CN1886100A - Surfactant-based gel as an injectable, sustained drug delivery vehicle - Google Patents
Surfactant-based gel as an injectable, sustained drug delivery vehicle Download PDFInfo
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- CN1886100A CN1886100A CN 200480035276 CN200480035276A CN1886100A CN 1886100 A CN1886100 A CN 1886100A CN 200480035276 CN200480035276 CN 200480035276 CN 200480035276 A CN200480035276 A CN 200480035276A CN 1886100 A CN1886100 A CN 1886100A
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Abstract
The present invention provides methods and compositions for the sustained delivery of beneficial agents. In certain embodiments, the invention provides compositions comprising a surfactant, a solvent, and a beneficial agent, wherein upon exposure to a hydrophilic environment, the surfactant and solvent form a viscous gel and the beneficial agents is dispersed or dissolved in the gel. In other embodiments, the invention provides compositions comprising a surfactant, a solvent, a hydrophilic media, and a beneficial agent, wherein the surfactant solvent, and hydrophilic media form a viscous gel and the beneficial agent is dispersed or dissolved in the gel.
Description
The cross reference of related application
[0001] rights and interests of No. the 10/985th, 228, the U.S. Patent application of No. the 60/519th, 989, U.S. Provisional Application submitting on November 14th, 2003 and submission on November 10th, 2004 are enjoyed in the application's request, and it is introduced into this paper with for referencial use.
Invention field
[0002] the application relates to compositions and the method that is used to continue to send beneficial agent.In certain embodiments, the present invention relates to comprise the compositions of surfactant, solvent and beneficial agent, wherein, in case be exposed to hydrophilic environment for example water or body fluid or tissue, said composition just forms viscogel.
Background of invention
[0003] implantable or injectable polymeric drug delivery vector has a lot of shortcomings, verified for beneficial agent to continue to send be less-than-ideal method.Utilize the implantable drug delivery system of thermoplasticity or thermosetting biodegradable polymer to have to by medicine being mixed polymer and mixture being formed such as the shape of cylinder, disk or fiber and in external shaping.Implant must be inserted in the body by otch then.
[0004] avoiding a kind of method of the required otch of implantable drug delivery system is that injection comprises granule, microsphere or the microcapsule that can be released into intravital activating agent.Although these materials can be with injector to inject in body, yet because their particle properties, they can't form some prosthese required continuous film with structural intergrity or solid implant.In addition, if microgranule has bigger surface area, then just medicine occurs when initial and discharge in a large number through being everlasting once injection.In addition, because used strong solvent and extreme temperature degraded in the encapsulation process of being everlasting based on the medicine of albumen and DNA.Must be when the administration for microgranule by the situation of reconstruct, the injection microgranule also comprises two step processes.
[0005] polymer composition that utilizes in the injectable implant usually uses easily molten or dissolves in the solvent/plasticizer of aqueous body fluid relatively, to promote polymer at the implant site rapid solidification with promote that medicine spreads from implant.The rapid release of those solvents often causes beneficial agent initial rapid release from polymer composition, especially when useful reagent dissolves in solvent and solvent and is distributed in the body fluid fast.Outburst discharges and often to cause most of beneficial agent, if not whole, for example discharges in a few hours or a couple of days in the very short time.
[0006] relevant with microgranule and gel " outburst discharges " effect is can not be received, especially under those situations that needs continue to send, be that sending of beneficial agent will be through a week or January or longer time, or there is the narrow treatment window, the excessive release of beneficial agent can cause under the situation of being treated patient's negative consequence, or must simulate treated such as beneficial agents such as hormones generate naturally in patient's body every day curve situation under.In this respect, very typically, traditional compositions and microgranule based on solvent have medicine outburst release, and wherein, 30%-75% medicine contained in the compositions has just discharged within a day of initial injection.
[0007] in addition, the quick picked-up of body fluid can cause polymer precipitation, to such an extent as to produce the implant of hardening or make the patient have the skin of hardening, this has caused internal void, inner most restricted can not the contacts with body fluid of polymer.Although medicine is from this polymerization storage storehouse slowly diffusion in time, body fluid slowly enters storage inside, storehouse to be caused just finishing the complete biodegradable of implanting polymer for a long time, and this is undesirable for long-term chronic treatment.
[0008] therefore, this area needs such compositions and method existence, and said composition and method allow beneficial agent to continue to send and overcome this area about problem implantable or that injectable polymeric drug delivery vector is run into.
Brief summary of the invention
[0009] the present invention relates to non-polymeric, that be easy to inject, bio-compatible and biodegradable compositions, it is as continuing drug delivery vehicle, and wherein, initial medicine outburst discharges and is reduced to minimum.In certain embodiments, the present invention relates to be used for the Injectable composition that comprises surfactant, solvent and beneficial agent that beneficial agent continues to send, wherein, in case be exposed to hydrophilic environments, surfactant and solvent have just formed beneficial agent and have been dispersed or dissolved in wherein viscogel.Other embodiment of the present invention relates to the method that beneficial agent is passed to the patient in one period persistent period, comprise that the Injectable composition that will comprise surfactant, solvent and beneficial agent delivers medicine to the patient, wherein, in case be exposed to aqueous body fluid, surfactant and solvent have just formed beneficial agent and have been dispersed or dissolved in wherein viscogel.
[0010] in some other embodiment, the present invention relates to be used for the compositions that comprises surfactant, solvent, hydrophilic medium and beneficial agent that beneficial agent continues to send, wherein, surfactant, solvent and hydrophilic medium form viscogel, and beneficial agent is dispersed or dissolved in this gel.Other embodiment of the present invention relates to the method that beneficial agent is passed to the patient in one period persistent period, comprise that the compositions that will comprise surfactant, solvent, hydrophilic medium and beneficial agent delivers medicine to the patient, wherein, surfactant, solvent and hydrophilic medium form viscogel, and beneficial agent is dispersed or dissolved in the gel.
Brief description of the drawings
[0011] Fig. 1 has described the release in vitro curve that obtains from several lysozyme formulation that comprise different solvents and surfactant.
The detailed description of illustrative embodiment
[0012] term " beneficial agent " when being used for herein, refers to by using to the human or animal, no matter is separately or is and other medicines excipient or inert filler associating, the beneficial effect of realizing wanting, any reagent of pharmacological effect normally.
[0013] term " injectable " when being used for herein, referring to and is suitable for being expelled to skin or other in-house compositions.Injectable composition for example, can be used from syringe under the normality normal pressure, or under high pressure use from automatic injector.
[0014] term " continue to send ", " in one period persistent period, sending " and all changes form thereof, when being used for herein, referring to beneficial agent discharges from viscogel of the present invention in one section duration, this usually will be in a week or longer time, preferred 30 days or interior generation of longer time.In certain embodiments of the invention, beneficial agent continues to send and occurs in the present composition and deliver medicine to after the patient.
[0015] phrase " disperses or dissolves ", when being used for herein, referring to and makes beneficial agent be present in all methods in the present composition, comprises dissolving, dispersion and suspendible etc.
[0016] term " patient " when being used for herein, refers to animal, mammal or the mankind.
[0017] term " administration " and all changes form thereof refer to and comprise any method of the present composition being introduced the patient.When administration is during for therapeutic purposes, administration can be prevention or therapeutic purposes.When prophylactically supplying with, compositions will provide before any symptom.When therapeutic ground was supplied with, (or thereafter immediately) provided when compositions occurred in symptom.
[0018] term " viscogel " when being used for herein, referring to and has about 200,000 pools of about 100-, and preferably about 500-about 50,000 moors the present composition of viscosity.
[0019] term " hydrophilic medium " when being used for herein, refers to aqueous medium, for example the solution of water, saline solution, one or more buffer agents or body fluid or tissue.Term " hydrophilic environment " when being used for herein, refers to aqueous environments, for example the aqueous environments of the body fluid of humans and animals or tissue.
[0020] in certain embodiments, the present invention relates to non-polymeric, that be easy to inject, bio-compatible and compositions biodegradable, that comprise one or more surfactants and at least a solvent, it is as continuing drug delivery vehicle, wherein, initial medicine outburst discharges and is reduced to minimum.In some other embodiment, the present invention relates to beneficial agent is delivered to patient's method one period persistent period, comprise to the patient and use the compositions that comprises solvent, surfactant and beneficial agent.
[0021] comprises that the surfactant such as a lot of biomolecule of lipid is the amphiphatic molecule with hydrophilic segment and hydrophobic part.Most of lipids comprise phospholipid, only have slight surface activity, and promptly they have extremely low dissolubility in water, and have very low critical micelle concentration (CMC).PEG baseization lipid is the lipid that derives by linking to each other with Polyethylene Glycol (PEG) covalency of the about 1000-of molecular weight about 50,000.PEG baseization lipid and PEG baseization phospholipid are amphipathic, high surfaces, have much higher CMC and dissolubility than traditional lipid.In the presence of solvent and water, high concentration PEG baseization lipid and phospholipid form multiple firm gel phase.
[0022] when water-soluble or when being dissolved in the hydrophobic solvent, surfactant comprises PEG baseization phospholipid, spontaneous gathering forms various micro structures, and for example micelle, vesicle, thin slice and disk etc. are so that mixed free energy is reduced to minimum.According to hydrophilic-lipophilic balance value (HLB), surfactant concentration, aqueous medium character (comprising its salinity), solvent property and the temperature of surfactant, these ternary systems present complicated phase behavior.Under low surfactant concentration, shaft-like micellar phase can form viscoelastic solution.Under the high surface agent concentration, cube phase, concentrated micellar phase, hexagonal phase and some co-continuous can cause the formation of gel like structure phase mutually.
[0023] surfactant can form gel sample liquid crystalline phase in the ternary system that comprises surfactant, hydrophobic solvent and hydrophilic medium.This gel phase can be crossed over the major part of phasor, promptly big compositing range at various temperatures.In certain embodiments of the invention, can form gel phase by mixed surfactant, hydrophobic solvent and hydrophobic medium, or by mixing hydrophobic solvent and surfactant in advance, then by for example subcutaneous or intramuscular administration mixture, make mixture contact hydrophilic environment, cause original position to form gel.These two kinds of methods can be used for the therapeutic agent that parenteral uses as storage storehouse delivery platform, and the former can be used as topical drug's delivery platform.
[0024] in some aspects, the present invention relates to, by using compositions, form beneficial agent from surfactant and solvent and dissolve or be scattered in fully wherein viscogel substantially beneficial agent whole body or the local method of using to the patient.Beneficial agent discharged to the patient through the very long persistent period, thereby provided beneficial agent to break out the mode of sending that discharges and after this continue to discharge a kind of like this beneficial agent controllably.
[0025] the invention still further relates to the compositions that is used to continue to send beneficial agent, wherein, in the presence of hydrophilic medium or in hydrophilic environment, formed gel sample liquid crystalline phase by one or more surfactants and solvent, beneficial agent is dissolved or dispersed in the gel substantially.In preferred embodiments, the present composition exists with the liquid crystalline phase form, and the viscosity of this liquid crystalline phase is high enough to form gel, and low to being enough to can process and injectable via syringe or automatic injector with sending under the temperature in normal storage.
[0026] in some aspects, the present invention relates to comprise the compositions that continues to send beneficial agent of surfactant, solvent and beneficial agent.In a single day compositions is exposed to hydrophilic environment, has just formed beneficial agent and has been dissolved or dispersed in wherein viscogel.Other embodiment of the present invention relates to the method that beneficial agent is delivered to the patient in one period persistent period, comprises to the patient and uses the compositions that comprises surfactant, solvent and beneficial agent.In a single day aqueous body fluid be diffused in the compositions, just formed beneficial agent and be dissolved or dispersed in wherein viscogel.Beneficial agent discharges from viscogel in one period persistent period then.
[0027] in others, the present invention relates to be used to continue to send the compositions of beneficial agent, it comprises surfactant, solvent, hydrophilic medium and beneficial agent, and wherein, surfactant, solvent and hydrophilic medium have formed beneficial agent and be dissolved or dispersed in wherein viscogel.Other embodiment of the present invention relates to the method that beneficial agent is delivered to the patient in one period persistent period, comprises to the patient and uses the compositions that comprises surfactant, solvent, hydrophilic medium and beneficial agent.Said composition has formed viscogel, can be by injection or topical.
[0028] the suitable surfactant that is used for the inventive method and compositions comprises, for example, and ionic surface active agent (having at least one ionizing part) and non-ionic surface active agent (not having ionogen).Ionic surface active agent includes, but are not limited to: anion surfactant, for example fatty acid and soap (for example sodium lauryl sulfate); Sterol acid and salt thereof (for example cholate and dexycholate); Cationic surfactant, for example alkyl trimethyl ammonium bromide and alkyl triethyl group ammonium bromide (for example cetyltriethylammonium bromide (CTAB) and C
16TAB); Amphoteric surfactant, for example lysolipin (for example LYSO-PHOSPHATIDYLCHOLINE LYSOPC or PHOSPHATIDYL ETHANOLAMINE) and CHAPS; And zwitterionic surfactant (Zwittergents), for example Zwittergent
3-14.
[0029] ionic surfactant pack that is applicable to the inventive method and compositions is drawn together but is not limited to: aliphatic alcohol that is to say to have structural formula CH
3(CH
2)
nThe alcohol of C (H) OH (for example wherein n is 6 at least), for example lauryl alcohol, spermol and stearyl alcohol; Fat sugar, for example octyl glucoside and digitonin; Lubrol, for example Lubrol
PX; Tritons, for example TRITON
X-100; Nonidents, for example Nonident P-40; Sorbitan fatty acid esters is (for example with trade name SPAN
Those that sell), polyoxyethylene sorbitan fatty acid esters is (for example with trade name TWEEN
Those that sell), polyoxyethylene fatty acid ester is (for example with trade name MYRJ
Those that sell), polyoxyethylene steroid ester, the polyoxypropylene sorbitan fatty acid esters, the polyoxypropylene fatty acid ester, polyoxypropylene steroid ester, polyoxyethylene ether is (for example with trade name BRIJ
Those that sell), polyglycol ether is (for example with trade name TERGITOL
Those that sell), or the like.Preferred nonionic is polyglycol ether, polyoxyethylene three oleic acid sorbitan esters, single Palmic acid sorbitan ester, polyoxyethylene sorbitan monoleate, polyoxyethylene 4-lauryl ether, propylene glycol and composition thereof.
[0030] anion surfactant that is applicable to the inventive method and compositions includes, but are not limited to: chain alkyl sulfonate, carboxylate and sulfate, and alkylaryl sulfonates etc.The preferred anionic surfactants surfactant is sodium lauryl sulphate, dialkyl sodium sulfosuccinate (for example two-(2-ethylhexyl)-sodium sulfo-succinate), 7-ethyl-2-methyl-4-sodium lauryl sulphate and dodecylbenzene sodium sulfonate.
[0031] cationic surfactant that is applicable to the inventive method and compositions includes, but are not limited to: long-chain amine salt or quaternary ammonium salt, for example decyl trimethylammonium bromide, Dodecyl trimethyl ammonium chloride, Tetradecyl Trimethyl Ammonium Bromide and tetradecyl trimethyl ammonium chloride etc.
[0032] amphoteric surfactant that is applicable to the inventive method and compositions includes, but are not limited to: comprise carboxylate or phosphate group as anion and amino or quaternary ammonium part as cationic chemical compound.These surfactants for example comprise, each peptide species, albumen, alkyl betaine and such as the natural phospholipid of LYSOLECITHIN SUNLECITHIN A and lysocephalin.
[0033] preferred surfactants includes, but are not limited to: phospholipid, PEG baseization phospholipid, PEG baseization lipid, polyoxyethylene-polyoxypropylene copolymer, ethoxylation dehydrated sorbitol ester, sorbitan ester, ethoxylated ether, ethoxylated castor oil, vitamin E-TPGS (D-alpha-tocopherol base PEG 1000 succinates), sphingolipid, glycolipid, lysophosphatide, fatty acid, bile salts, ethoxylated glycerol ester, ethoxylized fatty alcohol and composition thereof.
[0034] the PEG baseization lipid that is applicable to the inventive method and compositions for example comprises, PEG-DSPE (Polyethylene Glycol of conjugation on the DSPE), mPEG-DS (methyl ether-Polyethylene Glycol of conjugation to the distearyl acyl group) and PEG-ceramide.
[0035] in the compositions of certain embodiments of the invention and method, be used as the lipid of surfactant and phospholipid can conjugation to the polymer except that PEG, polyvinylpyrrolidone for example, polyvinyl methyl ether, Ju Jia oxazolin, the Ju ethyl oxazoline, poly-Qiang Bing oxazolin, poly-hydroxypropyl-MAAm, the polyisobutylene amide, poly dimethyl-acrylamide, poly-hydroxypropyl methacrylate, the poly-hydroxyethyl acrylate, hydroxy methocel, hydroxyethyl-cellulose, Polyethylene Glycol, polyaspartamide, poly(ethylene oxide)-poly(propylene oxide) copolymer, copolymer of above-mentioned polymer and composition thereof.Therefore, lipid and the phospholipid of conjugation to any above-mentioned polymer can be used as surfactant in the compositions of certain embodiments of the invention and method.
[0036] in certain embodiments of the invention, compositions comprises the surfactant that accounts for the about 5%-of gross weight about 80%.In some preferred embodiment, the present composition comprises the surfactant that accounts for the about 10%-of gross weight about 70%.In addition preferred embodiment in, the present composition comprises the surfactant that accounts for the about 15%-of gross weight about 60%.
[0037] appropriate solvent that is used for the inventive method and compositions comprises hydrophilic, protophobic and hydrophobic solvent.Preferred solvent includes, but are not limited to: ethyl oleate, benzyl benzoate, ethyl benzoate, the lactic acid Lauryl Ester, benzylalcohol, lauryl alcohol, glycogen furfural (glycofurol), ethanol, tocopherol, Polyethylene Glycol, glyceryl triacetate, triglyceride, alkyl glycerol three esters, diglyceride, Oleum sesami, Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil, Oleum Gossypii semen, perfluorocarbon, N-methyl-ketopyrrolidine, DMSO, glycerol, oleic acid, the glycogen furfural, the lactic acid Lauryl Ester, perfluorocarbon, propylene carbonate and composition thereof.
[0038] in certain embodiments of the invention, compositions comprises the solvent that accounts for the about 20%-of gross weight about 95%.In some preferred embodiment, the present composition comprises the solvent that accounts for the about 30%-of gross weight about 90%.In a more preferred embodiment, the present composition comprises the solvent that accounts for the about 40%-of gross weight about 55%.
[0039] the suitable beneficial agent that is used for the inventive method and compositions comprises any physiology or pharmacological active substance, choose wantonly and pharmaceutically acceptable carrier and other composition, for example associatings such as antioxidant, stabilizing agent and penetration enhancer, they can influence the favourable outcome that the present composition and method can reach basically sharply.Beneficial agent can comprise pharmaceutical agent, medicine, vitamin and nutrient etc.Be included in and be low molecular weight compound, albumen, peptide, hereditary material, nutrient, vitamin, food supplement, sterilant, preparation, fertility inhibitor and fertility promoters in the types of agents that meets this description.Preferred beneficial agent comprises, for example, albumen, peptide, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, micromolecule includes, but are not limited to: steroidal, analgesic, local anaesthetics, antibiotic, antiphlogistic corticosteroid, antimicrobial, contrast agent, for example, Gd-DTPA (gadolinium (III) diethyl pentetic acid), gadodiamide, gadoteridol, the albumin of Gd-DTPA-labelling, dextran and the erythrocyte of chromium-labelling, eye medicinal and the chemotherapeutant of Gd-DTPA-labelling.
[0040] beneficial agent that can be used for the inventive method and compositions comprises the medicine that acts on peripheral nerve, adrenoreceptor, cholinoceptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation system, synapse (synoptic) position, neural effector binding site, endocrine and hormone system, immune system, reproductive system, skeletal system, autacoid system, digestion and Excretory system, histamine system and central nervous system.
[0041] example that can be used for the beneficial agent of the inventive method and compositions includes, but are not limited to: prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procamide, amfetamine sulfate, methamphetamine hydrochloride, benzene amphetamines (benzamphetamine) hydrochlorate, isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, Pilocarpine Hydrochloride, atropine sulfate, scotropin, isopropamide iodide, Tridihexethyl Chloride, phenformin hydrochloride, methylphenidate hydrochloride, Oxtriphylline, cefalexin hydrochloride, diphenidol, meclozine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine dimaleate, anisindione, diphenadione, erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorination glucosulfone (chloropromaide), tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, Aluminum Aspirin, methotrexate, acetylsulfafurazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and derivant thereof be betamethasone for example, triamcinolone, methyltestosterone, the 17-S-estradiol, ethinylestradiol, ethinylestradiol 3-methyl ester, prednisolone, 17-α-medroxyprogesterone acetate, the nor-Progesterone of 19-, norgestrel, norethindrone (norethindrone), norethindrone (norethisterone), norethiederone, Progesterone, norgesterone, Norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, sorbide nitrate, Propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cefalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, cefamandole nafate, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic acid, flufenamic acid, difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline and imipramine.Other example is albumen and peptide, include, but are not limited to: bone morphogenetic protein, insulin, colchicine, glucagon, thyrotropin, parathyroid gland and pituitary hormone, calcitonin, feritin, prolactin antagonist, thyroliberin, thyrotrophic hormone, follicle stimulating hormone, chorionic-gonadotropin hormone, gonadotropin releasing hormone, bovine growth hormone, pig growth hormone, oxytocin, vassopressin, GRF, somatostatin, lypressin, Pancreozymin, lutropin, LHRH, LHRH agonist and antagonist, leuprorelin acetate, interferons is Intederon Alpha-2a for example, Interferon Alpha-2b and combination (consensus) interferon, interleukin, growth hormone is human growth hormone and derivant thereof for example, methione-human growth hormone and go the phenylalanine human growth hormone for example, bovine growth hormone and pig growth hormone, the fertility inhibitor is prostaglandins for example, fertility promoters, somatomedin is insulin like growth factor for example, thrombin, the releasing factor of people's pancreas hormone, the analog of these chemical compounds and derivant, the acceptable salt of pharmacy of these chemical compounds or its analog or derivant.
[0042] in certain embodiments, the present invention has also found the application of chemotherapeutant, and this reagent topical application is minimized to avoid or to make systemic side effects.In some embodiments, the gel that the present invention comprises chemotherapeutant can be injected directly into tumor tissues, is used for continuing in time to send this chemotherapeutant.In some embodiments, especially behind tumor resection, this gel directly can be implanted in the chamber of formation or be applied to the tissue of reservation as coating.In the embodiment of implanted gel, it is possible utilizing the gel with viscosity higher, because they needn't pass through the minor diameter injection needle after operation.The typical chemotherapeutant that can be used for the method and composition of certain embodiments of the invention comprises, for example, the functional derivatives of carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecine, etoposide (etopside), cytokine, ribozyme, interferon, the translation of inhibition oncogene and the oligonucleotide of transcribing and oligonucleotide sequence, aforementioned substances, for example be described in United States Patent (USP) the 5th, 651, the chemotherapeutant of knowing in No. 986, it all is incorporated herein with for referencial use.In certain embodiments of the invention, said composition and method the water-soluble chemical therapeutic agent continue have special application in sending, for example, the soluble derivative of cisplatin and carboplatin and paclitaxel.It is useful especially in the administration of all kinds water solublity beneficial agent that certain embodiments of the invention make the minimized characteristic of outburst releasing effect, especially those clinical useful and effective chemical compounds that still may have adverse side effect.
[0043] for the above-mentioned scope of not mentioning, be described in United States Patent (USP) the 5th, 242, the beneficial agent in No. 910 also can be used for the compositions and the method for certain embodiments of the invention, and it all is incorporated herein with for referencial use.
[0044] especially, be difficult to the material that wraps into microcapsule or be made into microsphere, such as protein (for example lysozyme), mix the cDNA and the DNA of virus and non-virus carrier, can mix in the present composition, and can not appear in other process technology ever-present owing to being exposed to the degraded that high temperature and degeneration solvent cause.
[0045] in certain embodiments of the invention, by for example dry grinding, wet grinding, micronization, lyophilizing, spray drying, spraying-lyophilization, homogenize, or the supercritical fluid micronization is made granule with beneficial agent.In some embodiments of the present invention, with granule coating so that the further sustained release of beneficial agent to be provided.In certain embodiments of the invention, the beneficial agent granule comprises stabilizing agent, for example sucrose, trehalose, mannitol and glycine; Buffer agent, phosphate for example, histidine and succinate; Or antioxidant, for example vitamin E or methionine.In some embodiments of the present invention, the beneficial agent granule comprises one or more stabilizing agents, buffer agent, antioxidant or its combination.In certain embodiments of the invention, the beneficial agent granule can be compound so that it stable with other molecule or one or more polymer such as zinc salt.
[0046] in a preferred embodiment of the invention, beneficial agent is mixed in the viscogel with particle form, viscogel is formed by surfactant, solvent and hydrophilic medium, granule has about 200 microns of about 0.1-usually, about 125 microns of preferred about 1-often is the about 100 microns mean diameter of about 2-.
[0047] in order to form suspension or the dispersion of beneficial agent granule in the viscogel that forms by surfactant, solvent and hydrophilic medium, can use the low shear of any routine, for example two planetary stirrers.By this way, can obtain effective distribution of beneficial agent substantially and can not make the beneficial agent degraded.
[0048] in preferred embodiments, beneficial agent, often is dissolved or dispersed in the present composition for the amount that accounts for the about 10%-of gross weight about 30% preferably to account for the amount of the about 5%-of gross weight about 40% usually to account for the amount of the about 1%-of gross weight about 50%.According to the amount that is present in the beneficial agent in the compositions, can obtain different release profiles and outburst release index.
[0049] in certain embodiments of the invention, regulate the rate of release and the load capacity of beneficial agent, effectively send in the treatment that expection continues delivery phase so that beneficial agent to be provided.Preferably, beneficial agent exists with the concentration that is higher than the saturated concentration of beneficial agent in water in gel.Simultaneously, the rate of release of beneficial agent depends on specific environment, specific beneficial agent for example to be administered, about 7 days-Yue 90 days during in, can obtain about 0.1 microgram every day-Yue 100 milligrams of every days, 10 milligrams of every days of preferred about 10 micrograms every day-Yue the order of magnitude rate of release.To take place in the short period of time if send, can send relatively large beneficial agent.Generally speaking, discharge if can tolerate bigger outburst, higher rate of release is possible.In addition, the dosage of beneficial agent can be by regulating implanted or being controlled by the volume of injectable composition.
[0050] in certain embodiments of the invention, hydrophilic medium includes, but are not limited to: the solution of water, saline solution, one or more buffer agents, body fluid or bodily tissue.Hydrophilic environment includes, but are not limited to aqueous environments, for example, and the aqueous environments of human or animal's body fluid or tissue.
[0051] comprise in the present composition in the embodiment of surfactant, solvent, hydrophilic medium and beneficial agent, said composition comprises the hydrophilic medium that accounts for the about 0.1%-of gross weight about 10%.More preferably in the embodiment, said composition comprises the hydrophilic medium that accounts for the about 0.1%-of gross weight about 2% at some.In a more preferred embodiment, compositions comprises the hydrophilic medium that accounts for the about 0.1%-of gross weight about 0.5%.
[0052] in certain embodiments, can there be other composition in the present composition, on this meaning, these adding ingredients be want or for compositions provides useful properties, for example Polyethylene Glycol, water absorbing agent, stabilizing agent, buffer agent, foaming agent, viscosifier etc.When compositions is included in the aqueous environments solvable or unsettled peptide or albumen, just may want very much to comprise the dissolubility regulator in the compositions, may be stabilizing agent for example.For example, United States Patent (USP) the 5th, 654, No. 010 and the 5th, 656, various dissolubility regulators have been described in No. 297, it all is incorporated herein with for referencial use.For hGH, for example, preferably comprise a certain amount of divalent metal salt, preferred zinc salt.Can form complex with beneficial agent or comprise with this dissolubility regulator that stabilisation or adjustment release effect are provided and the example of stabilizing agent: metal cation with its association, preferred bivalence, be present in the compositions as magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, zinc chloride, magnesium chloride, magnesium oxide, magnesium hydroxide and other antacid etc.The amount of these used reagent will depend on the character of the complex that forms, if any, and the perhaps association character between beneficial agent and this reagent.In certain embodiments of the invention, the mol ratio of common utilizable dissolubility regulator or stabilizing agent and beneficial agent is about 100: 1-1: 1, preferred 10: 1-1: 1.
[0053] in certain embodiments of the invention, described compositions can comprise the reagent that makes the macromole stabilisation, and such as dissolving protective agent (lyoprotectant), these reagent include, but are not limited to, trehalose, sucrose and glycine.In some embodiments, the present composition can comprise buffer agent, for example phosphate, succinate, histidine and acetate.In other embodiments, the present composition can comprise other surfactant, for example polysorbas20.
[0054] in certain embodiments, viscosifier can be dispersed or dissolved in the compositions of the present invention, make its stabilisation to increase the viscosity of compositions.Viscosifier include, but are not limited to polymer, for example polyvinylpyrrolidone, methylcellulose, ethyl cellulose, hetastarch, poly--lactide-glycolic, polycaprolactone-LA-GA copolymer.In certain embodiments of the invention, compositions comprises the viscosifier that account for the about 0.1%-of gross weight about 5%.
[0055] in certain embodiments of the invention, compositions implant or injection before unusual thickness.Can be by in compositions, dispersing or dissolving the viscosity that other surfactant reduces compositions, reduce viscosity to being enough to allow that compositions passes through syringe needle.And the dissolubility regulator of foaming agent and beneficial agent can join in the compositions together with typical pharmaceutical excipient and other additive of the beneficial effect that does not change the certain embodiments of the invention compositions, so that required release profiles to be provided.
[0056] in certain embodiments, because compositions of the present invention is preferably formed viscogel, the administering mode of compositions is not limited to injection, although this delivery modality may often be preferred.In certain embodiments of the invention, compositions can be implanted by operation and carry out administration.In other embodiments, the present composition can be applied topically to skin or other tissue.When compositions is carried out administration as retention (leave-behind) product, the body cavity that they can be shaped and exist after operation is finished to fill, but perhaps by being brushed or be taped against to remain on tissue or the bone, uses gel as flow-gel.This application can allow beneficial agent load capacity in the gel greater than the concentration that exists usually in the Injectable composition.
[0057] certain embodiments of the present invention relate to and do not comprise useful combination of agents thing, and it can be used for wound healing, bone reparation and other structural support purpose.
[0058] in certain embodiments, some preferred composition of the present invention comprises the surfactant that accounts for gross weight 5%-80%, accounts for the solvent of gross weight 20%-95% and accounts for the beneficial agent of gross weight 1%-50%.In other embodiments, preferred composition of the present invention comprises the surfactant, the solvent that accounts for gross weight 20%-95% that account for gross weight 5%-80%, accounts for the hydrophilic medium of gross weight 0.1%-10% and accounts for the beneficial agent of gross weight 1%-50%.
[0059] the following example is for example understood certain embodiments of the present invention, should not be seen as the scope of the present invention that limited.
Embodiment 1: the preparation of compositions that is used to continue to send lysozyme
[0060] sample preparation
Be prepared as follows four test specimens and two control samples.For each sample, the weight ratio of surfactant and the description of solvent following table is mixed in the 20ml scintillation vial.The surfactant in each sample and the gross weight of solvent are about 5 grams.Used Keyence Hybrid blender biased sample then 10 minutes.Then lysozyme (17 970u/mgDW are available from Wo Xindun) is added in each scintillation vial in drying baker, increasing to until mixture viscosity is enough to allow sample to load to level in the release room, causes and has added about 1 gram lysozyme in each sample.The sealing scintillation vial placed the Keyence blender 1 minute.Use built on stilts blender to stir scintillation vial then up to obtaining uniform homogeneous blend.Obtain clear and bright gel phase for aqueogel (Pluronic F127/ water/butanols).
| Sample | Preparation (mg) | Lysozyme (mg) | The Wt% lysozyme |
| Pluronic F127/ water/butanols (18/72/10) | 4.1682 | 0.8668 | 20.80 |
| Anti-phase pluronic 31R1/ benzyl benzoate (80/20) | 5.1432 | 0.8557 | 16.64 |
| Pluronic L62/ benzyl benzoate (80/20) | 3.8020 | 0.8205 | 21.58 |
| Polyoxyethylene sorbitan monoleate/benzyl benzoate (80/20) | 5.5760 | 1.3730 | 24.62 |
| Polyvinylpyrrolidone/benzyl benzoate (50/50): rapid release contrast | 4.1008 | 1.0001 | 24.39 |
| Poly-(lactide-be total to-the Acetic acid, hydroxy-, bimol. cyclic ester)/benzyl benzoate (25/75) that contains 2wt% Pluronic F68 storage storehouse: sustained release contrast | 4.5522 | 1.0458 | 22.97 |
[0061] extracorporeal releasing test
Sample is loaded in the 500mg release in vitro chamber.Bath temperature maintains 37 ℃, and pH maintains 7.4.After 1 hour, 4 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days and 14 days, take out sample respectively, analyze to determine protein concentration with HPLC.As shown in Figure 1, at the 14th day, 4 test specimens showed than the slower rate of release of rapid release contrast, have also shown than sustained release and have contrasted rate of release faster.At the 14th day, anti-phase pluronic 31R1/ benzyl benzoate sample has shown rate of release the fastest in the test specimen, pluronic F127/ water/butanols sample shows as in the test specimen the second fast rate of release, pluronic L64/ benzyl benzoate sample shows as in the test specimen the 3rd fast rate of release, and polyoxyethylene sorbitan monoleate/benzyl benzoate has shown rate of release the slowest in the test specimen.
Embodiment 2: the preparation of compositions that is used for continuing deliverer's growth hormone
[0062] by recombinant human somatropin, sucrose, glycine and the phosphate of the following indicatrix of lyophilization, reduce granule then and sieve, and/or spray drying, preparation recombinant human somatropin granule.Mixing polysorbate 20 and benzyl benzoate (with the amount of following indication) then in two planetary stirrers is dissolved in benzyl benzoate up to polysorbate 20 and prepares gel.Then the polyvinylpyrrolidone of following indicatrix is slowly joined in polysorbate 20/Benzyl Benzoate ester admixture and form viscogel.Then human growth hormone's granule slowly is distributed in the gel to form dosage form.
| Composition | Function | Compositing range |
| Polysorbate 20 | Surfactant | 9.9％-69.9％ |
| Benzyl benzoate | Solvent | 9.9％-69.9％ |
| Polyvinylpyrrolidone (PVP) | Viscosifier | 0.1％-1.0％ |
| The human growth hormone | Therapeutic agent | 10％ |
| Sucrose/glycine | Stabilizing agent | 8％ |
| Phosphate | Buffer agent | 2％ |
Embodiment 3: the preparation of compositions that is used to continue to send lysozyme
[0063] in the 20ml scintillation vial, by mixing two components with built on stilts blender or accent spatula, the surfactant/solvent mixtures that comprises 80% weight polyoxyethylene sorbitan monoleate (Croda) and 20% weight benzyl benzoate (Charkit) of preparation gross weight 10 grams.By the lysozyme soln spray drying is prepared the lysozyme granule, make about 5 microns lysozyme granule, perhaps, make the lysozyme granule of about 38-125 micron by milling and sieve freeze dried lysozyme agglomerate.Take by weighing 1 to 2 gram lysozyme granule, use built on stilts blender or transfer spatula that it is scattered in the surfactant/solvent mixtures fully, this has increased the viscosity of preparation.Preparation is loaded in the release in vitro chamber, obtains release profiles.
Embodiment 4: the preparation of compositions that is used to continue to send monoclonal antibody
[0064] in the small capacity double planetary stirrer, the surfactant/solvent mixtures that comprises 60% weight Pluronic L64 (BASF) and 40% weight benzyl benzoate (Charkit) of preparation gross weight 40 grams.10 gram polyvidone 17pF or polyvinylpyrrolidone (BASF) are joined in the solvent mixture to increase preparation viscosity.Allow polyvinylpyrrolidone to be dissolved in the carrier.Prepare the monoclonal antibody granule of about 5-10 micron grain size by spray drying, it is added in the adhesive carrier, under vacuum, disperse to prevent bubble formation with two planetary stirrers.The gained preparation is changed in the big syringe of HDPE, in the little glass syringe of 0.5ml of there it being packed into.
Embodiment 5: the preparation of compositions that is used to continue to send the recombinant human somatropin
[0065] in large-scale pair of planetary stirrer, the surfactant/solvent mixtures that comprises 50% weight Cremophor ELP (BASF) and 50% weight Oleum Ricini (Croda) of preparation gross weight 500 grams.By mixing continuously in a vacuum solid recombinant human somatropin (rhGH) uniform particles is distributed in the surfactant/solvent mixtures.In closed system, preparation is transferred in the filler cartridge case, fills independent syringe or bottle there.
[0066] whole disclosures of every patent, patent application and the publication of quoting in this article or describing all are incorporated herein hereby with for referencial use.
Claims (27)
1. the Injectable composition that is used to continue to send beneficial agent that comprises surfactant, solvent and beneficial agent, wherein, in case be exposed to hydrophilic environment, described surfactant and solvent just form viscogel, and beneficial agent is dispersed or dissolved in this gel.
2. the compositions of claim 1, wherein, described surfactant is anionic, cationic, amphoteric ion type or nonionic.
3. the compositions of claim 2, wherein, described surfactant is phospholipid, PEG baseization phospholipid, polyoxyethylene-polyoxypropylene copolymer, ethoxylation dehydrated sorbitol ester, sorbitan ester, ethoxylated ether, ethoxylated castor oil, D-alpha-tocopherol base PEG 1000 succinates, sphingolipid, glycolipid, lysophosphatide, fatty acid, bile salts, ethoxylated glycerol ester, ethoxylized fatty alcohol or its mixture.
4. the compositions of claim 1 comprises the described surfactant that accounts for gross weight 5%-80%.
5. the compositions of claim 1, wherein, described solvent is hydrophobic.
6. the compositions of claim 5, wherein, described hydrophobic solvent is ethyl oleate, benzyl benzoate, ethyl benzoate, lactic acid Lauryl Ester, benzylalcohol, lauryl alcohol, glycogen furfural, ethanol, tocopherol, Polyethylene Glycol, glyceryl triacetate, triglyceride, alkyl glycerol three esters, diglyceride, Oleum sesami, Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil, Oleum Gossypii semen, perfluorocarbon, N-methyl-ketopyrrolidine, DMSO, glycerol, oleic acid, glycogen furfural, lactic acid Lauryl Ester, perfluorocarbon, propylene carbonate or its mixture.
7. the compositions of claim 1 comprises the described solvent that accounts for gross weight 20%-95%.
8. the compositions of claim 1, wherein, described beneficial agent is albumen, peptide, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroidal, analgesic, local anaesthetics, antibiotic, antiphlogistic corticosteroid, antimicrobial, contrast agent, eye medicinal or chemotherapeutant.
9. the compositions of claim 1 comprises the described beneficial agent that accounts for gross weight 1%-50%.
10. the compositions of claim 1, wherein, described hydrophilic environment comprises water, saline solution or body fluid or tissue.
11. the compositions of claim 1 comprises the described surfactant that accounts for gross weight 5%-80%, accounts for the described solvent of gross weight 20%-95% and accounts for the described beneficial agent of gross weight 1%-50%.
12. comprise the compositions that is used to continue to send beneficial agent of surfactant, solvent, hydrophilic medium and beneficial agent, wherein, described surfactant, solvent and hydrophilic medium form viscogel, beneficial agent is dispersed or dissolved in this gel.
13. the compositions of claim 12, wherein, described surfactant is anionic, cationic, zwitterionic or nonionic.
14. the compositions of claim 13, wherein, described surfactant is phospholipid, PEG baseization phospholipid, polyoxyethylene-polyoxypropylene copolymer, ethoxylation dehydrated sorbitol ester, sorbitan ester, ethoxylated ether, ethoxylated castor oil, vitamin E-TPGS, sphingolipid, glycolipid, lysophosphatide, fatty acid, bile salts, ethoxylated glycerol ester, ethoxylized fatty alcohol or its mixture.
15. the compositions of claim 12 comprises the described surfactant that accounts for gross weight 5%-80%.
16. the compositions of claim 12, wherein, described solvent is hydrophobic.
17. the compositions of claim 16, wherein, described hydrophobic solvent is ethyl oleate, benzyl benzoate, ethyl benzoate, lactic acid Lauryl Ester, benzylalcohol, lauryl alcohol, glycogen furfural, ethanol, tocopherol, Polyethylene Glycol, glyceryl triacetate, triglyceride, alkyl glycerol three esters, diglyceride, Oleum sesami, Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil, Oleum Gossypii semen, perfluorocarbon, propylene carbonate, N-methyl-ketopyrrolidine, DMSO, glycerol, oleic acid, glycogen furfural, lactic acid Lauryl Ester, perfluorocarbon or its mixture.
18. the compositions of claim 12 comprises the described hydrophobic solvent that accounts for gross weight 20%-95%.
19. the compositions of claim 12, wherein, described hydrophilic medium is water, saline solution, body fluid or bodily tissue.
20. the compositions of claim 12 comprises the described hydrophilic medium that accounts for gross weight 0.1%-10%.
21. the compositions of claim 12, wherein, described beneficial agent is albumen, peptide, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroidal, analgesic, local anaesthetics, antibiotic, antiphlogistic corticosteroid, antimicrobial, contrast agent, eye medicinal or chemotherapeutant.
22. the compositions of claim 12 comprises the described beneficial agent that accounts for gross weight 1%-50%.
23. the compositions of claim 12 comprises the described surfactant, the described solvent that accounts for gross weight 20%-95% that account for gross weight 5%-80%, accounts for the described hydrophilic medium of gross weight 0.1%-10% and accounts for the described beneficial agent of gross weight 1%-50%.
24. in one period persistent period, beneficial agent is delivered to patient's method, comprises the compositions of using claim 1 to the patient.
25. the method for claim 24, wherein, described compositions is given the patient by injected delivery.
26. in one period persistent period, beneficial agent is delivered to patient's method, comprises the compositions of using claim 12 to the patient.
27. the method for claim 26, wherein, described compositions is delivered to the patient by injection or local application.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51998903P | 2003-11-14 | 2003-11-14 | |
| US60/519,989 | 2003-11-14 | ||
| US10/985,228 | 2004-11-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1886100A true CN1886100A (en) | 2006-12-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480035276 Pending CN1886100A (en) | 2003-11-14 | 2004-11-12 | Surfactant-based gel as an injectable, sustained drug delivery vehicle |
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| Country | Link |
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| CN (1) | CN1886100A (en) |
| ZA (1) | ZA200604881B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843586A (en) * | 2010-04-29 | 2010-09-29 | 山东迅达康兽药有限公司 | Water-soluble micro powder containing florfenicol and preparation method thereof |
| CN108743952A (en) * | 2018-06-11 | 2018-11-06 | 西安力邦医药科技有限责任公司 | Phosphatide-miscible agent-oil sustained release drug delivery systems the prescription and preparation method of local anesthetic |
| CN115212187A (en) * | 2014-11-05 | 2022-10-21 | 西莱克塔生物科技公司 | Methods and compositions related to the use of low HLB surfactants in synthetic nanoparticles comprising RAPALOG |
-
2004
- 2004-11-12 CN CN 200480035276 patent/CN1886100A/en active Pending
-
2006
- 2006-06-13 ZA ZA200604881A patent/ZA200604881B/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843586A (en) * | 2010-04-29 | 2010-09-29 | 山东迅达康兽药有限公司 | Water-soluble micro powder containing florfenicol and preparation method thereof |
| CN101843586B (en) * | 2010-04-29 | 2012-05-23 | 山东迅达康兽药有限公司 | Water-soluble micro powder containing florfenicol and preparation method thereof |
| CN115212187A (en) * | 2014-11-05 | 2022-10-21 | 西莱克塔生物科技公司 | Methods and compositions related to the use of low HLB surfactants in synthetic nanoparticles comprising RAPALOG |
| CN115212186A (en) * | 2014-11-05 | 2022-10-21 | 西莱克塔生物科技公司 | Methods and compositions related to the use of low HLB surfactants in synthetic nanoparticles comprising RAPALOG |
| CN108743952A (en) * | 2018-06-11 | 2018-11-06 | 西安力邦医药科技有限责任公司 | Phosphatide-miscible agent-oil sustained release drug delivery systems the prescription and preparation method of local anesthetic |
| CN108743952B (en) * | 2018-06-11 | 2021-08-31 | 西安力邦医药科技有限责任公司 | Phospholipid-miscible solvent-oil sustained-release drug delivery system formula of local anesthetic and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| ZA200604881B (en) | 2008-09-25 |
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