutique de 15-desoxy-delta-12,14-prostaglandine j2 dans un systeme micellaire a base de poloxamere et son utilisation dans le traitement d'etats inflammatoires Download PDF

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WO2016044902A1
WO2016044902A1 PCT/BR2014/000349 BR2014000349W WO2016044902A1 WO 2016044902 A1 WO2016044902 A1 WO 2016044902A1 BR 2014000349 W BR2014000349 W BR 2014000349W WO 2016044902 A1 WO2016044902 A1 WO 2016044902A1
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pgj2
poloxamer
inflammatory
composition according
injection
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Inventor
Marcelo Henrique NAPIMOGA
Juliana Trindade Clemente NAPIMOGA
Daniele Ribeiro de ARAUJO
Leonardo Fernandes Fraceto
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Fundacao Universidade Federal Do ABC
Regional De Ensino E Saude Ss Ltda Soc
Cristalia Produtos Quimicos e Farmaceuticos Ltda
Universidade Estadual de Campinas UNICAMP
Universidade Estadual Paulista Julio de Mesquita Filho UNESP
Original Assignee
Fundacao Universidade Federal Do ABC
Regional De Ensino E Saude Ss Ltda Soc
Cristalia Produtos Quimicos e Farmaceuticos Ltda
Universidade Estadual de Campinas UNICAMP
Universidade Estadual Paulista Julio de Mesquita Filho UNESP
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Priority to PCT/BR2014/000349 priority Critical patent/WO2016044902A1/fr
Priority to BR112017006057-4A priority patent/BR112017006057B1/pt
Publication of WO2016044902A1 publication Critical patent/WO2016044902A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • 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

Definitions

  • the present invention is directed to a poloxamer-based micellar system as a new pharmaceutical composition with prolonged residence of 15-deoxy-A-12 , 14-prostaglandin J2 at the site of administration and its use in therapy, particularly as an analgesic and anti-inflammatory composition that has a potential effect in joints.
  • Pain is a consequence of the inflammatory process, being one of its classical signals. It is now accepted that the sensitization of the primary sensory neurons is essential to inflammatory pain.
  • the peripheral pharmacologic control of inflammatory pain is based on two main strategies. The first is the use of drugs that prevent the nociceptor sensitization, such as non-steroidal antiinflammatory drugs (NSAIDs) (aspirin and aspirin-like drugs), which inhibit prostaglandin synthesis, and therefore, prevent the development of hypernociception .
  • NSAIDs non-steroidal antiinflammatory drugs
  • the second strategy is the direct blockade of the ongoing nociceptor sensitization, which can be achieved by the use of peripheral morphine (opioids), dipyrone and diclofenac. In fact, these drugs reverse the already established hypernociception induced by prostaglandin E2 (PGE2) .
  • PGE2 prostaglandin E2
  • Arthritis refers to a group of rheumatic diseases and other conditions that are characterized as a chronic and progressive inflammatory disorder with synovitis and severe joint destruction which can cause pain, stiffness and swelling in the joint.
  • TMJ temporomandibular joint
  • RA rheumatoid arthritis
  • Inflammation of the TMJ induced by RA have often resulted in persistent pain and caused distress to many patients.
  • temporomandibular disorders in RA patients from 67 to 92.9% in which the most common clinical findings are pain in the TMJ area, tenderness of the masticatory muscles, joint sounds and limited joint function (Lin et al., J. Clin. Med. Assoc. 70: 527-34, 2007; Aliko et al., Int. J. Oral Maxilofac. Surg. 40: 704-9, 2011) .
  • articular pain includes a large number of conservative treatments with limited efficacy .
  • -Mild articular pain may be controlled initially by the use of simple analgesics such as acetaminophen, propoxyphene and tramadol, which are the first line of articular treatment. If these analgesics do not sufficiently control the pain, a NSAID can be used, with similar effectiveness, but with significant side effects on gastrointestinal tract, including stomach upset, cramping diarrhea, ulcers and even bleeding.
  • the cyclooxygenase- (COX) 2-specific NSAIDs have lower rates of gastrointestinal side effects but are associated with higher rates of cardiovascular disease including myocardial infarction. Because of these side effects of NSAIDs, physicians are increasingly considering intra-articular (IA) treatment when oral therapies are not effective or show considerable systemic side effects.
  • IA intra-articular
  • Intra-articular drug delivery can be very useful when a small number of joints are affected or when the disease does not respond to systemic medications.
  • IA treatment has several advantages, for example, acting directly on selected joints, lower total drug dose, initial high local drug concentrations, reducing the exposure of unaffected sites to the drug, diminishing systemic side effects, fewer drug interactions, and enabling the administration of drugs with efficacy but low oral bioavailability, such as proteins or drugs with low solubility. Therefore, IA therapy not only reduces the costs of treatment but also improves the efficacy of therapy for patients suffering from articular pain.
  • osteoarthritis the most common form of arthritis and the most frequent form of joint disease
  • anti-inflammatory drugs directed at cytokines directed at cytokines to prevent the progression of structural changes of the joint has been disappointing for a number of reasons and needs further investigation in regards to delivery form and reduction of toxicity.
  • Another group of drugs is disease-modifying osteoarthritis drugs, which has the ability to slow down the disease process, including compounds that inhibit matrix- metalloproteinases , bisphosphonates , cytokine blockers, calcitonin, inhibitors of inducible nitric oxide synthase (iNOS), doxycycline, glucosamine and diacerein.
  • Surgical treatments including joint replacement are indicated in advanced cases with significant disability and for those patients in whom more conservative management has failed.
  • liposomes have been developed to encapsulate drugs for sustained local delivery and are believed to have promise for intra-articular drug therapy, although they generally exhibit a burst release due to instability in physiologic environments.
  • Microspheres have also been used to encapsulate drugs for arthritis (e.g., methotrexate, paclitaxel), using degradable polymers such as poly(lactic) or poly ( lactic-coglycolic acid), albumin, N-N- dicarboxymethyl chitosan and gelatin/chondroitin sulfate. These approaches have been found to improve the residence time of synthetic drugs or active compounds within the joint space by as much as 10-fold.
  • thermogelling polymers such as polyethylene glycol (PEG) copolymers or chitosans that have been evaluated as "drug depot"-forming materials for sustained release in systemic drug delivery.
  • PEG polyethylene glycol
  • prostaglandin derivatives have emerged as a promising class of anti-inflammatory substances.
  • Prostaglandins are autacoids synthesized in response to appropriate stimulus from 20 carbon-containing polyunsaturated fatty acids, principally arachidonic acid (AA) , from cell membranes, a reaction catalyzed by phospholipase A2 and derived from dietary sources.
  • the eicosanoids C20-hydroxy-fatty acids
  • PGs are not stored in tissues or cells. Instead, their production may increase in response to diverse stimuli, and they produce a broad spectrum of biological effects. Once synthesized, PGs are released and/or exported to the extracellular space.
  • PGs exert their functions mainly in proximity to their sites of synthesis, contributing to inflammation, smooth muscle tone, hemostasis, thrombosis, parturition and gastrointestinal secretion, among others.
  • Prostanoids play a critical role in inflammation and for many years, COX enzymes and their products have been considered mainly pro-inflammatory agents.
  • PGH2 an unstable oxygenated intermediate prostaglandin H2
  • COX oxygenated intermediate prostaglandin H2
  • the PGH2 intermediate may be converted into various prostaglandins such as PGE2, prostacyclin, prostacyclin F2 or prostaglandin D2 (PGD2), by a range of specific enzymes called prostaglandin synthases (e.g. PGE synthase or PGE-S, PGD synthase or PGD-S etc.) .
  • PGD2 is very short lived, and undergoes dehydration in vivo and in vitro to yield biologically active prostaglandins of the J2 series, including prostaglandin 15-deoxy-A-12 , 14-prostaglandin J2 (herein after PGJ2) .
  • PGJ2 14-prostaglandin J2
  • PGJ2 may exert anti-inflammatory effects.
  • this prostaglandin is a natural, chemically stable anti-inflammatory derivative of PGD2 with high- affinity ligand for the peroxisome proliferator-activated receptor (PPAR) subtype PPAR- ⁇ , which regulates gene expression of enzymes associated with lipid homeostasis, inflammation, cell proliferation, and malignancy.
  • PPAR- ⁇ is found in many cell types, including macrophages /monocytes , lymphocytes, neutrophils, mast cells, myocytes, fibroblasts, breast cells, human bone marrow precursors, and hepatocytes, and adipocytes.
  • PPAR- ⁇ represents a major anti-inflammatory mediator through which PGJ2 is able to suppress immune reactivity.
  • PPAR- ⁇ agonists have been reported to attenuate a variety of pathologies, including inflammation in arthritis models, neuronal cytotoxicity, inflammatory bowel disease, ischemia- reperfusion injury, Alzheimer's disease, glomerulonephritis, and activation of PPAR- ⁇ on cardiac myocytes has been shown to reduce cardiac hypertrophy.
  • PGJ2-mediated PPAR- Y activation has been shown to promote inflammatory resolution through the apoptotic induction of macrophages as well as blocking LPS-induced NO production in macrophages.
  • cytokines such as interleukin- ⁇ (IL- ⁇ ) and tumor necrosis factor-a (TNF-a) are central mediators in RA.
  • cytokines such as TNF-a, IL- ⁇ , IL-6 and the chemokines IL-8, chemokine-induced neutrophil chemoattractant-1 and keratinocyte-derived chemokine, trigger the release of prostanoids or sympathetic amines that act directly on the nociceptors to cause hypernociception .
  • AIA adjuvant-induced arthritis
  • micelles have an enormous importance for drug-delivery.
  • the main features to be considered are the small size, the particular nanostructure, the capacity to solubilize hydrophobic drugs in the core and the presence of a hydrophilic shell for the stabilization and protection of the drug from the external medium, pointing them as depot for hydrophobic drugs and also providing advantages for sustained release .
  • micellar delivery systems One of the most used components for micellar delivery systems are the copolymers of the poloxamer class.
  • Poloxamers which are also known as Kolliphor® (formerly Pluronics® (US) and Lutrols® (Europe)), have been introduced in 1950 as a non-ionic triblock copolymer consisting of propylene oxide (PO) and ethylene oxide (EO) blocks-specifically, i.e., poly (a-oxyethylene-b- oxypropylene-a-oxyethylene ) triblock copolymers, consisting of two hydrophilic chains of ethylene oxide chains (PEO) that sandwiched one hydrophobic propylene oxide chain (PPO) giving a chemical formula HO (C2H4O) a (C3H6O) b (C2H4O) aH where a and b values varies and gives rise to different polymers identified as 124, 188, 237, 338, 403, and 407 showing a slight difference in their properties.
  • PPO propylene oxide
  • EO ethylene oxide
  • PPO poly (a-oxyethylene-b- oxypropylene-
  • Poloxamers in general, are non-toxic polymeric surfactants and have been incorporated into drug delivery systems likely to be administered through oral, parenteral, topical routes and has been used as solubilizer, emulsifier and stabilizer. Poloxamers exhibit a spectacular range of structures in solution depending on concentration, copolymer composition, cosolutes, and temperature.
  • micellar carriers composed of poloxamers have been employed in different studies as drug carriers (antiinflammatories, local anesthetics ) due to their self-assembly properties and micellar nanostructure (Sharma and Bathia, Int. J. Pharm. 278:361-77, 2004; Sharma et al . , Colloids Surf. B Biointerfaces . 63:229-35, 2008) .
  • poloxamer 407 prolonged the residence time of the Ag85A antigen optimizing the immune response to Mycobacterium turbeculosis following pulmonary delivery (Todoroff et al . , Eur. J. Pharm. Biopharm. 84:40-8, 2013) .
  • poloxamer 188 has been shown to reduce the inflammation and tissue damage after brain injury (Curry et al., J. Neurosurg. 101(1 Suppl) : 91-6, 2004) .
  • a synergistic mixed poloxamer systems for solubilizing drugs was disclosed in the US Patent No. 8,460,644 ( aelor Pharmaceuticals Ltd), incorporated herein by reference. Particularly, it discloses combinations of poloxamers manipulating micelle properties between room temperature and body temperature, with significant advantages over solutions of single poloxamers, mainly regarded to its capability of solubilizing more drug, often substantially more, than single poloxamer systems, intended to be injectable, directed mainly to drugs that causes pain on injection, or that are difficult to formulate as injectable or in aqueous formulations in general, for example, sedatives, anaesthetic agents, anti-schizophrenic agents, antiseptic and anti-fungal agents.
  • the poloxamers are selected from P188, P234, P237, P338 and P407, and the ratio of poloxamers used is between 7:3 and 3:7 (w/w) , and the total concentration of poloxamer is between 3-15% (w/v) .
  • the present invention describes a new pharmaceutical composition comprising a poloxamer-based micellar system containing PGJ2 as active ingredient incorporated into the micellar core for enhancing its analgesic and anti-inflammatory effects.
  • the object of the present invention is to provide a new pharmaceutical composition for local injection of PGJ2 presenting thermal responsively and biocompatibility, being possible the administration of reduced doses of PGJ2 which is released for prolonged period of time.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a poloxamer-based micellar system, PGJ2 as the active ingredient, and an aqueous carrier, with enhanced analgesic and anti-inflammatory efficacy .
  • the present invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a poloxamer-based micellar system comprising an association of P407 and P188, PGJ2 and water for injection.
  • the present invention provides the use of the pharmaceutical composition of the instant invention for the manufacture of a medicament for treatment or prophylaxis of acute or chronic inflammatory conditions of temporomandibular joint (TMJ) , arthritis and other conditions mediated by inflammatory intermediates (for example, enhanced levels of prostaglandin E2 or other metabolites of COX-2) .
  • TMJ temporomandibular joint
  • inflammatory intermediates for example, enhanced levels of prostaglandin E2 or other metabolites of COX-2
  • the present invention provides a method for the treatment or prophylaxis of acute or chronic inflammatory conditions of temporomandibular joint (TMJ) , arthritis or other conditions mediated by inflammatory intermediates characterized by comprising the administration of an effective amount of the composition of claim 1 to a subject in need thereof.
  • TMJ temporomandibular joint
  • the pharmaceutical composition comprising a poloxamer-based micellar system and PGJ2 (PL-PGJ2) presents advantages in relation to plain PGJ2 or PGJ2-loaded polymeric nanocapsules in inflammation animals models, namely:
  • Fig. 1 shows the analgesic effect of different doses of a composition comprising poloxamer-based micellar system and PGJ2 (PL-PGJ2), injected directly into the joint, in the formalin-induced inflammatory pain model.
  • PL-PGJ2 was injected into the rats TMJ followed by the administration of formalin, into the same joint, and their pain behavior monitored.
  • rats were treated with PL-PGJ2 in the contralateral joint (ct) .
  • Fig. 2 shows the comparative efficacy of pretreatment with plain PGJ2 (100 ng/T J) and PL-PGJ2 (1 ng/TMJ) injected directly into the joint 15 minutes before the administration of formalin, in the formalin-induced inflammatory pain.
  • Fig. 3 shows the effects of pretreatment with a single injection of PL-PGJ2 (1 ng/TMJ) at different time intervals (15 minutes, 24 hours, 48 hours, 72 hours, 7 days, 10 days, and 14 days) in the formalin-induced inflammatory painful behavior at temporomandibular joint (TMJ) .
  • Fig. 4 shows the effect of the pretreatment with the PL-PGJ2 (1 ng/TMJ) at different time intervals (15 min, 24 hours, 7 days, 10 days, and 14 days) in plasma extravasation induced by formalin into the TMJ.
  • Fig. 5 shows the effect of pretreatment with single injection of PL-PGJ2 (1 ng/TMJ) at different time intervals (15 min, 24 hours, 7 days, 10 days, and 14 days) in leukocyte migration into joints.
  • Fig. 6 shows the experimental design of rheumatoid arthritis induced TMJ inflammatory hypernociception.
  • Fig. 7 shows the effect of a single injection of PL- PGJ2 (1 ng/TMJ) on rheumatoid arthritis-induced acute and chronic pain, compared to non-arthritic animals (control), and to arthritic animals which did not received PL-PGJ2 treatment .
  • Fig. 8 shows the comparative efficacy of pretreatment with plain PGJ2 (100 ng/TMJ) and PL-PGJ2 (1 ng/TMJ) injected directly into the joint, on rheumatoid arthritis-induced acute pain.
  • the development of new drugs and/or new formulations to treat chronic inflammatory diseases continues to be of considerable research interest.
  • the pharmacological response to a drug is directly associated with its concentration at the required site of action.
  • a non-specific distribution leads to high drug concentrations in healthy organs, tissues and cells, resulting in toxicity.
  • several drug delivery systems have increasingly been employed .
  • the present invention is directed to a new pharmaceutical composition comprising a poloxamer-based micellar system containing PGJ2 as the active ingredient, and an aqueous carrier, with increased analgesic and anti- inflammatory effect.
  • the poloxamer-based micellar system of the instant invention composition comprises the hydrophilic poloxamers P188, P407 or associations thereof. More preferably the poloxamer-based micellar system of the instant invention composition comprises an association between poloxamers P188 and P407 with different hydrophilic-lipophilic balances.
  • the ratio between poloxamer 407 and poloxamer 188 can vary since adequate fluidity for injection is maintained. Preferably the ratio between poloxamer 407 and poloxamer 188 is 1:1.
  • the amount of poloxamer in the pharmaceutical composition as described herein ranges from 7.5% w/v to 15% w/v of the total composition. More preferred are pharmaceutical compositions in which the total amount of poloxamer is 15% (w/v) of the total composition.
  • compositions of the instant invention were prepared in order to obtain a micellar system, avoiding micellar aggregation, and prevent the formation of a hydrogel. For this reason, final poloxamer concentration was maintained up to 15% (w/v) .
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of PGJ2.
  • “Therapeutically effective” means any amount of PGJ2 that, when administered to a subject, is sufficient to produce clinical analgesic or anti-inflammatory effect. This amount may vary over a considerable range depending on the inflammatory condition being treated, the age and relative health of the subject, the route of administration (systemic or local) and other factors apparent to one skilled in the art .
  • the aqueous carrier used in the present invention composition is selected from water for injection, saline physiological solution or an appropriate buffer, being water for injection the preferred carrier.
  • micellar systems preparation poloxamers were dispersed in water under 4°C, under magnetic stirring, until the complete poloxamer solubilization (transparent solution) .
  • the active ingredient PGJ2 is solubilized in dimethyl sulfoxide (DMSO), or in a poloxamer solution, and an appropriated volume of the resulting PGJ2 solution is dispersed into the micellar solution of poloxamers.
  • DMSO dimethyl sulfoxide
  • compositions of the present invention further pharmaceutical additives may be used, if desired.
  • pharmaceutical additives include for example preservatives, antioxidants, stabilizers and agents to adjust pH or osmolarity.
  • the pharmaceutical composition of the instant invention presents as a liquid or a viscous-liquid, with final pH of 5.5-6.0 (in order to achieve the pH of the inflammated tissue), suitable for both systemic and local administration through injection.
  • the pharmaceutical composition comprising PL-PGJ2 as described herein presents the ability to incorporate hydrophobic molecules, such as PGJ2, in association with its solvent, without modifying the micelles thermoreversible properties.
  • the pharmaceutical composition of the instant invention is thermodynamically stable in a temperature ranging from 0 to 150°C, enabling the sterilization by autoclaving. Moreover, it is also advantageous that the instant composition presents micellar diameter in the range of 50 to 70 nm, depending on the temperature, making it also possible the sterilization by filtration.
  • the proposed pharmaceutical composition PL-PGJ2 remains at the site of injection for a long period of time.
  • the pharmaceutical composition of the present invention comprising a poloxamer-based micellar system and PGJ2 functions as a depot formulation, with prolonged residence of the composition at the site of injection, controlling the release of PGJ2 during prolonged period of time .
  • the PL-PGJ2 compositions described herein showed improved characteristics when injected into inflammated joints, providing good efficacy, good tolerability , and prolonged release, allowing single injection each 7-10 days.
  • composition PL-PGJ2 as describe herein, have significant advantages of being able to maintain PGJ2 stability and enhanced therapeutic efficacy for long period of time, in a dose-dependent manner.
  • composition PL-PGJ2 has the advantage of permitting the administration of very low frequency dosing, very small doses of the PGJ2 , minimizing the side effects due to high doses of the active substance.
  • compositions described herein have a rapid onset of action, which lasts up to 7 to 10 days.
  • PL-PGJ2 composition has been shown to potentiate PGJ2 analgesic and anti-inflammatory activity, and reducing the inflammatory pain due to rheumatoid arthritis .
  • the pharmaceutical composition of the present invention PL-PGJ2 is intended to deliver PGJ2 directly to the injured site, enabling the use of very small doses, with increased efficacy, reduced side effects, and extended residence at the site of injection, consequently allowing greater intervals between dosages.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a poloxamer-based micellar system, PGJ2 as the active ingredient, and an aqueous carrier (PL-PGJ2), for use in treatment or prophylaxis of acute or chronic inflammatory conditions in human or animal, with enhanced PGJ2 analgesic and anti-inflammatory effect.
  • the present invention provides the use of the pharmaceutical composition of the instant invention PL-PGJ2 for the manufacture of a medicament for treatment or prophylaxis of . acute or chronic inflammatory conditions of TMJ, arthritis or other conditions mediated by inflammatory intermediates.
  • the present invention also provides a method for the treatment or prophylaxis of acute or chronic inflammatory conditions of temporomandibular joint (TMJ) , arthritis or other conditions mediated by inflammatory intermediates characterized by comprising the administration of an effective amount of the composition PL-PGJ2 to a subject in need thereof.
  • TMJ temporomandibular joint
  • the analgesic and anti-inflammatory potential of the pharmaceutical composition PL-PGJ2 was investigated employing an animal model.
  • FIG. 1 depicts the effect of PL-PGJ2 in formalin-induced inflammatory pain.
  • the pre- treatment with PL-PGJ2 at doses of 0.3, 1 and 3 ng injected directly into the joint significantly decreased the pain response induced by intra-articular injection of formalin.
  • Some effect following the injection of PL-PGJ2 at the contralateral joint (ct) was also observed. This find suggests some systemic effect with doses of 3 ng/TMJ (Fig. 1) or greater (not shown) .
  • the pharmaceutical composition PL-15-PGJ2 of the present invention has shown analgesic and anti-inflammatory activity almost 100 times greater than plain PGJ2 , as shown in Fig. 2, thus confirming the ability of the pharmaceutical composition disclosed herein in potentiate the analgesic and anti-inflammatory activity of PGJ2 following the administration of very smaller doses .
  • another advantage of the instant invention is the long-term effect promoted by PL-PGJ2 following a single injection (1 ng/TMJ) .
  • the PL-PGJ2 antinociceptive effect was observed until 10 days after a single injection, showing the prolonged residence of the poloxamer-based micellar system at the site of injection together with the controlled release of the active compound from the micelles.
  • This analgesic action demonstrated by the PL-PGJ2 was due to its ability to reduce the inflammation in the injured site .
  • Plasma extravasation and leucocyte migration were evaluated to confirm the antinociceptive and anti-inflammatory effect of the PL-PGJ2 composition.
  • Plasma extravasation was significantly reduced until 24h after the administration of the PL-PGJ2 composition (Fig. 4), while the inflammatory cells migration was reduced until 10 days after de injection (Fig. 5) confirming the anti-inflammatory effect of the composition of the instant invention.
  • the pharmaceutical composition of the instant invention was evaluated on experimental arthritis model, as described in the Example 7 and 8.
  • the PL-PGJ2 composition advantageously presents significantly reduced rheumatoid arthritis-induced acute and chronic pain upon administration of 1 ng of PGJ2 in poloxamer- based micelles, as shown by the decreased nociceptive pain.
  • the pharmaceutical composition as described in this invention presented the same effect as the dose of 100 ng/TMJ of plain PGJ2 but with a dose 100 times smaller (1 ng/TMJ) (Fig.8), confirming that the poloxamer- based micellar composition enable the administration of very small doses with the same effect than the free drug.
  • the present invention describes a pharmaceutical composition comprising poloxamer-based micellar system, PGJ2 as the active ingredient, and an aqueous carrier, as a new promising composition that can overcome some drawbacks of the arthritis treatment, since it promotes analgesic and anti-inflammatory effect in both acute and chronic phases, allowing reduced dosing schedule together with reduced doses, and consequently, reduced systemic and side effects .
  • the poloxamer-based micellar system as described herein presents an increased residence time at the site of injection (joints), leading a longer period of pain relief to the patient.
  • Example 1 is merely illustrative, and must be applied solely for a better understanding of the present invention embodiments, and are not to be used with the intention of limiting the described objects.
  • Example 1 is merely illustrative, and must be applied solely for a better understanding of the present invention embodiments, and are not to be used with the intention of limiting the described objects.
  • 0.01% w/v PGJ2 (Calbiochem, San Diego, CA, USA) solution was prepared by adding 10 mL of dimethyl sulfoxide (DMSO) to 1.0 mg of PGJ2. Following, the obtained solution can be aliquoted and frozen or stored at -20 °C for up to 3 months .
  • DMSO dimethyl sulfoxide
  • 15 % w/v poloxamer solutions were prepared by adding 75 g of total poloxamer to 350 mL of water for injection at 4°C, under magnetic stirring (100 rpm) , until the complete poloxamer solubilization (transparent solution) . This solution was then made up to 500 mL with cold water for injection. Table 1 presents the different formulations prepared as described.
  • compositions on poloxamer-based micellar system were prepared by dispersing 30 to 300 pL, respectively, of PGJ2 stock solution 0.01%, obtained as described in A) to 20 ml of the poloxamer stock solution, as prepared B) F5, above. After PGJ2 incorporation, compositions were stirred (100 rpm) at 4°C, for at least 6 hours. The obtained compositions must be stored at 2-8°C until further use. All compositions presented total DMSO concentration of 0.15 to 1.5 % v/v.
  • micellar hydrodynamic diameter was determined using Dynamic Light Scattering (DLS) to evaluate micelle-PGJ2 interaction and its influence on micellar assembly. Measurements were performed using a particle analyzer Zetasizer ZS (Malvern®, UK) at a fixed angle of 173° and temperatures of 25°C and 37°C. All measurements were determined at least three times for each sample.
  • DLS Dynamic Light Scattering
  • micellar hydrodynamic diameter determination was used as a parameter for monitoring the formation of mixed micelles composed of poloxamer 407 and poloxamer 188 in the presence or absence of PGJ2.
  • micellar hydrodynamic diameter for PL407-PL188 systems after PGJ2 incorporation (Table 2) .
  • Micellar diameters of ⁇ 70 nm were observed at 25 °C and when the temperature was raised to 37 °C, a reduction on micellar dimensions ( ⁇ 50 nm) was obtained (with a 99.5 % average distribution) .
  • Polydispersity values were from 0.25 at 25 °C to 0.15 at 37 °C. These parameters showed an important contribution of temperature on micellar diameter.
  • micellar dimension will be reduced at physiological temperature
  • micelles can remain for long periods of time at the site of administration and also should be small enough ( ⁇ 100 nm) to avoid the uptake by the reticuloendothelial system, favoring the therapeutic efficacy of the drug carrier (Wei et al., Int. J. Pharm. 376:176-185, 2009) .
  • Poloxamer 407-188 (0.1 ng PGJ2 ) 68.9 ⁇ 1.5 45.7 ⁇ 2.8
  • Poloxamer 407-188 (1 ng PGJ2) 68.9 ⁇ 2.5 48.4 ⁇ 1.6
  • Poloxamer 407-188 (3 ng PGJ2 ) 69.7 ⁇ 2.1 47.1 ⁇ 2.2
  • DSC Differential Scanning Calorimetry
  • micellization process is endothermic (Table 3) .
  • the main advantage of this system is the capability for incorporating hydrophobic molecules, such as PGJ2, in association with its solvent, without modifying thermoreversible properties at physiological temperature (since the final temperature for micelles formation is below to the body temperature for all formulations) .
  • Tonset initial temperature for micelles formation
  • T m i C eiuzation peak temperature for micelles formation
  • T en dset final temperature for micelles formation
  • Testing sessions took place during light phase (between 09:00 a.m. and 05:00 p.m.) in a quiet room maintained at 23°C. Each animal was manipulated for 7 days to be habituated to the experimental manipulation. After this period, the animal was placed in a test chamber (30x30x30 cm mirrored wood chamber with a glass at the front side) for 15 min habituation period to minimize stress. Animals were briefly anesthetized by inhalation of halothane to allow the TMJ injection, which was performed with a 30 gauge needle connected to a 50 ⁇ - Hamilton syringe (Roveroni et al . , Pain. 94:185-91, 2001) .
  • Rats were pretreated (15 min) with an intra-TMJ injection of PL-PGJ2 (0.3, 1.0 or 3.0 ng/TMJ) followed by ipsilateral intra-TMJ injection of 1.5% formalin in a final volume of 45 . Behavioral nociception response was evaluated for a 45 min observation period.
  • the two highest dose of PL-PGJ2 was also injected in the contralateral TMJ (ct) that received injection of 1.5% formalin.
  • the nociceptive response score was defined as the cumulative total number of seconds that the animal spent rubbing the orofacial region asymmetrically with the ipsilateral fore or hind paw plus the number of head flinches counted during the observation period (as shown in Figure 1) . Since head flinches followed a uniform pattern of 1 s of duration, each flinch was expressed as 1 s . Results are expressed as the duration time of nociceptive behavior (Roveroni et al., Pain. 94:185-91, 2001; Clemente et al., Neurosci. Lett. 372:250-5 2004) .
  • Formalin solution was prepared from commercially stock formalin (an aqueous solution of 37 % of formaldehyde - Sigma Aldrich, St. Louis, MO, USA) and further diluted in 0.9 % NaCl .
  • mice was administered with a single injection of 1.0 ng/TMJ of PL-PGJ2 and the nociceptive behavior was evaluated after injection of formalin solution. Animals received the formalin injection 15 minutes, 24 h, 48 h, 72 h, 7 days, 10 days and 14 days after the injection of PL-PGJ2 (Fig. 3) .
  • mice were anesthetized by an intraperitoneal injection of a mixture of urethane (1 g/kg) and ct-chloralose (50 mg/kg), followed by i.v. administration of Evan's blue dye (1%; 5 mg/kg), to visualize formalin-induced plasma extravasation upon post-mortem examination of injected TMJs (Haas et al., Arch. ⁇ Oral Biol. 37:417-422, 1992) .
  • This procedure also confirmed that the plasma extravasation induced by TMJ injection at the correct site was restricted to the immediate TMJ region (Fig. 4) .
  • a different investigator performed each test, prepared the solution, and administered the TMJ injections.
  • Example 6 Leucocyte Migration to TMJ Periarticular Tissues After behavioral experiments, the rats were euthanized and the articular cavity was washed with 10 ⁇ . with phosphate buffer saline (PBS) containing 1 mM EDTA for leukocytes migration analysis. The TMJ periarticular tissues were also removed and homogenized in 500 ⁇ of the appropriate buffer containing protease inhibitors (Ripa Lysis Buffer, Santa Cruz, Biotechnology, Dallas, Texas, USA) followed by a centrifugation of 10 min/10,000 rpm/4°C.
  • PBS phosphate buffer saline
  • Total leukocyte counts were performed in a Neubauer chamber diluting the exudate in Turk solution (1:2) and expressed as number of cells x lOVcavity.
  • the differential leukocyte counts was performed by preparing smears in a cytocentrifuge, which were stained with fast Panotic kit, and for differentiated cells (100 cells total), an optical microscope (under oil immersion at 1000 x magnification) was utilized. The result of each cell type was calculated using the percentage of those cells and the total number of cells obtained in the total count (as shown in Fig. 5) .
  • mBSA methylated bovine serum albumin
  • PBS phosphate buffered saline
  • CFA Freund' s complete adjuvant
  • Booster injections of mBSA dissolved in Freund' s incomplete adjuvant (IFA) were given 7 and 14 days after the first immunization in different sites in the back of the rat.
  • IFA Freund' s incomplete adjuvant
  • Example 8 Effect of the PL-PGJ2 in the hypernociception of on arthritis-induced acute and chronic pain in TMJ of rats:
  • TMJ-arthritis hypernociception it was used the measurement of the behavioral nociceptive response induced by formalin injections (as described on Example 4, above) .
  • the rats were pretreated with an intra-TMJ injection of PL-PGJ2 (1.0 ng/ TMJ) or vehicle 24 hours after the last mBSA challenge (day 22 for arthritis acute phase pain evaluation, and day 36 for arthritis chronic pain evaluation) .
  • an intra- TMJ injection of formalin 0.5%) was administered.
  • the behavioral nociceptive response was evaluated for a 45 min observation period ( Fig . 7 ) .
  • immunized (arthritic) and non- immunized (non-arthritic) animals received intra-TMJ injection 100 ng plain PGJ2 or 1 ng PL-PGJ2 24h after the mBSA challenge (Fig. 8) . After 15 minutes an injection of 0.5% formalin was administered to the animals and the painful behavior was evaluated. As the controls, non-immunized animals received only injections of PBS or formalin or mBSA+formalin, and immunized animals received PBS injection.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un système micellaire à base de poloxamère, de la 15-désoxy-Δ-12,14-prostaglandine J2 en tant que principe actif et un excipient aqueux, ladite composition présentant un temps de séjour prolongé au site d'injection, induisant un effet analgésique anti-inflammatoire puissant et prolongé, et étant particulièrement utile dans le traitement d'états inflammatoires d'articulations et de l'arthrite.
PCT/BR2014/000349 2014-09-26 2014-09-26 Composition pharmaceutique de 15-desoxy-delta-12,14-prostaglandine j2 dans un systeme micellaire a base de poloxamere et son utilisation dans le traitement d'etats inflammatoires Ceased WO2016044902A1 (fr)

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PCT/BR2014/000349 WO2016044902A1 (fr) 2014-09-26 2014-09-26 Composition pharmaceutique de 15-desoxy-delta-12,14-prostaglandine j2 dans un systeme micellaire a base de poloxamere et son utilisation dans le traitement d'etats inflammatoires
BR112017006057-4A BR112017006057B1 (pt) 2014-09-26 2014-09-26 Composição farmacêutica à base de prostaglandina J2 incorporada em sistemas micelares baseados em poloxâmeros para potencialização das atividades analgésica e anti-inflamatória

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2018056905A1 (fr) * 2016-09-20 2018-03-29 Nanyang Technological University Co-cristaux de nurr1-lbd dans un complexe avec une prostaglandine cyclopenténone et des modulateurs de nurr1
US11406610B2 (en) 2016-09-20 2022-08-09 Nanyang Technological University Co-crystals of Nurr1-LBD in complex with a cyclopentenone prostaglandin and modulators of Nurr1
US12036195B2 (en) 2016-09-20 2024-07-16 Nanyang Technological University Co-crystals of NURR1-lbd in complex with a cyclopentenone prostaglandin and modulators of NURR1

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