EP3880176A1 - Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating diseases due to reduced bone density or cartilage loss and uses thereof - Google Patents
Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating diseases due to reduced bone density or cartilage loss and uses thereofInfo
- Publication number
- EP3880176A1 EP3880176A1 EP19884612.3A EP19884612A EP3880176A1 EP 3880176 A1 EP3880176 A1 EP 3880176A1 EP 19884612 A EP19884612 A EP 19884612A EP 3880176 A1 EP3880176 A1 EP 3880176A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- therapeutic agent
- bone density
- treating
- cartilage loss
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
Definitions
- the present invention is directed to a sustained-release pharmaceutical composition for treating diseases due to reduced bone density or cartilage loss, with a high drug to lipid ratio and a high encapsulation efficiency using at least one trapping agent.
- the high drug to lipid ratio, high drug encapsulation efficiency and sustained release profile of the pharmaceutical composition reduce the frequency of drug administration, increase patient compliance and improve the therapeutic outcome.
- Bone remodeling is a physiological process determined by the sequential and coordinated interaction involving osteoclasts and osteoblasts, as well as osteocytes, inflammatory cells and mediators. The balance between osteoblasts and osteoclasts activity maintains the bone homeostasis. Functional disorders of osteoclasts increase bone resorption and causes various bone and joint diseases, for instance, osteoporosis, osteopetrosis, rheumatoid arthritis, osteoarthritis, bone tumor and Paget’s bone disease.
- Cathepsin K a cysteine protease expressed at high levels in osteoclasts, plays crucial roles in degradation of bone matrix composed of hydroxyapatite and protein, especially type I collagen. Cathepsin K is also involved in the cleavage of type II collagen in human articular cartilage. Recent studies show that once or twice daily oral administration of cathepsin K inhibitors prevent both bone loss and cartilage degeneration. It is highly desirable to maintain the therapeutic concentration of a cathepsin K inhibitor and minimize the frequency of administration to treat diseases due to reduced bone density and cartilage loss.
- Liposomes as a drug delivery system has been widely used for developing sustained- release formulations for various drugs.
- Drug loading into liposomes can be attained either passively (the drug is encapsulated during liposome formation) or remotely/actively (creating a transmembrane pH- or ion-gradient during liposome formation and then the drug is loaded by the driving force generated from the gradients after liposome formation) (US Patent No. 5,192,549 and 5,939,096).
- US Patent No. 5,192,549 and 5,939,096 Although the general method of drug loading into liposomes is well documented in the literature, only a small number of therapeutic agents were loaded into liposomes with high encapsulation efficiency.
- a sustained release pharmaceutical composition comprises (a) at least one liposome comprising a bilayer membrane, said bilayer membrane comprises at least one lipid; (b) a trapping agent; and (c) a therapeutic agent for treating diseases due to reduced bone density or cartilage loss, wherein the molar ratio of the therapeutic agent to the lipid is equal to or higher than about 0.1 is provided.
- methods are provided for treating a disease due to reduced bone density or cartilage loss, comprising the steps of administering the pharmaceutical composition described herein to a subject in need thereof.
- a medicament for treating a disease due to reduced bone density or cartilage loss comprising a therapeutically effective amount of the sustained pharmaceutical composition described herein.
- FIG. 1 is a line graph showing the plasma L-006235 concentration in rats after intraarticular injection of free L-006235 and liposomal L-006235.
- an “effective amount” as used herein refers to a dose of the pharmaceutical composition described herein to reduce the symptoms and signs of diseases due to bone resorption and reduced bone density, such as decreased/increased bone mass, loss of subchondral bone or cartilage, joint pain or joint swelling in arthritis.
- the term“effective amount” and“therapeutically effective amount” are used interchangeably.
- the term“treating,”“treated,” or“treatment” as used herein includes preventative (e.g. prophylactic), palliative, and curative methods, uses or results.
- the terms“treatment” or “treatments” can also refer to compositions or medicaments.
- by treating is meant a method of increasing bone density or reducing cartilage loss and hence, reducing or delaying one or more symptoms or signs of diseases due to reduced bone density or cartilage loss or the complete amelioration of diseases due to reduced bone density or cartilage loss as detected by art-known techniques.
- Art recognized methods are available to detect diseases due to reduced bone density or cartilage loss and its symptoms.
- biomarkers for example, detection of C- reactive protein, anti-cyclic citrullinated peptide, serum alkaline phosphatase, creatine kinase BB isoenzyme, tartrate-resistant acid phosphatase, matrix metalloproteinase-3, C-terminal telopeptide of type I collagen, C-telopeptide of type II collagen, N-terminal telopeptide of type I collagen, N-terminal propeptide of collagen IIA and serum hyaluronan) in body fluid (for example, serum, urine or synovial fluid) or biopsy/histopathological evaluation (for example, cartilage and subchondral bone staining), to name a few.
- body fluid for example, serum, urine or synovial fluid
- biopsy/histopathological evaluation for example, cartilage and subchondral bone staining
- a disclosed method is considered to be a treatment if there is at least 1% increase in bone density, as measured by bone mineral densitometry, or about a 1% reduction in one or more symptoms of the disease due to reduced bone density or cartilage loss in a subject when compared to the subject prior to treatment or control subjects.
- the reduction can be about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between.
- subject can refer to a vertebrate having or at risk of developing a disease due to reduced bone density or cartilage loss or to a vertebrate deemed to be in need of treatment to increase bone density and/or repair cartilage.
- Subjects include all warm-blooded animals, such as mammals, such as a primate, and, more preferably, a human. Non-human primates are subjects as well.
- the term subject includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.) and laboratory animals (for example, mouse, rabbit, rat, gerbil, guinea pig, etc.).
- livestock for example, cattle, horses, pigs, sheep, goats, etc.
- laboratory animals for example, mouse, rabbit, rat, gerbil, guinea pig, etc.
- the terms“liposome,”“liposomal” and related terms as used herein are characterized by an interior aqueous space sequestered from an outer medium by one or more bilayer membranes forming a vesicle.
- the interior aqueous space of the liposome is substantially free of a neutral lipid, such as triglyceride, non-aqueous phase (oil phase), water-oil emulsions or other mixtures containing non-aqueous phase.
- Non-limiting examples of liposomes include small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), and multi-lamellar vesicles (MLV) with an average diameter ranges from 50-500 nm, 50-450 nm, 50-400 nm, 50-350 nm, 50-300 nm, 50-250 nm, 50-200 nm, 100-500 nm, 100-450 nm, 100-400 nm, 100-350 nm, 100-300 nm, 100-250 nm or 100-200 nm.
- SUV small unilamellar vesicles
- LUV large unilamellar vesicles
- MLV multi-lamellar vesicles
- Bilayer membranes of liposomes are typically formed by at least one lipid, i.e. amphiphilic molecules of synthetic or natural origin that comprise spatially separated hydrophobic and hydrophilic domains.
- lipid including but not limited to, dialiphatic chain lipids, such as phospholipids, diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin and glycosphingolipid, and combinations thereof.
- Examples of phospholipid according to the present disclosure include, but not limited to, 1 ,2-dilauroyl-,v/7- glycero-3-phosphocholine (DLPC), 1 ,2-dimyristoyl-.s77-glycero-3-phosphocholine (DMPC), 1 ⁇ -dipalmitoyl-sn-glycero-S -phosphocholine (DPPC) , 1 -palmitoyl-2-stearoyl-.s/7-glycero-3- phosphocholine (PSPC), 1 -palmitoyl-2-oleoyl-.s77-glycero-3-phosphatidylcholine (POPC), 1,2- distearoyl-.s77-glycero-3-phosphocholine (DSPC), 1 ,2-dioleoy 1 -,s77-glycero-3-phosphocholine (DOPC), hydrogenated soy phosphatidylcholine (HSPC), 1 ,2-dimyristoy
- the lipid is a lipid mixture of one or more of the foregoing lipids, or mixtures of one or more of the foregoing lipids with one or more other lipids not listed above, membrane stabilizers or antioxidants.
- the mole percent of the lipid in the bilayer membrane is equal or less than about 80, 79, 78, 77, 76, 75, 74, 73, 72, 71,70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45 or any value or range of values therebetween (e.g., about 45-80%, about 45-75%, about 45-70%, about 45-65%, about 50-80%, about 50-75%, about 50-70% or about 50-65%).
- the lipid of the lipid bilayer is a mixture of a first lipid and a second lipid.
- the first lipid is selected from the group consisting essentially of phosphatidylcholine (PC), HSPC, DOPC, POPC, DSPC, DPPC, DMPC, PSPC and combination thereof and the second lipid is selected from the group consisting essentially of a phosphatidylethanolamine, phosphatidylglycerol, PEG-DSPE, DPPG, DOPG and combination thereof.
- the mole percent of the first lipid in the bilayer membrane is equal or less than about 79.9, 79.5, 79.1, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44,
- the mole percent of the second lipid in the bilayer membrane is equal or higher than 0.1 or 0.5 to less than about 25, 24, 23 or any value or range of values therebetween (e.g., about 0.1-25%, about 0.1-24%, about 0.1-23%, about 0.5-25%, about 0.5-24%, about 0.5-23%, about 0.7-25%, about 0.7-24% or about 0.7-23%).
- Bilayer membranes of liposomes further comprise less than about 55 mole percentage of steroids, preferably cholesterol.
- the mole % of cholesterol in the bilayer membrane is about 20-55%, about 20-50%, about 20-45%, about 25-55%, about 25- 50%, about 25-45%, about 30-55%, about 30-50% or about 30-45%.
- the mole % of the lipid and cholesterol in the bilayer membrane is about 45-80%: 20-55% or 50-75%: 25-50%.
- the mole % of the first lipid, the second lipid and cholesterol in the bilayer membrane is about 30-79.9%: 0.1%-25%: 20-55%, 30-75%: 0.1-25%: 20-50% or 35-70%: 0.5-25%: 20-45% and the first phospholipid is HSPC and the second phospholipid is DSPE-PEG2000.
- the term“remote loading” as used herein is a drug loading method which involves a procedure to transfer drugs from the external medium across the bilayer membrane of the liposome to the interior aqueous space by a polyatomic ion-gradient.
- Such gradient is generated by encapsulating at least one polyatomic ion as a trapping agent in the interior aqueous space of the liposome and replacing the outer medium of the liposome with an external medium with a lower polyatomic ion concentration, for example, pure water, sucrose solution or saline by known techniques, such as column separation, dialysis or centrifugation.
- a polyatomic ion gradient is created between the interior aqueous space and the external medium of the liposomes to trap the therapeutic agent in the interior aqueous space of the liposomes.
- Exemplary polyatomic ion as trapping agents include, but are not limited to, sulfate, sulfite, phosphate, hydrogen phosphate, molybdate, carbonate and nitrate.
- Exemplary trapping agents include, but are not limited to, ammonium sulfate, ammonium phosphate, ammonium molybdate, ammonium sucrose octasulfate, triethylammonium sucrose octasulfate, dextran sulfate, or a combination thereof.
- the concentration of triethylammonium sucrose octasulfate is about 10 to about 200 mM, about 50 to about 150 mM or about 60 to about 100 mM. In another embodiment, the concentration of ammonium sulfate is about 100 to about 600 mM, about 150 to about 500 mM or about 200 to about 400 mM.
- the liposome encapsulating a trapping agent can be prepared by any of the techniques now known or subsequently developed.
- the MLV liposomes can be directly formed by a hydrated lipid film, spray-dried powder or lyophilized cake of selected lipid compositions with trapping agent;
- the SUV liposomes and LUV liposomes can be sized from MLV liposomes by sonication, homogenization, microfluidization or extrusion.
- the present invention is directed to a sustained release pharmaceutical composition, comprising (a) at least one liposome comprising a bilayer membrane; (b) a trapping agent; and (c) a therapeutic agent for treating disease due to reduced bone density or cartilage loss, wherein the bilayer membrane comprises at least one lipid and the molar ratio of the therapeutic agent to the lipid is above or equal to about 0.1.
- the sustained release pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, diluent, medium for an active ingredient, a preservative, cryoprotectant or a combination thereof.
- the weight percent of the bilayer membrane is about 0.1-15%; the weight percent of the trapping agent is about 0.1-12%; and the weight percent of the pharmaceutically acceptable excipient (such as sucrose, histidine, sodium chloride and ultrapure water), diluent, medium for the active ingredient, a preservative, cryoprotectant or a combination thereof is about 75.0-99.9%.
- the therapeutic agent for treating a disease due to reduced bone density or cartilage loss is a cathepsin K inhibitor.
- cathepsin K inhibitor include balicatib (C23H33N5O2), odanacatib (C25H27F4N3O3S), L-006235
- the therapeutic agent for treating a disease due to reduced bone density or cartilage loss is non-water soluble or hydrophobic.
- the sustained release profile of the pharmaceutical composition prolongs the half-life, the therapeutic concentration and the duration of action of the therapeutic agent for treating a disease due to reduced bone density or cartilage loss, and hence, sustains the therapeutic effect and reduces the administration frequency of the therapeutic agent.
- the sustained release profile of the pharmaceutical composition is due to a high drug encapsulation efficiency.
- the encapsulation efficiency of the pharmaceutical composition is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.
- the sustained release profile of the pharmaceutical composition is due to the higher therapeutic agent to lipid molar ratio.
- the molar ratio of the therapeutic agent for treating a disease due to reduced bone density or cartilage loss to the one or more lipids is above or equal to about 0.1, alternatively above or equal to about 0.1 to less than about 20, less than about 15, less about 10, less than about 5, less than about 4, less than about 3, less than about 2 or less than about 1.5.
- the half-life of the therapeutic agent for treating a disease due to reduced bone density or cartilage loss is extended by at least 2-fold, at least 5-fold, at least 7.5- fold, at least 10-fold, or at least 20-fold compared to that of a free therapeutic agent for treating a disease due to reduced bone density or cartilage loss.
- the invention also provides methods of treating a disease due to reduced bone density or cartilage loss, comprise the administration of an effective amount of the pharmaceutical composition as described herein to a subject in need thereof, whereby the symptoms and/or signs of the disease due to reduced bone density or cartilage loss in the subject are reduced.
- the pharmaceutical composition is formulated to be suitable for injection, such as intraarticular, subcutaneous, subdermal, intradermal, transdermal or intramuscular route.
- the pharmaceutical composition is also formulated to be administered as a transdermal patch.
- the dosage of the pharmaceutical composition of the present invention can be determined by the skilled person in the art according to the embodiments. Unit doses or multiple dose forms are contemplated, each offering advantages in certain clinical settings. According to the present invention, the actual amount of the pharmaceutical composition to be administered can vary in accordance with the age, weight, condition of the subject to be treated, any existing medical conditions, and on the discretion of medical professionals.
- the pharmaceutical compositions disclosed herein display a significant extended-release profile of the therapeutic agent for treating a disease due to reduced bone density or cartilage loss.
- the pharmaceutical composition of the present invention extended the half-life of L-006235 to 56.6 hours in rats, which is 16.6 times longer compared to the half-life of L-006235 in rats (3.4 hours) via oral administration (J Med Chem 2005 1:48(24) :7520-34).
- compositions are developed to reduce the dosing frequency from once to twice daily to once every two days, once every three days, once every four days, once every five days, once every six days, weekly, once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months or once every six months.
- trapping agent such as triethylammonium sucrose octasulfate
- Triethylammonium sucrose octasulfate was also used. After five freeze-thaw cycles between liquid nitrogen and water at 60°C, the empty liposomes were subsequently extruded ten times through polycarbonate filter membranes with a pore size of 0.2 pm. Unencapsulated trapping agent was removed by dialysis method or diafiltration method against a 9.4% sucrose solution or 0.9% NaCl solution to create a polyatomic ion gradient between the inner aqueous phase and the outer aqueous phase of the empty liposomes.
- a reaction mixture containing 3.0 mg/mL of L-006235 (commercially available from DC Chemicals, China), empty liposomes (with 6.0 mM of lipids), and 50 mM histidine buffer (pH 6.5) was incubated at 60°C for 15 min.
- the unencapsulated L-006235 of the reaction mixture was separated by a SephadexTM G-50 Fine gel (GE Healthcare, USA) or dialysis bag (Spectrum Labs, USA) against a 9.4% sucrose solution to obtain a liposomal L-006235 formulation.
- the concentration of encapsulated L-006235 of the liposomal L-006235 formulation was measured using HPLC and the concentrations of lipids of the liposomal L- 006235 formulation were measured using an ultraviolet/visible (UV/Vis) spectrophotometer.
- UV/Vis ultraviolet/visible
- the encapsulation efficiency was calculated by dividing the drug to lipid molar ratio (D/L) of the liposomal L-006235 formulation by the nominal D/L of the reaction mixture, which was calculated by dividing the concentration of L-006235 by the lipid concentration of the empty liposomes.
- the particle size distribution was measured by a dynamic light scattering instrument (Zetasizer Nano-ZS90, Malvern, USA).
- the liposomal L-006235 formulation has a final D/L of 1.00, an encapsulation efficiency of 93.4%, and the mean diameter of the liposomes was 193.7 nm.
- Cathepsin K inhibitors used in this example included L-006235 and balicatib (MedChem Express, USA).
- the empty liposomes were prepared according to Example 1, with the following trapping agents: (1) 300 mM of ammonium sulfate and (2) 75 mM of triethylammonium sucrose octasulfate.
- the loading procedures of liposomal L-006235 formulations were based on Example 1.
- the liposomal balicatib formulation was prepared as follows: a reaction mixture containing 2 mg/mL of balicatib, empty liposomes and 50 mM histidine buffer (pH 6.5) was incubated at 60°C for 15 minutes.
- the rats were divided into two groups (n - 4 in each group).
- the rats in the first group each received an intraarticular injection of 2.5 mg/kg of free L-006235, prepared by dissolving L-006235 in a 9.4% sucrose solution, containing 0.06 N HC1, with a final concentration of 10.0 mg/mL and the rats in the second group each received an intraarticular injection of 5.0 mg/kg of liposomal L-006235 formulation, prepared according to Example 1 with a final concentration of 18.1 mg/mL.
- Blood samples were collected at 5, 15, 30 mins, 1, 2, 4, 8, 24, 48, 72, 96 and 168 hours post- injection. Plasma samples were obtained by centrifugation and analyzed using liquid chromatography-tandem mass spectrometry.
- the dose-normalized area under the curve (AUCo- t /D) of the liposomal L-006235 formulation indicates that 89.7% of L-006235 was released from the liposomal L-006235 formulation 168 hours post-injection compared to the AUCo- t /D of the free L-006235 formulation, which indicates that 100% of L-006235 was released 24 hours post injection.
- FIG. 1 shows plasma L-006235 was undetectable 24 hours post free L- 006235 injection whereas plasma L-006235 was detected up to 168 hours after the administration of the liposomal L-006235 formulation.
- the results support a conclusion that the claimed pharmaceutical composition sustained the release of cathepsin K inhibitors.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US201862767254P | 2018-11-14 | 2018-11-14 | |
PCT/US2019/061143 WO2020102323A1 (en) | 2018-11-14 | 2019-11-13 | Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating diseases due to reduced bone density or cartilage loss and uses thereof |
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EP3880176A1 true EP3880176A1 (en) | 2021-09-22 |
EP3880176A4 EP3880176A4 (en) | 2022-08-03 |
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EP19884612.3A Pending EP3880176A4 (en) | 2018-11-14 | 2019-11-13 | Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating diseases due to reduced bone density or cartilage loss and uses thereof |
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JP (1) | JP7431419B2 (en) |
CN (1) | CN113056259A (en) |
TW (1) | TWI729562B (en) |
WO (1) | WO2020102323A1 (en) |
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US8658203B2 (en) * | 2004-05-03 | 2014-02-25 | Merrimack Pharmaceuticals, Inc. | Liposomes useful for drug delivery to the brain |
CN104188952A (en) | 2005-03-02 | 2014-12-10 | 默沙东公司 | Composition for inhibition of cathepsin k |
CN101199505B (en) * | 2007-12-20 | 2012-05-23 | 沈阳药科大学 | Verapamil liposome and preparing method thereof |
EP2630953B1 (en) * | 2010-12-27 | 2017-08-09 | Terumo Kabushiki Kaisha | Liposome composition and process for production thereof |
CA2834968C (en) * | 2011-01-05 | 2018-01-09 | Livon Laboratories | Methods of making liposomes, liposome compositions made by the methods, and methods of using the same |
RU2571077C2 (en) | 2011-03-25 | 2015-12-20 | Терумо Кабусики Кайся | Long-acting controlled release liposomal composition and method for producing it |
EP2537532A1 (en) | 2011-06-22 | 2012-12-26 | J. Stefan Institute | Cathepsin-binding compounds bound to a nanodevice and their diagnostic and therapeutic use |
EP2734500A4 (en) * | 2011-07-20 | 2015-04-08 | Gen Hospital Corp | Histone deacetylase 6 selective inhibitors for the treatment of bone disease |
CN102406606B (en) * | 2011-11-29 | 2013-01-23 | 海南美大制药有限公司 | Solid quetiapine fumarate liposome preparation |
US9789062B2 (en) * | 2012-07-05 | 2017-10-17 | Tlc Biopharmaceuticals, Inc. | Methods of treating arthritis |
SI3922241T1 (en) * | 2013-02-01 | 2024-03-29 | Celator Pharmaceuticals, Inc. | Remote loading of sparingly water-soluble drugs into liposomes |
RU2020127879A (en) * | 2015-10-16 | 2021-11-02 | Ипсен Биофарм Лтд. | STABILIZING PHARMACEUTICAL COMPOSITIONS OF CAMPTOTHETECIN |
CN115837006A (en) * | 2016-05-06 | 2023-03-24 | 布里格姆及妇女医院股份有限公司 | Binary self-assembling gels for controlled delivery of encapsulated agents into cartilage |
EP3826615A4 (en) * | 2018-07-24 | 2022-05-04 | Taiwan Liposome Company, Ltd. | Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating dementia and uses thereof |
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- 2019-11-13 CN CN201980074616.4A patent/CN113056259A/en active Pending
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- 2019-11-13 EP EP19884612.3A patent/EP3880176A4/en active Pending
- 2019-11-13 JP JP2021525745A patent/JP7431419B2/en active Active
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WO2020102323A1 (en) | 2020-05-22 |
TWI729562B (en) | 2021-06-01 |
JP7431419B2 (en) | 2024-02-15 |
TW202031247A (en) | 2020-09-01 |
EP3880176A4 (en) | 2022-08-03 |
JP2023510658A (en) | 2023-03-15 |
CN113056259A (en) | 2021-06-29 |
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