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    • 专利摘要:
    OPHTHALIMIC DRUG RELEASE SYSTEM CONTAINING PHOSPHOLIPIDE AND CHOLESTEROL An ophthalmic drug release system containing phospholipid and cholesterol to prolong the life of the drug in the eyes is disclosed.
    公开号:BR112012002981B1
    申请号:R112012002981-9
    申请日:2010-01-29
    公开日:2020-12-01
    发明作者:Po- Chun Chang；Luke S. Guo；Keelung Hong；Sheue-Fang Shih；Yun-Long Tsen
    申请人:Taiwan Liposome Co. Ltd；
    IPC主号:
    专利说明:

    CROSS REFERENCE TO RELATED ORDER
    [001] This order claims the priority of the US Order. No. 12 / 538,435, filed on August 10, 2009. The contents of the application are fully incorporated as a reference in this report. BACKGROUND OF THE INVENTION
    [002] As the eyes are organs involved with slow blood circulation, most therapeutic agents cannot reach them in effective amounts when administered systemically.
    [003] To solve this problem, intravitreal injection was adopted for the ophthalmic release of therapeutic agents, particularly in the posterior extremities of the eyes (for example, retina and choroid). As a therapeutic agent typically remains in the eyes for a limited period, repetitive intravitreal injections are necessary to achieve the intended therapeutic effect. However, frequent administration using this invasive method is highly undesirable.
    [004] There is a need for a drug delivery system that prolongs the life of a therapeutic agent in the eyes, in order to reduce the times of intravitreal injection required in a treatment. SUMMARY OF THE INVENTION
    [005] The present invention is based on an unexpected discovery that a drug delivery system containing phospholipid and cholesterol significantly prolongs the lifespan of Avastin (an antibody specific for vascular endothelial growth factor) in the eyes.
    [006] Consequently, one aspect of this invention relates to a drug delivery system containing a therapeutic agent (e.g., protein, nucleic acid or small molecule) and a delivery vehicle that includes phospholipid and cholesterol. The percentage in moI of cholesterol in the delivery vehicle (for example, in lyophilized form) can be 5 to 40% (for example, 10 to 33% or 20 to 25%). The delivery vehicle and the therapeutic agent can be mixed or separated.
    [007] In the drug delivery system of this invention, 50 to 90% of the therapeutic agent is in unassociated form and the weight ratio of phospholipid and cholesterol in combination with the therapeutic agent is 5 to 80 to 1. In one example, the therapeutic agent is an antibody against vascular endothelial growth factor (VEGF) and 60 to 90% of the antibody is in the unassociated form and the weight ratio of phospholipid and cholesterol in combination with the antibody is 5 to 40 to 1. In another example, the therapeutic agent is an anti-inflammatory molecule (for example, a corticosteroid).
    [008] The phospholipid in the release vehicle described in this report can be a mixture of two phospholipids. For example, phospholipid can be one of 2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), soy phosphatidylcholine (SPC) or egg phosphatidylcholine (EPC) mixed with distearoylphosphatidylethanolamine-polyethylene glycol (PEG-DSPE) or diolelfosfatidylglycerol (DOPG). When phospholipid is a mixture of DOPC and DOPG, the mol% of the former can be 29.5 to 90% (for example, 50 to 80%) and the mol% of the latter can be 3 to 37.5% (for example, 3 to 18.75%). In one example, the delivery vehicle contains DOPC, DOPG and cholesterol in a mol% ratio of 56.25 to 72.5: 7.5 to 18.75: 20 to 25.
    [009] Another aspect of this invention relates to a method of delivering a therapeutic agent to a patient's eye. This method includes (i) providing the drug delivery system described above, which may be in the form of an aqueous suspension, and (ii) administering it to an eye of a patient in need, for example, through intravitreal injection. The delivery system can be prepared by mixing phospholipid, cholesterol and one or more therapeutic agents to form a mixture; lyophilization of the mixture; and, prior to administration, suspending the mixture in an aqueous solution to form the aqueous suspension. Alternatively, it is prepared by mixing phospholipid and cholesterol to form a mixture; lyophilization of the mixture; and, prior to administration, suspending the mixture together with one or more therapeutic agents in an aqueous solution to form the aqueous suspension.
    [0010] Furthermore, within the scope of this invention, the use of the delivery vehicle described above in the release of an ophthalmically therapeutic agent and in the preparation of a drug to treat an ophthalmic disease is disclosed.
    [0011] Details of one or more embodiments of the invention are presented in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of various embodiments and also from the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS
    [0012] The drawings are first described.
    [0013] Fig. 1 is a graph showing Avastin vitreous concentrations on days 7, 21, 28, 35, 41 and 49 after intravitreal injection. The TLC release vehicle refers to a release vehicle containing DOPC / Cholesterol / DOPG in a ratio of 67.5 / 25 / 7.5. “*” And “**” refer to the points in time, where the eyes of 1 and 2 rabbits were examined, respectively. The eyes of 4 rabbits were examined at the other points in time.
    [0014] Fig. 2 is a graph showing Avastin glass concentrations on days 7, 28, 49, 70, 91 and 112 after intravitreal injection. The TLC release vehicle refers to a release vehicle containing DOPC / Cholesterol / DOPG in a ratio of 67.5 / 25 / 7.5. “**” and “***” refer to the points in time, in which the eyes of 2 and 3 rabbits were examined, respectively. The eyes of 4 rabbits were examined at other points in time.
    [0015] Fig. 3 is a graph showing the glassy dexamethasone phosphate (DSP) concentrations at 2 h, 1 d, 4 d, 8 d, 15 d and 35 d after intravitreal injection. The TLC release vehicle refers to a release vehicle containing DOPC / Cholesterol / DOPG in a ratio of 67.5 / 25 / 7.5. DETAILED DESCRIPTION OF THE INVENTION
    [0016] An advantageous drug delivery system for the ophthalmic administration of at least one therapeutic agent that, on release, exhibits a prolonged life in the eyes, particularly in the vitreous, is described in this report. Release Vehicle
    [0017] This drug delivery system described in this report includes a delivery vehicle containing phospholipid and cholesterol. The phospholipid can be a population homologous to a phospholipid, preferably a neutral phospholipid, or a mixture of different types of phospholipids. Examples of phospholipid for preparing the delivery vehicle include, but are not limited to, phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol (P1), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylethanolamine (EPE), egg phosphatidylserine (EPS), egg phosphatidic acid (EPA), egg phosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soy phosphatidylcholine soy phosphatidylglycerol (SPG), soy phosphatidylethanolamine (SPE), soy phosphatidyl serine (SPS), soy phosphatidic acid (SPA), soy phosphatidylinositol (SPI), dipalmitoylphosphatidylcholine (DPPC), 1,2-glycerol-snole -3-phosphatidylcholine (DOPC), dimiristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycerol (DPPG), dioleylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), dihydrophilic (PH), hexadecyl roilfosfatidilglicerol (DSPG), dioleoyl phosphatidylethanolamine (DOPE), palmitoilestearoilfosfatidilcolina (PSPC), palmitoilestearoilfosfatidilglicerol (PSPG), mono-oleoilfosfatidiletanolamina (MOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), diestearoilfosfatidiletanolaminapolietilenoglicol (PEG-DSPE) , dipalmitoylphosphatidylserine (DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dipalmitoylphosphalic acid-glycolic acid (DPPA), 3-phosphatidic (DOPA), dimiristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidylinositol (DPPI), 1,2-dioleoyl-sn-glycero-3-phosphatidylinositol (DOPI), dimirisylsulphylate and a mixture of them.
    [0018] In one example, the delivery vehicle is free of fatty acid (ie, carboxylic acid with a long unbranched aliphatic tail), cationic lipid (ie, lipid carrying a positive net charge at physiological pH); and mucoadhesive polymer (for example, Carbopol 934 P, polyoxymer, carbomer and plant lectin).
    [0019] The delivery vehicle can be prepared by methods known in the pharmaceutical industry. An example follows. Phospholipid, cholesterol and other components are suspended in distilled water or an aqueous solution to form a suspension. The suspension is then subjected to homogenization by conventional methods, for example, sonication, agitation or extrusion. After being sterilized, the suspension of homogenized vehicle can be aseptically placed in a container and then lyophilized to form a powder. Therapeutic Agent
    [0020] Any therapeutic agents (e.g., small molecule, protein, peptide or nucleic acid) to treat an ophthalmic disease can be mixed with the delivery vehicle described above and administered to a patient's eye. In one example, the therapeutic agent is an anti-inflammatory drug, such as a corticosteroid compound. The term “corticosteroid compound” refers to naturally occurring steroid hormones (including glucocorticoids) and their derivatives, which are preferably water-soluble. Examples of corticosteroids include, but are not limited to, cortisone, hydrocortisone, hydrocortisone acetate, tixocortol pívalate, flucinolone, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone, acetone, ammononide, fluoride, budside, mononide, fluocinolone, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone17-valerate, aclomethasone dipropionate, betamethasone dihydrate, betamethasone dihydrate, betamethasone dihydrate clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate. In another example, the agent is a VEGF antagonist, which may be a VEGF specific antibody, a soluble VEGF receptor, a nucleic acid that binds to VEGF, or a small molecule that interferes with the interaction between VEGF and its receptor cognate and blocks the VEGF signaling pathway. The term “antibody” used in this report refers to a naturally occurring immunoglobulin, a functional fragment of it, such as Fab, Fab ', F (ab) 2 or F (ab') 2, or a genetically modified immunoglobulin, such as such as humanized antibody, chimeric antibody, diabody and single chain antibody. Drug Delivery System
    [0021] The drug delivery system of this invention includes the delivery vehicle described above and one or more therapeutic agents also described above. It may contain a vehicle-drug mixture in lyophilized form. In one example, the mixture is prepared by suspending all vehicle components in water or an aqueous solution to form a suspension, homogenizing the suspension, mixing the suspension homogenized with one or more therapeutic agents to form a mixture, and finally lyophilization of the mixture. In another example, the mixture is prepared by suspending all components of the vehicle and one or more therapeutic agents in water or an aqueous solution to form a suspension and then lyophilizing the suspension to form a lyophilized mixture, a cryoprotectant (eg mannitol, sucrose, trehalose and lactose) can be added to the vehicle-drug suspension during lyophilization. When mannitol is used, the preferred concentration range is 0.5 to 5% (for example, 0.5 to 2% or 1%). Before administration, the lyophilized vehicle-drug mixture is resuspended in an aqueous solution, which can then be released to a patient's eye.
    [0022] In this drug delivery system, 50 to 90% of the therapeutic agent are in the non-associated form. The term "therapeutic agent in unassociated form" refers to therapeutic molecules separable by means of gel filtration from the phospholipid / cholesterol fraction of the delivery system. The percentage of the non-associated therapeutic agent is determined, following the method described in Example 7 below.
    [0023] Optionally, the drug delivery system of this invention may further include a pharmaceutically acceptable carrier, that is, a carrier compatible with the therapeutic agent in the system, and preferably capable of stabilizing the therapeutic agent and not harmful to the patient at to be treated.
    [0024] The drug delivery system described above can be administered to a patient's eye, for example, through intravitreal injection, to treat ophthalmic diseases.
    [0025] Without further elaboration, it is believed that a person skilled in the art, based on the description above, can use the present invention in its full form. Therefore, the following specific modalities should be interpreted as merely illustrative and not limiting disclosure. All publications cited in this report are incorporated by reference.
    [0026] Example 1: Preparation of Compositions Containing Phospholipid-Cholesterol for Drug Release in the Eyes
    [0027] The phospholipids DOPC and DOPG were mixed with cholesterol in several molar ratios (ie 67.5: 7.5: 25, 72: 8: 20 and 56.25: 18.75: 25) to form mixtures of lipid, The mixtures were suspended in chloroform and dried under vacuum on a rotary evaporator. Each of the dry mixtures was resuspended in deionized H20, homogenized by a horn-shaped sonicator (Misonix Sonicator 3000), and then sterilized using a sterile filter. The sterile lipid mixtures were aseptically introduced into vials, mixed with 1% mannitol and then lyophilized. The total concentration of phospholipids in each of the lyophilized mixtures was determined by a phosphorus test. Prior to release to the eyes, a suitable amount of a lipid mixture mentioned above was mixed with a suitable amount of Avastin and suspended in an aqueous solution to form an aqueous suspension.
    [0028] Example 2: Use of Release Vehicles Containing DOPC / PEG-DSPE / Cholesterol to Release Avastin to the Eyes
    [0029] Release vehicles containing DOPC, PEG-DSPE and cholesterol in various molar ratios were prepared, following the method described in Example 1 above. Each of these release vehicles was mixed with an adequate amount of Avastin to form aqueous suspensions.
    [0030] The effect of the aforementioned release vehicles on extending the life of Avastin in the eyes was examined, following the method described in Bakri et al, Ophthalmology, 2007, 114: 5, 855-859. Briefly, New Zealand white rabbits were sedated by intramuscular injection of a mixture containing Zoletil (15 mg / ml) and Rompun (7 mg / ml). The eyes of each rabbit were injected intravitreally with 50 pl of Avastin (25 mg / ml) or one of the aqueous suspensions mentioned above (at a dose of 1.25 mg Avastin per eye) using a 30 gauge needle. The rabbits were sacrificed on the 7th or 21st after the injection and their eyes were immediately enucleated. The vitreous humor was isolated from each eye along with the retina and the Avastin concentration was determined by ELISA, as follows. A NUNC-IMMUNO F96 MaxisorpTM plate was coated with VEGF (10 pg / ml in PBS, pH 7.4; 100 pl / well) at 4 ° C overnight. The VEGF-coated plate was washed with PBS and then blocked with a blocking buffer (5% skimmed milk in PBS) at room temperature for 1 hour. The vitreous / retina humor samples mentioned above were diluted in the same blocking buffer and the resulting diluents were added to the VEGF-coated plate at 100 µl / well. After being incubated at room temperature for 1 hour, the plate was washed with 0.1% Tween-20 and 0.5% skimmed milk in PBS 5 times and with PBS 5 more times. HRP-labeled goat anti-human IgG (Jackson lmmunoResearch Lab. lnc.), diluted in the blocking buffer, was then added to the plate. After being incubated at room temperature for 30 minutes, the plate was washed extensively. A reagent containing tetramethyl benzidine was then added to the plate for color development. After a sufficient period, the reaction was completed by adding 2 N HCl to each 50 µl well. The absorbance at 450 nm (OD450) of each well was determined by an ELISA reader. Various predetermined Avastin concentrations (3.125 to 25 ng / ml) were used to establish a standard Avastin OD450 concentration / curve. The Avastin concentration in each sample was determined based on its OD450 value, in view of the standard curve.
    [0031] The results obtained from this study are shown in Table 1 below: Table 1 Avastin Concentrations Released by Vehicles Containing DOPC / PEGDSPE / Cholesterol in Various Molar Ratios Seven Days After Intravitreal Injection
    * figures in parentheses refer to the mol% of phospholipids and cholesterol
    [0032] As shown in Table 1 above, Avastin remained in the eye for a longer period of time when coliberized with vehicles containing DOPC / PEG DSPE / cholesterol, as compared to Avastin released alone. The results also indicate that cholesterol is essential to the effect of the delivery vehicle in prolonging the life of Avastin in the eyes and the molar percentage of PEG-DSPE does not affect this effect.
    [0033] Example 3: Use of Release Vehicles Containing Various Phospholipids to Extend Avastin Eye Life
    [0034] Delivery vehicles containing various phospholipids and cholesterol in different molar ratios were prepared, following the method described in Example 1 above. The vehicles were mixed with Avastin and the resulting mixtures were intravitreally injected into the eyes of New Zealand rabbits. 7 or 21 days after the injection, the concentrations of Avastin in the eyes of the rabbits were examined, following the method described in Example 2 above.
    [0035] The results obtained are shown in Tables 2 and 3 below: Table 2. Concentrations of Avastin Released by Vehicles Containing Different Phospholipids and Cholesterol Seven Days After Intravitreal Injection
    * figures in parentheses refer to the mole percentages of phospholipids and cholesterolTable 3. Avastin concentrations released by vehicles containing different cholesterol and phospholipids twenty-one days after intravitreal injection
    * figures in parentheses refer to percentages in moles of phospholipids and cholesterol
    [0036] Example 4: Use of Release Vehicles Containing Anionic Phospholipids to Extend Avastin Eye Life
    [0037] Release vehicles containing DOPG, an anionic phospholipid, PEG-DSPE or DOPC, with or without cholesterol, were prepared, following the method described in Example 1 above. These vehicles were mixed with Avastin and the resulting mixtures were intravitreally injected into the eyes of New Zealand rabbits. 7 or 21 days after injection, Avastin concentrations in the eyes of the rabbits were examined, following the method described in Example 2 above.
    [0038] As shown in Table 4 below, the release vehicle containing the anionic phospholipid DOPG led to an increased Avastin concentration 7 days after injection, as compared to the release vehicle that does not contain DOPG. Table 4. Avastin Glass Concentration Released by Vehicles Containing Anionic Phospholipids Seven Days After Injection
    * Numbers in parentheses refer to percentages in moI of phospholipids
    [0039] The results obtained from this study also indicate that the delivery vehicles containing cholesterol and DOPG dramatically increased the concentration of glassy Avastin 21 days after the injection. See Table 5 below. Table 5. Avastin Vitreous Concentration Released by Vehicles Containing Anionic Phospholipids and Cholesterol 21 Days After Injection

    [0040] Example 5: Use of Release Vehicles Containing Cholesterol in Various Anion Percents in Moles to Extend Avastin Eye Life
    [0041] The release vehicles containing cholesterol in various mole percentages, DOPC and DOPG, were prepared, following the method described in Example 1 above. These vehicles were mixed with Avastin and the resulting mixtures were intravitreally injected into the eyes of New Zealand rabbits. 21 days after injection, Avastin concentrations in the eyes of the rabbits were examined, following the method described in Example 2 above. The results obtained from this study are shown in Table 6 below: Table 6. Avastin Glass Concentration Released by Vehicles Containing Cholesterol 21 days after injection

    [0042] Example 6: Pharmacokinetic Properties of Avastin Released to the Vitreous through Vehicles Containing Phospholipid and Cholesterol
    [0043] The rabbits were intravitreally injected with Avastin alone (control rabbits) or Avastin mixed with a release vehicle containing DOPC / Cholesterol / DOPG in a ratio of 67.5 / 25 / 7.5 (test rabbits). The glassy Avastin concentrations of the control rabbits were examined by ELISA on days 7, 21 and 28 post-injection and those of the test rabbits were examined on days 7, 21, 28, 35, 41 and 49 post-injection.
    [0044] The glass concentration of Avastin injected alone decreased very quickly over time compared to that of Avastin injected with the release vehicle. See Fig. 1. This result demonstrates that the release vehicle prolongs the life of Avastin in the eyes.
    [0045] In a similar study, Avastin glass concentrations were monitored 7, 28, 49, 70, 91 and 112 days post intravitreal injection. For control rabbits, the Avastin vitreous concentration was 13 pg / ml 28 days after injection, while for test rabbits, the Avastin vitreous concentration at the same point in time was 265 pg / ml, 20 times higher than that the rabbits control. See Fig. 2. Avastin intravitreal half-life in control rabbits is 3.9 days. In contrast, the intravitreal Avastin half-life in test rabbits exhibits a 2-compartment characteristic with the initial and terminal half-lives being 5.5 (ti / 2a) and 40.5 (ti / 2e) days, respectively . Avastin's AUC (ie area under the curve) from day 7 to infinity (AUC ~ Oo) in test rabbits is 6.8 times greater than that of control rabbits and AUC (112 ~ 00) ) of Avastin in the test rabbits is 1.1 times greater than the AUC (7 ~ oo) of Avastin in the control rabbits. See Table 7 below.Table 7. Pharmacokinetic Properties of Avastin Vitreous

    t1 / 2: half-life; t y2 a: initial half-life; + ti / 2B terminal half-life; ++ AUC (7-112) area under the curve from day 7 to day 112, ± AUC (ii2 ~ 00) area under the curve from day ii2 to infinity, ±> AUC (7 ~ 00) area under the curve from day 7 to infinity.
    [0046] In summary, the results discussed above demonstrate that the delivery vehicle significantly prolongs the life of Avastin in the eyes.
    [0047] Example 7: Preparation of Compositions to Release Various Therapeutic Agents
    [0048] DOPC, DOPG and cholesterol in a weight ratio of 8.8 / i / i, 6 were dissolved in chloroform, which was then evaporated under vacuum using a rotary evaporator. The dry mixture of phospholipids and cholesterol produced was suspended in deionized water to form an aqueous suspension. The suspension was then homogenized by sonication using a horn-shaped sonicator (Misonix i Sonicator 3000), sterilized by filtration, aseptically introduced into a vial and lyophilized to form a delivery vehicle containing phospholipid-cholesterol. The phospholipid concentration in the vehicle was determined by a conventional phosphorus assay to ensure an appropriate total amount of phospholipids in the vehicle.
    [0049] The delivery vehicle was then mixed with various therapeutic agents, i.e., tryptophan (i0 mg / ml), tyrosine (i0.4 mg / ml), HFRRHLC peptide (i0 mg / ml), HWRGWVC peptide (i0 mg / ml), protein W (i3 mg / ml), bovine serum albumin (50 mg / ml), Avastin (25 mg / ml) and dexamethasone sodium phosphate (6.7 mg / ml), all dissolved in phosphate buffer 50 mM, pH 6.2. The formed mixtures were diluted 18 to 100 times in the same phosphate buffer and an aliquot of each mixture (50 to 200 ml) was subjected to gel filtration to determine the percentage of the therapeutic agent that was presented in the non-associated form. Soon, an aliquot of a mixture was loaded onto a Sepharose 4B column (diameter: 1.8 mm: length: 315 mm). The components in the mixture were then eluted by 50 mM phosphate buffer (pH 6.2). Fractions containing the therapeutic agent in a different form, that is, a form not associated or associated with phospholipids, were collected, their absorbance being measured at 215 nm and 254 nm. The amount of the therapeutic agent in each fraction was determined based on the values of OD215 and OD254. Based on these values, the percentages of the non-associated therapeutic agents and the lipid weight ratios for drugs were determined and shown in Table 8 below. Table 8. Percentages of Unassociated Drug Agents and Lipid Weight Ratio for Drugs

    [0050] Example 8: Pharmacokinetic Properties of Dexamethasone Sodium Phosphate Released to the Vitreous by Vehicles Containing Phospholipid and Cholesterol
    [0051] The rabbits were intravitreally injected with dexamethasone sodium phosphate (DSP) alone (control rabbits) or DSP mixed with a release vehicle containing DOPC / Cholesterol / DOPG in a ratio of 67.5 / 25 / 7.5 (rabbits) of test). The eyes of each rabbit were injected intravitreally with 50 | j | of DSP or the DSP-release vehicle mixture in a DSP dose of 0.2 mg. The glassy DSP concentrations of the control rabbits were examined by high performance liquid chromatography (ACQUITY UPLCTM) with a photodiode array detector (PDA) at 2 h, 1 d, 4 d, 8 d and 15 d after injection and those of the Test rabbits were examined at 2 h, 1 d, 4 d, 8 d, 15 and 35 d post-injection. Both eyes were examined for each point in time.
    [0052] As shown in Fig. 3, the glass concentration of injected DSP alone decreased very quickly after the injection; in contrast, a significant level of DSP injected with the delivery vehicle was still observed 35 days after the injection. This result demonstrates that the delivery vehicle prolongs the life of DSP in the eyes. Other Modalities
    [0053] All features disclosed in this specification can be combined. Each feature disclosed in this specification can be replaced by an alternative, equivalent or similar feature. So, unless expressly stated otherwise, each feature disclosed is just an example. generic series of equivalent or similar characteristics.
    [0054] From the description above, a person skilled in the art can easily determine the essential characteristics of the present invention and, without departing from the inventive concept and scope, can make several modifications of the invention to adapt it to the various uses and conditions . Thus, other modalities are also included in the claims.
    权利要求:
    Claims (16)
    [0001]
    1. Drug delivery system, CHARACTERIZED by the fact that it comprises a delivery vehicle containing cholesterol and a mixture of a first phospholipid and a second phospholipid, where the first phospholipid is DOPC, POPC, SPC, or EPC and the second phospholipid it is PEG-DSPE or DOPG, in which cholesterol is present in an amount of 10 to 33 mol percent in relation to the delivery vehicle; and a therapeutic agent for the eye; wherein 50 to 90% of the therapeutic agent for the eye is in the unassociated form and the weight ratio of the mixture of the first phospholipid and the second phospholipid and cholesterol in combination with the therapeutic agent for the eye is 5 to 80 to 1.
    [0002]
    2. Drug delivery system according to claim 1, CHARACTERIZED by the fact that the therapeutic agent for the eye is a specific antagonist for VEGF or an anti-inflammatory molecule.
    [0003]
    3. Drug delivery system according to claim 2, CHARACTERIZED by the fact that the VEGF specific antagonist is a VEGF specific antibody, a VEGF receptor, a nucleic acid, or a small molecule.
    [0004]
    4. Drug delivery system, according to claim 3, CHARACTERIZED by the fact that the specific antibody to VEGF is a naturally occurring immunoglobulin, a functional fragment thereof, a humanized antibody, a chimeric antibody, a diabody or a single chain antibody.
    [0005]
    5. Drug delivery system according to claim 4, CHARACTERIZED by the fact that the specific antibody to VEGF is Avastin.
    [0006]
    6. Drug delivery system according to claim 4, CHARACTERIZED by the fact that the VEGF specific antibody is a Fab, Fab ', F (ab) 2 or F (ab') 2 fragment.
    [0007]
    7. Drug delivery system, according to claim 2, CHARACTERIZED by the fact that the anti-inflammatory molecule is a corticosteroid.
    [0008]
    8. Drug delivery system according to claim 7, CHARACTERIZED by the fact that the corticosteroid is selected from the group consisting of cortisone, hydrocortisone, fluocinolone, prednisolone, prednisone, triamcinolone, methylprednisolone, dexamethasone and betamethasone.
    [0009]
    9. Drug delivery system, according to claim 1, CHARACTERIZED by the fact that the delivery vehicle and the therapeutic agent for the eye are mixed and in lyophilized form.
    [0010]
    10. Drug delivery system according to claim 1, CHARACTERIZED by the fact that the delivery vehicle and the therapeutic agent for the eye are separated.
    [0011]
    11. Drug delivery system, according to claim 10, CHARACTERIZED by the fact that the delivery vehicle is in lyophilized form.
    [0012]
    12. Drug delivery system, according to claim 1, CHARACTERIZED by the fact that cholesterol is present in an amount of 20-25 mol percent in relation to the delivery vehicle.
    [0013]
    13. Drug delivery system, according to claim 1, CHARACTERIZED by the fact that the first phospholipid is DOPC and the second phospholipid is DOPG.
    [0014]
    14. Drug delivery system, according to claim 13, CHARACTERIZED by the fact that the mol% of DOPC is from 29.5% to 90% and the mol% of DOPG is from 3% to 37.5 %.
    [0015]
    15. Drug delivery system according to claim 13, CHARACTERIZED by the fact that the DOPC: DOPG: cholesterol ratio is 56.25 to 72.5: 7.5 to 18.75: 20 to 25 per cent in mol.
    [0016]
    16. Drug delivery system according to claim 14 or 15, CHARACTERIZED by the fact that the therapeutic agent is a specific antagonist for VEGF and 60 to 90% of said antagonist is in the unassociated form and the weight ratio of mixture of the first phospholipid and the second phospholipid and cholesterol in combination with the said antagonist is 5 to 40 to 1.
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    RU2572213C2|2015-12-27|
    TWI515008B|2016-01-01|
    CA2769929A1|2011-02-17|
    CN102573800A|2012-07-11|
    KR101921852B1|2018-11-23|
    EP3275445A1|2018-01-31|
    KR20170107106A|2017-09-22|
    PT2464343T|2018-12-05|
    EP2464343B1|2018-08-29|
    WO2011019410A1|2011-02-17|
    HK1214946A1|2016-08-12|
    CY1121467T1|2020-05-29|
    KR20120083316A|2012-07-25|
    CN102573800B|2015-09-30|
    AU2010282983B2|2016-09-22|
    EP2813229B1|2018-08-29|
    NZ623450A|2015-06-26|
    US8956600B2|2015-02-17|
    TW201105350A|2011-02-16|
    US20150147320A1|2015-05-28|
    US20180169248A1|2018-06-21|
    CN105148278B|2019-11-05|
    ES2699178T3|2019-02-07|
    US20110033468A1|2011-02-10|
    EP2464343A1|2012-06-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US550960A|1895-12-10|Island |
    US2004A|1841-03-12|Improvement in the manner of constructing and propelling steam-vessels |
    US4804539A|1986-07-28|1989-02-14|Liposome Technology, Inc.|Ophthalmic liposomes|
    AU598958B2|1987-11-12|1990-07-05|Vestar, Inc.|Improved amphotericin b liposome preparation|
    US4865846A|1988-06-03|1989-09-12|Kaufman Herbert E|Drug delivery system|
    BE1001869A3|1988-10-12|1990-04-03|Franz Legros|METHOD OF PACKAGING liposomal AMINOGLUCOSIDIQUES ANTIBIOTICS IN PARTICULAR THE GENTAMYCIN.|
    DK0625898T3|1992-02-12|1996-06-03|Janssen Cilag S P A|The liposome piroxicamformuleringer|
    TR199701683A3|1997-12-18|2001-06-21|Eldem Tuerkan|Ocular and parenteral polymer coated liposomal drug delivery systems.|
    CA2372053C|1999-04-28|2008-09-02|Board Of Regents, The University Of Texas System|Compositions and methods for cancer treatment by selectively inhibiting vegf|
    US6248353B1|1999-12-10|2001-06-19|Dade Behring Inc.|Reconstitution of purified membrane proteins into preformed liposomes|
    DE10032627A1|2000-07-07|2002-01-17|Km Europa Metal Ag|Use of a copper-nickel alloy|
    EP1404298A2|2001-06-25|2004-04-07|Yissum Research Development Company Of The Hebrew University Of Jerusalem|A method for preparation of vesicles loaded with biological material and different uses thereof|
    US8946295B2|2002-07-25|2015-02-03|Sunny Pharmtech Inc.|Histone hyperacetylating agents for promoting wound healing and preventing scar formation|
    US20040224010A1|2002-11-15|2004-11-11|Optime Therapeutics, Inc.|Ophthalmic liposome compositions and uses thereof|
    WO2004047801A2|2002-11-26|2004-06-10|Gilead Sciences, Inc.|Method of drug loading in liposomes by gradient|
    JP2006248978A|2005-03-10|2006-09-21|Mebiopharm Co Ltd|New liposome preparation|
    US20070072933A1|2005-09-26|2007-03-29|Peyman Gholam A|Delivery of an ocular agent|
    PT2944306T|2006-06-16|2021-02-15|Regeneron Pharma|Vegf antagonist formulations suitable for intravitreal administration|
    WO2008039989A2|2006-09-28|2008-04-03|Transave, Inc.|Formulations of dnase and methods of use thereof|
    US20080118500A1|2006-11-16|2008-05-22|Taiwan Liposome Company|Sustained releasing composition via local injection for treating eye diseases|
    PE20091029A1|2007-09-26|2009-08-19|Genentech Inc|ANTI-ALPHA ANTIBODIES 5 BETA 1|
    US8956600B2|2009-08-10|2015-02-17|Taiwan Liposome Co. Ltd.|Ophthalmic drug delivery system containing phospholipid and cholesterol|US8956600B2|2009-08-10|2015-02-17|Taiwan Liposome Co. Ltd.|Ophthalmic drug delivery system containing phospholipid and cholesterol|
    EA201491453A1|2012-01-31|2014-12-30|Сантен Фармасьютикал Ко., Лтд.|NONWATER LIQUID COMPOSITION|
    TWI620578B|2012-02-10|2018-04-11|台灣微脂體股份有限公司|Pharmaceutical compositions to reduce complications of ocular steroid|
    JP6044920B2|2012-03-27|2016-12-14|国立研究開発法人農業・食品産業技術総合研究機構|Liposomes that act on oxidized LDL receptors|
    WO2014008469A2|2012-07-05|2014-01-09|Taiwan Liposome Company, Ltd.|Methods of treating arthritis|
    CN104768615B|2012-07-17|2019-02-22|密执安大学评议会|The non-operative treatment for treating cataract|
    JP6336448B2|2012-08-21|2018-06-06|オプコ ファーマシューティカルズ、エルエルシー|Liposome preparation|
    EA022183B1|2012-12-24|2015-11-30|Общество С Ограниченной Ответственностью "Технология Лекарств"|Method of producing cytochrome c liposomal form|
    US10342846B2|2013-02-04|2019-07-09|University Of Notre Dame Du Lac|Nanoparticle drug delivery systems|
    US20160120888A1|2013-06-07|2016-05-05|Ktn Biotec, Inc.|Anticancer drug|
    US9895312B2|2014-04-08|2018-02-20|Pablo E. Vivas-Mejia|Nanoliposomal c-MYC-siRNA inhibits in vivo tumor growth of cisplatin-resistant ovarian cancer|
    EP3397276A4|2015-12-30|2019-12-18|Kodiak Sciences Inc.|Antibodies and conjugates thereof|
    EP3448359A1|2016-04-29|2019-03-06|Enceladus Pharmaceuticals B.V.|Liposomal corticosteroids for topical injection in inflamed lesions or areas|
    CN109922794A|2016-08-18|2019-06-21|特洛伊.布雷莫|Urea is delivered to the cell of macula lutea and retina using liposome constructs|
    CN110743035A|2019-11-06|2020-02-04|广西大学|Preparation method and application of intelligent antibacterial hydrogel|
    GB201917487D0|2019-11-29|2020-01-15|Oxular Ltd|Methods for the treatment of retinoblastoma|
    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-17| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-03-19| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-08-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 01/12/2020, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-05-25| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/01/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    US12/538,435|US8956600B2|2009-08-10|2009-08-10|Ophthalmic drug delivery system containing phospholipid and cholesterol|
    US12/538,435|2009-08-10|
    PCT/US2010/022487|WO2011019410A1|2009-08-10|2010-01-29|Ophthalmic drug delivery system containing phospholipid and cholesterol|
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