CN113056259A - Sustained release pharmaceutical composition comprising therapeutic agent for treating diseases caused by decreased bone density or cartilage loss and use thereof - Google Patents
Sustained release pharmaceutical composition comprising therapeutic agent for treating diseases caused by decreased bone density or cartilage loss and use thereof Download PDFInfo
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- CN113056259A CN113056259A CN201980074616.4A CN201980074616A CN113056259A CN 113056259 A CN113056259 A CN 113056259A CN 201980074616 A CN201980074616 A CN 201980074616A CN 113056259 A CN113056259 A CN 113056259A
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- pharmaceutical composition
- therapeutic agent
- bone density
- lipid
- cartilage loss
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Abstract
The invention relates to a pharmaceutical composition with high drug lipid ratio and high embedding efficiency, which comprises at least one liposome and a therapeutic agent for treating diseases caused by reduction of bone density or cartilage loss. The pharmaceutical composition improves the pharmacokinetic profile and maintains the release of the therapeutic agent. The present invention also provides methods of using the pharmaceutical compositions disclosed herein for treating diseases caused by decreased bone density or cartilage loss.
Description
The present application claims the benefit of U.S. patent application No. 62/767,254 filed on 11/14/2018, which is incorporated herein by reference in its entirety.
Technical Field
The present invention is directed to a sustained-release pharmaceutical composition for treating diseases caused by decreased bone density or cartilage loss using at least one trapping agent and having a high drug to lipid ratio (drug to lipid ratio) and high encapsulation efficiency (encapsulation efficiency). The high drug-to-lipid ratio, high encapsulation efficiency and sustained release profile of the pharmaceutical composition reduces the frequency of administration, increases patient compliance and improves therapeutic efficacy.
Background
Bone remodeling is a physiological process determined by sequential and coordinated interactions involving both osteoclasts and osteoblasts, as well as osteocytes, inflammatory cells, and mediators. The balance between osteoblast and osteoblast activity maintains bone constancy. Loss of function of osteoblasts increases bone resorption and contributes to a variety of bone and joint diseases, for example, osteoporosis, osteopetrosis, rheumatoid arthritis, osteoarthritis, bone cancer and Paget's disease.
Cathepsin K is a cysteine protease highly expressed in bone eroding cells and plays a key role in the degeneration of bone matrix composed of hydroxyapatite and proteins, particularly type I collagen. Cathepsin K is also implicated in type II collagen cleavage in human articular cartilage. Recent studies have shown that oral administration of cathepsin K inhibitors once or twice daily can prevent bone loss and cartilage degradation. It is therefore desirable to maintain therapeutic concentrations of cathepsin K inhibitors and minimize the frequency of dosing for the treatment of diseases caused by decreased bone density and cartilage loss.
Liposomes have been widely used in the development of sustained release formulations for a variety of drugs. Drug loading into liposomes can be achieved either passively (entrapment of the drug during liposome formation) or remotely (remotely)/actively (actively) (transmembrane pH-or ion-gradients are created during liposome formation and then the drug is loaded after liposome formation by the driving force due to the gradient) (U.S. patent nos. 5,192,549 and 5,939,096). Although the general method of drug loading into liposomes is well documented, only a very few therapeutic agents are loaded into liposomes with high encapsulation efficiency. Various factors can influence the Drug lipid ratio and the encapsulation efficiency of liposomal drugs, including but not limited to physical and chemical properties of the therapeutic agents, such as hydrophilicity/hydrophobicity characteristics, dissociation constants, solubility and partition coefficients, lipid composition, capture agents, reaction solvents and particle size (Proc Natl Acad Sci U S A.2014; 111(6): 2283-.
There remains an unmet need for sustained release formulations with high drug lipid ratios and high drug encapsulation efficiencies to reduce the frequency of administration of cathepsin K inhibitors and improve therapeutic efficacy. The present invention addresses this need, as well as other needs.
Disclosure of Invention
In one embodiment, provided is a sustained release pharmaceutical composition comprising (a) at least one liposome comprising a bilayer membrane comprising at least one lipid; (b) a capture agent; and (c) a therapeutic agent for treating a disease caused by decreased bone density or cartilage loss, wherein the molar ratio of therapeutic agent to lipid is equal to or greater than about 0.1.
According to another embodiment of the present invention, there is provided a method for treating a disease caused by decreased bone density or cartilage loss, the method comprising the step of administering to a subject in need thereof a pharmaceutical composition described herein.
Also provided is the use of a pharmaceutical composition as described herein in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disease caused by decreased bone density.
Further provided are medicaments comprising a therapeutically effective dose of a pharmaceutical composition described herein for the treatment of a disease caused by decreased bone density or cartilage loss.
The terms "invention", "the invention" and "the present invention" as used in this patent are intended to refer broadly to all the subject matter of this patent and the claims that follow. Statements containing these terms should be understood as not limiting the subject matter of the application described herein or as not limiting the meaning or scope of the following claims. Embodiments of the invention covered by this patent are defined by the following claims, not this summary. This summary is a high-level overview of various aspects of the invention and is directed to some concepts that are further described in the following paragraphs of embodiments. This summary is not intended to define key or essential features of the claimed subject matter, nor is it intended to be used as an aid in defining the scope of the claimed subject matter when used alone. The subject matter of the application should be understood by reference to the entire specification, any or all drawings, and appropriate portions of the claims.
A further understanding of the nature and advantages of the inventions herein may be realized by reference to the remaining portions of the specification and the attached drawings.
Brief Description of Drawings
FIG. 1 shows a line graph of plasma L-006235 concentration in rats after intraarticular injection of free L-006235 and L-006235 liposomes.
Detailed description of the preferred embodiments
As used above and throughout this disclosure, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
All numbers herein may be understood to be modified by the term "about". As used herein, the term "about" refers to a range of a particular value ± 10%.
As used herein, the term "effective amount" refers to a reduction in symptoms or signs of disease caused by bone resorption and decreased bone density, such as decreased/increased bone mass, subchondral hard bone or cartilage loss, arthritic joint pain or joint swelling. The terms "effective amount" and "therapeutically effective amount" are used interchangeably.
As used herein, the terms "treating", "treatment" or "treatment" include preventing (e.g., prophylactic), soothing (palliative) and methods of treatment (curative methods), uses or results. The terms "treatment" or "treatments" may also refer to compositions or medicaments. In the context of the present invention, treatment refers to a method of increasing bone density or reducing cartilage loss, thereby reducing or delaying the symptoms or signs of one or more diseases caused by decreased bone density or cartilage loss, or completely alleviating a disease caused by decreased bone density or cartilage loss. The aforementioned decrease in bone density or cartilage loss can be measured by techniques known in the art. The prior art recognized methods are useful for detecting diseases and their symptoms caused by decreased bone density or cartilage loss. This includes, but is not limited to, clinical examination, radiographic examination (e.g., bone mineral densitometer, X-ray contrast, dual-energy X-ray absorptiometry, magnetic resonance imaging, computed tomography, ultrasound and nuclear contrast), measurement of biomarkers in bodily fluids (e.g., serum, urine or synovial fluid) (e.g., detection of C-reactive protein, anti-cyclic citrullinated peptide, serum alkaline phosphatase, creatine kinase BB isoenzyme, tartrate-resistant phosphatase, matrix metalloproteinase-3, C-terminal peptide chain of type I collagen (telopeptide), C-terminal peptide chain of type II collagen, N-terminal peptide chain of type I collagen, N-terminal peptide chain of type IIA collagen, and serum hyaluronic acid), or biological specimen/histopathological assessment (e.g., cartilage and subchondral hard bone staining), and so on. For example, a subject is considered a treatment if the subject has at least a 1% increase in bone density as measured by a bone mineral densitometer, or the subject has about a 1% decrease in one or more symptoms of the disease caused by decreased bone density or lack of cartilage, as compared to the subject prior to treatment or as compared to the control group. Thus, the reduction may be about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any number reduced therebetween.
As used herein, the term "disease caused by decreased bone density or cartilage loss (disease to reduced bone defect or cartilage loss)" encompasses various types and subtypes of bone and joint diseases, and various known or unknown etiologies and causes caused by bone resorption or cartilage degradation, including but not limited to: osteoporosis, osteomyelitis, rheumatoid arthritis, osteoarthritis, bone cancer, bone fracture, and Paget's disease.
As used herein, the term "subject" may refer to a vertebrate that has or is at risk of developing a disease caused by decreased bone density or cartilage loss, or is considered to be in need of treatment to increase bone density and/or repair cartilage. The subject includes all warm blooded animals, such as mammals, such as primates, and more preferably humans. A non-human primate is also a subject. The term individual includes domesticated animals such as cats, dogs, etc., livestock (e.g., cows, horses, pigs, sheep, goats, etc.), and experimental animals (e.g., mice, rabbits, rats, gerbils, guinea pigs (guineapig), etc.). Accordingly, veterinary uses and pharmaceutical dosage forms are contemplated herein.
Liposomes
As used herein, the terms "liposome", "liposome" and related terms are characterized as a vesicle formed by one or more bilayer membranes, isolating an internal aqueous space (interior aqueous space) from an external medium. In certain embodiments, the internal aqueous space of the liposome is substantially free of neutral lipids, such as triglycerides (trigycerides), non-aqueous (non-aqueous) phases (oil phase), water-oil emulsions, or other mixtures containing a non-aqueous phase. Non-limiting examples of liposomes include Small Unilamellar Vesicles (SUV), Large Unilamellar Vesicles (LUV), and multilamellar vesicles (MLV) having mean diameters ranging from 50-500nm, 50-450nm, 50-400nm, 50-350nm, 50-300nm, 50-250nm, 50-200nm, 100-500nm, 100-450nm, 100-400nm, 100-350nm, 100-250nm, or 100-200 nm.
The bilayer membrane of liposomes is typically formed by at least one lipid, i.e., a synthetic or natural amphipathic molecule (amphpilicic molecules) comprising spatially separated hydrophobic and hydrophilic domains. Examples of lipids include, but are not limited to, double-chain lipids (diolipidic lipids) such as phospholipids (phospholipids), diglycerides (diglycerides), and diolipidic glycolipids (diolipidic lipids), mono-lipids such as sphingomyelin (sphingomyelin) and glycosphingolipids (glycolipidic), and combinations thereof. Examples of phospholipids according to the present invention include, but are not limited to, 1,2-dilauroyl-sn-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1-palmitoyl-2-stearoyl-glycero-3-phosphocholine (1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, PSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatylcholine, POPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (1, 2-dioleoyl-sn-glycero-3-phosphocholine, DSPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (1,2-dioleoyl 1-sn-glycero-3-phosphocholine, HSPC), Hydrogenated Soybean Phosphatidylcholine (HSPC), 1, 2-dimyristoyl-sn-glycero-3-phosphocholine- (1' -rac-glycerol) (sodium salt) (1, 2-dimyristoyl-sn-glycerol-3-phosphate- (1 '-rac-glycerol) (sodium salt), DMPG), 1, 2-dipalmitoyl-sn-glycerol-3-phosphate- (1' -rac-glycerol) (sodium salt) (1, 2-dipalmitoyl-sn-glycerol-3-phosphate- (1 '-rac-glycerol) (sodium salt), DPPG), 1-palmitoyl-2-stearoyl-sn-glycerol-3-phosphate- (1' -rac-glycerol) (sodium salt) (1-palmitoyl-2-stearoyl-sn-glycerol-3-phosphate- (1 '-rac-glycerol) (sodium salt), PSPG), 1, 2-distearoyl-sn-glycerol-3-phosphate- (1' -rac-glycerol) (sodium salt), PSPG) rac-glycerol) (sodium salt) (1, 2-dioleoyl-sn-glycerol-3-phosphate- (1 ' -rac-glycerol) (sodium salt), DSPG), 1, 2-dioleoyl-sn-glycerol-3-phosphate- (1 ' -rac-glycerol) (1, 2-dioleoyl-sn-glycerol-3-phosphate- (1 ' -rac-glycerol), DOPG), 1, 2-dimyristoyl-sn-glycerol-3-phosphate-L-serine (sodium salt) (1, 2-dimyristoyl-sn-glycerol-3-phosphate-L-serine (sodium salt), DMPS), 1, 2-dipalmitoyl-sn-glycerol-3-phosphate-L-serine (sodium salt) (1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (sodium salt), (DPPS), 1, 2-distearoyl-sn-glycerol-3-phospho-L-serine (sodium salt) (1,2-distearoyl-sn-glycero-3-phospho-L-serine (sodium salt), (DSPS), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (sodium salt) (1,2-dimyristoyl-sn-glycero-3-phospho (sodium salt), DMPA), 1, 2-dipalmitoyl-sn-glycerol-3-phosphate (sodium salt) (1, 2-dipalmitoyl-sn-glycerol-3-phosphate (sodium salt), DPPA), 1, 2-distearoyl-sn-glycerol-3-phosphate (sodium salt) (1, 2-distearoyl-sn-glycerol-3-phosphate (sodium salt), DSPA), 1, 2-dioleoyl-sn-glycerol-3-phosphate (sodium salt) (1, 2-dioleoyl-sn-glycerol-3-phosphate (sodium salt), DOPA), 1, 2-dipalmitoyl-sn-glycerol-3-phosphoethanolamine (1, 2-dipalmitoyl-sn-glycerol-3-phosphoethanolamine, DPPE), N- (carbonyl-methoxy-polyethylene glycol) -1, 2-dipalmitoyl-sn-glycerol-3-phosphoethanolamine (N- (carboxymenthyleneglycol) -1, 2-dipalmitoyl-sn-glycerol-3-phosphoethanolamine, PEG-DPPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphoethanolamine (1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphoethanolamine, POPE), 1, 2-distearoyl-sn-glycerol-3-phosphoethanolamine (1, 2-distearoyl-sn-glycerol-3-phosphoethanolamine, DSPE), N- (carbonyl-methoxypolyethylene glycol) -1, 2-distearoyl-sn-glycerol-3-phosphoethanolamine (N- (carboxymenthyleneglycol) -1, 2-distearoyl-sn-glycerol-3-phosphoethanolamine (PEG-DSPE), 1, 2-dioleoyl-sn-glycerol-3-phosphoethanolamine (1, 2-dioleoyl-sn-glycerol-3-phosphoethanolamine, DOPE), 1, 2-dipalmitoyl-sn-glycerol-3-phosphate- (1 ' -inositol) (ammonium salt) (1, 2-dipalmitoyl-sn-glycerol-3-phosphoinositide- (1 ' -myo-inositol) (DPPI), 1, 2-distearoyl-sn-glycerol-3-phosphoinositide (ammonium salt) (1, 2-distearoyl-sn-glycerol-3-phosphoinositide) (ammonium salt), 1, 2-distearoyl-sn-glycerol-3-phosphoinositide) (DSPI), 1, 2-distearoyl-sn-glycerol-3-phosphoinositide (1 ' -phosphoinositide) (ammonium salts) (1, 2-diolyl-sn-glycerol-3-phophato- (1' -myo-inositol) (ammonium salt), DOPI), cardiolipin (cardiolipin), L- α -phosphatidylcholine (EPC), and L- α -phosphatidylethanolamine (EPE). In some embodiments, the lipid is a lipid mixture of one or more of the foregoing lipids, or a mixture of one or more of the foregoing lipids with one or more lipids, a membrane stabilizer (membrane stabilizer), or an antioxidant, not listed.
In some embodiments, the mole percentage of lipid in the liposome bilayer membrane is equal to 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 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%).
In some embodiments, the lipid in the bilayer membrane is a mixture of a first lipid and a second lipid. In some embodiments, the first lipid is selected from the group consisting essentially of Phosphatidylcholine (PC), HSPC, DOPC, POPC, DSPC, DPPC, DMPC, PSPC, and combinations thereof, and the second lipid is selected from the group consisting essentially of phosphatidylethanolamine (phosphatidylethanolamine), phosphatidylglycerol (phosphatidylglycerol), PEG-DSPE, DPPG, DOPG, and combinations thereof. In another embodiment, the molar percentage of the first lipid in the bilayer membrane is equal to or less than about 79.9, 79.5, 79.1, 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, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30 or any value or range therebetween (e.g., about 30-79.9%, about 30-79.5%, about 30-79.1%, about 30-70%, about 35-65%, or about 40-60%), and the molar percentage of the second lipid in the bilayer membrane is equal to or greater than 0.1 or 0.5 at least about 25, 24, 23, or any value or range therebetween (e.g., about 0.1-25, 23, or any value or range therebetween) 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%).
The bilayer membrane of the liposome further comprises less than about 55 mole percent of a steroid, preferably cholesterol. In certain embodiments, 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%.
In an exemplary embodiment, the molar percentage of lipid and cholesterol in the bilayer membrane is about 45-80%: 20-55% or 50-75%: 25 to 50 percent. In another exemplary embodiment, the mole percentage of the first lipid, the second lipid, and the cholesterol in the bilayer membrane is about 30-79.9%: 0.1% -25%: 20-55% and 30-75%: 0.1-25%: 20-50% or 35-70%: 0.5-25% to 20-45%, and the first lipid is HSPC and the second lipid is DSPE-PEG 2000.
Distal loading
As used herein, the term "remote loading" is a drug loading method that involves a procedure to transport a therapeutic agent from an external medium across the bilayer membrane of the liposome to the internal aqueous space by polyatomic ion-gradient (polyatomic-gradient). These gradients are created by embedding at least one polyatomic ion as a trapping agent in the internal aqueous space of the liposome and displacing the external medium of the liposome with an additional medium having a lower concentration of polyatomic ions, such as pure water, sucrose solution (sucrose solution) or physiological saline, by known techniques such as column separation, dialysis or centrifugation. A polyatomic ionic gradient is created between the internal aqueous space of the liposome and the external medium to entrap the therapeutic agent in the internal aqueous space of the liposome. Exemplary polyatomic ions that act as traps include, but are not limited to, sulfate (sulfate), sulfite (sulfate), phosphate (phosphate), hydrogen phosphate (hydrogen phosphate), molybdate (molybdate), carbonate (carbonate), and nitrate (nitrate). Exemplary capture agents include, but are not limited to, ammonium sulfate (ammonium sulfate), ammonium phosphate (ammonium phosphate), ammonium molybdate (ammonium molybdate), ammonium sucrose octasulfate (ammonium sucrose octasulfate), triethylammonium sucrose octasulfate (ammonium sucrose octasulfate), and dextran sulfate (dextran sulfate), and combinations thereof.
In one embodiment, the concentration of triethylammonium sucrose octasulfate is from about 10 to about 200mM, from about 50 to about 150mM, or from about 60 to about 100 mM. In another embodiment, the concentration of ammonium sulfate is about 100 to about 600mM, about 150 to about 500mM, or about 200 to about 400 mM.
According to the present invention, the capture agent-embedded liposomes can be prepared by any known or later developed technique. For example, MLV liposomes can be formed directly by combining selected lipid compositions with a capture agent via hydrated lipid membranes (hydrated lipid films), spray dried powders, or lyophilized cakes (lyophilized cakes); MLV liposomes are sized into SUV liposomes and LUV liposomes by sonication (homogenization), microfluidization (microfluidization) or extrusion (extrusion).
Pharmaceutical composition
The present invention is directed to a sustained release pharmaceutical composition comprising: (a) at least one liposome comprising a bilayer membrane; (b) a capture agent; and (c) a therapeutic agent for treating a disease caused by decreased bone density or cartilage loss, wherein the bilayer membrane is comprised of at least one lipid and the molar ratio of the therapeutic agent to the lipid is greater than or equal to about 0.1.
In one embodiment, the sustained release pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, diluent, vehicle for the active ingredient, preservative, cryoprotectant, or a combination thereof. In one exemplary embodiment, the weight percent of the bilayer membrane is about 0.1-15%; the weight percent of the capture agent is about 0.1-12%; and about 75.0-99.9% by weight of pharmaceutically acceptable excipients such as sucrose, histidine (histidine), sodium chloride and ultrapure water, diluents, vehicles for active ingredients, preservatives, cryoprotectants or combinations thereof.
In a particular embodiment, the therapeutic agent for treating a disease caused by a cartilage defect having reduced bone density is a cathepsin K inhibitor. Non-limiting examples of cathepsin K inhibitors include balacati (basilicaib, C)23H33N5O2) Odacartib, C25H27F4N3O3S)、L-006235(C24H30N6O2S)、ONO-5334(C21H34N4O4S), MIV-711, and Racaniti (C)27H32N4O6S). In other embodiments, the therapeutic agent for treating a disease caused by decreased bone density or cartilage defects is non-water soluble or hydrophobic. The sustained release profile of the pharmaceutical composition extends the half-life, therapeutic concentration, and duration of action of a therapeutic agent for treating a disease caused by decreased bone density or cartilage defect, thereby maintaining the therapeutic effect of the therapeutic agent and reducing the frequency of administration.
In one aspect, the sustained release profile of the pharmaceutical composition is due to high drug encapsulation efficiency. The encapsulation efficiency of these pharmaceutical compositions is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.
In another aspect, the sustained release profile of the pharmaceutical composition is due to a higher therapeutic agent to lipid mole ratio. In an exemplary embodiment, the molar ratio of therapeutic agent to one or more lipids used to treat a disease caused by decreased bone density or cartilage loss is greater than or equal to about 0.1, optionally from greater than or equal to 0.1 to less than about 20, less than about 15, less than about 10, less than about 5, less than about 4, less than about 3, less than about 2, or less than about 1.5.
In yet another aspect, the half-life of a therapeutic agent used herein to treat a disease caused by reduced bone density or cartilage defect is extended at least 2 fold, at least 5 fold, at least 7.5 fold, at least 10 fold, or at least 20 fold as compared to the free therapeutic agent used to treat the disease caused by reduced bone density or cartilage defect.
The present invention also provides a method of treating a disease caused by decreased bone density or cartilage defect, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition described herein, thereby reducing the symptoms and/or signs of the disease caused by decreased bone density or cartilage defect in the subject in need thereof.
The pharmaceutical compositions are formulated for injection, for example, by the intra-articular (intraarticular), subcutaneous (subjuneous), sub-epidermal (subdermal), intradermal (intradermal), transdermal (transdermal), or intramuscular (intramuscular) routes. The pharmaceutical compositions are also formulated for transdermal patch administration.
The dosage of the pharmaceutical composition of the present invention can be determined by a person skilled in the art according to the examples. Single or multiple dose forms, each providing advantages in certain clinical settings, are contemplated. The actual amount of the pharmaceutical composition administered according to the present invention may depend on the age, weight, condition of the subject being treated, any medical conditions present, and on the judgment of the medical professional.
In one embodiment, the pharmaceutical composition of the present disclosure exhibits a significant extended release profile of a therapeutic agent for treating a disease caused by decreased bone density or cartilage defects. For example, the pharmaceutical composition of the present invention extends the half-life of L-006235 to 56.6 hours in rats, which is 16.6 times the half-life of L-006235 in rats via oral administration (3.4 hours) (J Med Chem 20051:48(24): 7520-34). These pharmaceutical compositions were developed to reduce the frequency of administration 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, once a week, once every two weeks, once every month, once every two months, once every three months, once every four months, once every five months, or once every six months.
Examples of the invention
Embodiments of the present invention are illustrated by the following examples, which should not be construed as imposing limitations upon the scope thereof in any way. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention. In the studies described in the examples below, conventional procedures will be followed, unless otherwise indicated.
Example 1: formulation for preparing L-006235 liposome
Empty liposomes were prepared by lipid film hydration-extrusion method. The bilayer membrane components, HSPC, cholesterol and DSPE-PEG2000 (mole percent 59.5/39.6/0.9), were dissolved in an organic solvent, for example: chloroform and dichloromethane. The organic solvent was removed by a rotary evaporator under vacuum to form a thin lipid film. The dried lipid film was hydrated with an aqueous solution containing 300mM ammonium sulfate at 60 ℃ for 30 minutes to form empty liposomes with an aqueous core (aquous core) entrapping ammonium sulfate. Other capture agents, such as triethylammonium sucrose octasulfate, may also be used. After five freeze-thaw cycles between liquid nitrogen and 60 ℃ water, the empty liposomes were then pressed 10 times through a polycarbonate filter with a pore size of 0.2 μm. The non-embedded capture agent is removed by dialysis (dialysis method) or diafiltration (diafiltration method) by displacement with 9.4% sucrose solution or 0.9% sodium chloride (NaCl) solution to create a polyatomic ion gradient between the empty liposome internal and external aqueous phases.
A mixture containing 3.0mg/mL of L-006235 (purchased from DC Chemicals, China), empty liposomes (containing 6.0mM lipid), and 50mM histidine buffer (pH 6.5) was reacted at 60 ℃ for 15 minutes. Non-embedded in the reaction mixtureL-006235 by SephadexTMG-50 fine gel (fine gel) (GE Healthcare) or dialysis bag (Spectrum Labs) were separated with 9.4% sucrose solution to obtain L-006235 liposome formulations. To calculate the drug-to-lipid mole ratio (D/L) in the L-006235 liposome formulation, the concentration of L-006235 entrapped in the L-006235 liposome formulation was measured by High Performance Liquid Chromatography (HPLC) and the concentration of lipid in the L-006235 liposome formulation was measured using ultraviolet/visible (UV/Vis) spectroscopy.
Encapsulation efficiency was calculated from the drug-to-lipid molar ratio (D/L) of the L-006235 liposome formulation compared to the nominal (nominal) D/L of the reaction mixture, which was obtained by dividing the concentration of L-006235 by the lipid concentration of the empty liposomes. The particle size distribution was measured by means of a dynamic light scattering instrument (Zetasizer Nano-ZS90, Malvern, USA).
Using 300mM ammonium sulfate as a capture agent, the final D/L of the L-006235 liposome formulation was 1.00, the encapsulation efficiency was 93.4%, and the mean particle size of the liposomes was 193.7 nm.
Example 2: preparation of various cathepsin K inhibitor liposome formulations
Cathepsin K inhibitors as used herein include L-006235 and barrecati (MedChem Express, usa). Empty liposomes were prepared according to example 1 and containing the following trapping agents: (1)300mM ammonium sulfate and (2)75mM triethylammonium sucrose octasulfate. The loading procedure for the L-006235 liposome formulation is based on example 1. The formulation of the palicati liposome was prepared as follows: a reaction mixture containing 2mg/mL of baccatin, empty liposomes and 50mM histidine buffer (pH 6.5) was reacted at 60 ℃ for 15 minutes. Via SephadexTMG-50 micelles (GE Healthcare) remove the unencapsulated drug to obtain the palicati liposome formulation. The D/L of the liposome formulation in this example was calculated according to the procedure of example 1. Table 1 presents the loading curves of L-006235 and Balika.
TABLE 1 Loading curves for different cathepsin K inhibitors
EE, embedding efficiency; n.d., not measured.
Example 3: pharmacokinetic (PK) study of L-006235 Liposome formulations
In vivo PK assessments of L-006235 liposome formulations were performed using seven to eight week female SD (Sprague-Dawley) rats. Rats were housed in a captive chamber (holing room) operated on a 12 hour light/12 hour dark diurnal cycle with no restriction on water and food intake.
Rats were divided into two groups (n-4 per group). The rats of the first group received an intra-articular injection of 2.5mg/kg free L-006235 prepared as L-00623 in 9.4% sucrose solution containing 0.06N hydrochloric acid (HCl) to a final concentration of 10.0mg/mL, while each rat of the second group received an intra-articular injection of 5.0mg/kg L-006235 liposome formulation prepared according to example 1 to a final concentration of 18.1 mg/mL. Blood samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, and 168 hours post-injection. Plasma samples were taken by centrifugation and analyzed using a liquid chromatography-tandem mass spectrometer. Plasma concentration versus time curves were analyzed using the non-compartmental model analysis module in PKSolver (comprehensive Methods Programs biomed. 2010; 99(3): 306-314). The PK parameters for the two L-006235 formulations are summarized in Table 2.
Table 2 shows dose normalization C for L-006235 liposome formulationsmax(Cmaxthe/D) is 40.5% of the free L-006235 formulation, and the half-life (t) of the L-006235 liposome formulation1/2) (56.6 hours) was significantly longer than the free L-006235 formulation (4.5 hours). AUC compared to free L-006235 formulation0-tDose normalized area under the Curve (AUC) for the L-006235 liposomal formulation (which indicates 100% of L-006235 released 24 hours post injection)0-t/D) indicated that 89.7% of L-006235 was released from the L-006235 liposome formulation 168 hours after injection.
TABLE 2 PK parameters derived after single intra-articular injection of free L-006235 formulation or L-006235 liposome formulation in rats
CmaxD, dose-normalized Cmax;AUC0-tDose normalized AUC0-t;AUC0-infDose normalized AUC0-inf。
In addition, FIG. 1 shows that no L-006235 could be detected in plasma 24 hours after injection of free L-006235, whereas L-006235 could still be detected in plasma 168 hours after administration of the L-006235 liposome formulation of the present invention. The results show that the pharmaceutical composition of the present invention can slowly release the cathepsin K inhibitor.
Claims (15)
1. A pharmaceutical composition comprising:
(a) at least one liposome comprising a bilayer membrane, wherein the bilayer membrane comprises at least one lipid;
(b) a capture agent; and
(c) a therapeutic agent for treating a disease caused by bone density or cartilage defect,
wherein the molar ratio of the therapeutic agent to the lipid is equal to or greater than about 0.1.
2. The pharmaceutical composition of claim 1, wherein the liposome has an average particle size of from about 50nm to 500 nm.
3. The pharmaceutical composition of claim 1, wherein the bilayer membrane further comprises cholesterol.
4. The pharmaceutical composition of claim 3, wherein the molar percentage of cholesterol in the bilayer membrane is about 20 to about 55%.
5. The pharmaceutical composition of claim 1, wherein the capture agent is selected from the group consisting of triethylammonium sucrose octasulfate (triethylammonium sulfate), ammonium sulfate (ammonium sulfate), and combinations thereof.
6. The pharmaceutical composition of claim 5, wherein the sucrose octasulfate triethylammonium concentration is about 10 to 200 mM.
7. The pharmaceutical composition of claim 5, wherein the concentration of ammonium sulfate is about 100 to 600 mM.
8. The pharmaceutical composition of claim 1, wherein the therapeutic agent for treating a disease caused by decreased bone density or cartilage loss is a cathepsin K inhibitor.
9. The pharmaceutical composition of claim 1, wherein the therapeutic agent for treating a disease caused by decreased bone density or cartilage loss is selected from the group consisting essentially of balacatib (balcatib), odanacatinib (odanacatinb), L-006235, ONO-5334, MIV-711, reiacartib (relacartib), and combinations thereof.
10. The pharmaceutical composition of claim 1, wherein the therapeutic agent for treating a disease caused by decreased bone density or cartilage loss is embedded in liposomes with an embedding efficiency of greater than about 50%.
11. A method of treating a disease caused by decreased bone density or cartilage loss comprising administering to a subject in need thereof a pharmaceutical composition comprising:
(a) at least one liposome comprising a bilayer membrane, wherein the bilayer membrane comprises at least one lipid;
(b) a capture agent; and
(c) therapeutic agents for the treatment of bone and joint diseases,
wherein the molar ratio of the therapeutic agent to the lipid is equal to or greater than about 0.1.
12. The method of claim 11, wherein the half-life of the therapeutic agent for treating a disease caused by decreased bone density or cartilage loss is extended at least 2-fold, at least 5-fold, at least 7.5-fold, at least 10-fold, or at least 20-fold compared to the half-life of the therapeutic agent free for treating a disease caused by decreased bone density or cartilage loss.
13. The method of claim 11, wherein the pharmaceutical composition is administered at least once every three days, at least once a week, at least once every two weeks, or at least once a month.
14. The method of claim 11, wherein the pharmaceutical composition is administered by injection.
15. The method of claim 14, wherein the injection comprises an intra-articular (intraarticular), subcutaneous (subnuttaneouslly), sub-epidermal (subdermal), intradermal (intradermal), or intramuscular (intramuscular) route.
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TWI729562B (en) | 2021-06-01 |
TW202031247A (en) | 2020-09-01 |
WO2020102323A1 (en) | 2020-05-22 |
EP3880176A1 (en) | 2021-09-22 |
JP2023510658A (en) | 2023-03-15 |
EP3880176A4 (en) | 2022-08-03 |
JP7431419B2 (en) | 2024-02-15 |
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