CN101495148B - Pharmaceutical composition comprising at least one anticancer drug and at least one polymer - Google Patents
Pharmaceutical composition comprising at least one anticancer drug and at least one polymer Download PDFInfo
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- CN101495148B CN101495148B CN200680039204XA CN200680039204A CN101495148B CN 101495148 B CN101495148 B CN 101495148B CN 200680039204X A CN200680039204X A CN 200680039204XA CN 200680039204 A CN200680039204 A CN 200680039204A CN 101495148 B CN101495148 B CN 101495148B
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Abstract
The present invention relates to novel and improved compositions of anticancer drugs, preferably taxanes, such as paclitaxel and docetaxel, their derivatives or their analogues, methods of manufacturing these compositions and methods of fractionating the particles in particular size range and methods of treating cancer patients with these compositions, which provide reduced chemotherapy-induced side-effects especially reduced chemotherapy-induced- alopecia. The composition is such that there is substantially no free drug in the said composition.
Description
The present invention relates to the anticarcinogen compositions.The present invention relates to treatment of cancer and use compositions, it has the inductive side effect of chemotherapy that reduces in fact.
The present invention relates to the anticarcinogen compositions, include but not limited to alkylating agent, antimetabolite class medicine, antibiotics anticarcinogen, vegetable alkaloids medicine, amerantrone class medicine (anthracenediones), natural product, hormone, hormone antagonist, other medicines (miscellaneous agents), radiosensitizer, platinum coordination complex, adrenal cortex inhibitor, immunosuppressant, functional therapeutic agent, gene therapeutic agents, antisense therapy agent, tyrosine kinase inhibitor, monoclonal antibody, immunotoxin, radioimmunoassay conjugate, cancer vaccine, interferon, interleukin, substituted urea class, taxanes and cox 2 inhibitor.
The present invention relates to the anticarcinogen compositions, preferred taxanes, for example paclitaxel and docetaxel (docetaxel), their derivant or their analog prepare the method for these preparations and these combination treatments of use cancer patient's method.
The present invention relates to the anticarcinogen compositions, the preferred taxanes of said anticarcinogen, for example paclitaxel and docetaxel; Their derivant or their analog; Prepare these method for compositions and will and use these combination treatments cancer patient's method in the fractionated method of the particle in the specified particle size scope; It provides the inductive side effect of chemotherapy that reduces, the inductive alopecia of chemotherapy that particularly reduces.Compositions does not contain free medicine in fact for making in said compositions.
Said anticarcinogen compositions; The preferred taxanes of said anticarcinogen, for example paclitaxel and docetaxel, their derivant or their analog; It is the colloidal state delivery system that is used for treatment of cancer; Have the inductive alopecia of chemotherapy that reduces in fact, in the particle size range of confirming, be produced, in compositions, do not contain free drug in fact.
Background of invention
So far develop anticarcinogen miscellaneous and be used to treat mammiferous various cancer; And developing more and more newer medicine as chemotherapeutics; The purpose of wherein said research is to develop the tumour-specific anticarcinogen, increases the usefulness to resistant tumors simultaneously.The clinical procedures of further upgrading relates to the anticarcinogen combination, with the therapeutic efficacy of activity increase.The discovery well afoot of this renewal; But at present; Chemotherapeutics for example 5-fluorouracil (5FU), doxorubicin and taxanes is the main treatment means that is used to suffer from the patient of various cancers, and said various cancers comprise ovarian cancer, breast carcinoma, pulmonary carcinoma, colon cancer, carcinoma of prostate, head and neck cancer, cervical cancer and the brain cancer, and other cancer.
Yet these have been subjected to xicity related restriction with the application of other medicines, and that said toxicity comprises is nauseating, bone marrow depression (myelosuppression), alopecia, vomiting and stomatitis and cardiac toxicity.
Above-mentioned all these xicity related in, the alopecia (or hair forfeiture) that is caused by chemotherapy is the most worried and one of traumatic side effect of cancer patient, because it causes depression, the impaired and humiliation sense of confidence in the masculinity and femininity patient of all age brackets.Because the health due to the alopecia that treatment is correlated with and the worry of emotion aspect, some patients' refusals are treated.The hair forfeiture has appreciable impact to patient's mental status, and is the major issue that influences patients ' life quality.Therefore, press for a kind of treatment of cancer that has in fact the inductive alopecia of chemotherapy that reduces is provided.
Taxanes is the anticancer cytotoxin of stabilized cell microtubule.The bearing taxanes that is used for compositions described herein and method comprises paclitaxel and docetaxel, and has the natural and synthetic analog of active anticancer or anti-angiogenesis activity.Paclitaxel and docetaxel have the activity of essence, and one of these medicines or its two be widely used as the component of treatment breast carcinoma in late period, pulmonary carcinoma and ovarian cancer.
Docetaxel is the antitumor agent that belongs to taxanes family (taxoid family).It begins through semi-synthetic preparation from the precursor of extraction from the needle-like biomass of reproducible Ramulus et folium taxi cuspidatae plant.
is aseptic docetaxel injection concentrate; Single dose bottle to comprise docetaxel and polysorbate 80 obtains; Be used for drug administration by injection for example contain alcoholic acid water dilution with diluent after, and be the invalid prescription drugs of treating the patient who suffers from local late period or transitivity breast carcinoma afterwards of chemotherapy that is used for formerly.TAXOTERE and doxorubicin and cyclophosphamide combination are suggested the auxiliary treatment that is used for the positive patients with mastocarcinoma of operable lymph node.
The paclitaxel that belongs to the taxanes chemotherapeutics is widely used for many years as intravenous dosage form, is used to treat breast carcinoma and ovarian cancer or nonsmall-cell lung cancer (NSCLC).Along with showing the great potential of paclitaxel as antineoplastic agent; About dissolubility, toxicity, bioavailability is low and form chemical sproof clinical problem becomes very serious, makes obvious for the needs of the preparation with better therapeutic efficacy and less toxic paclitaxel derivant or analog.
Paclitaxel
obtains as the solution that is used for the i.v. infusion in the vehicle of being made up of
EL, and
EL has shown and caused the for example life-threatening anaphylactic reaction of toxic action.The polyoxyethylene castor oil of this paclitaxel (cremophor)/ethanol preparation precipitates when diluting with infusion liquid, and in some compsns, in long-time storage process, forms fibery precipitate.Other information about the polyoxyethylene castor oil preparation of paclitaxel can find in people's such as Agharkar United States Patent (USP) 5,504,102.
There are many United States Patent (USP)s to comprise United States Patent (USP) 5,439,686,5,498,421,5 to this product
; 560,933,5,665,382,6,096; 331,6,506,405,6,537,579,6; 749,868 and 6,753,006.
According to the invention in the above-mentioned patent of mentioning; The compositions and the method that can be used for sending in the body water-insoluble in fact pharmacologically active agents (for example anticarcinogen paclitaxel) are provided, and wherein activating agent is sent to combine with protein (playing function of stabilizer) or to be coated with proteinic suspended particles form.In these inventions; Carried out attempting so that the pharmaceutical protein microsphere of interim preparation to be provided; In order to sending water-insoluble in fact activating agent at the water slurry that is used for parenterai administration, and do not cause because emulsifying agent and solubilizing agent the caused anaphylactic reaction that exists of (as be used for Taxol polyoxyethylene castor oil).At United States Patent (USP) 5,439, in 686, the inventor finds that water-insoluble in fact pharmacologically active agents can send with the particulate form that is suitable for parenterai administration in water slurry.This inventive compositions comprises the water-insoluble in fact activating agent (as solid or liquid) that is included in the polymer shell, and polymer shell is through crosslinked biocompatible polymer of existing of disulfide bond.
United States Patent (USP) 5; 560; 933 require the method for its above-mentioned inventive compositions of protection preparation; Its require protection " method of the water-insoluble in fact pharmacologically active agents that preparation is used for sending in the body; said method comprises makes mixture reach a period of time through the sonication condition, said mixture are included in the dispersant that wherein is dispersed with said pharmacologically active agents and the aqueous medium that comprises biocompatible polymer that can be through disulfide bond crosslinking, the said time be enough to promote said biocompatible polymer through disulfide bond crosslinking to be created in the polymer shell that wherein comprises pharmacologically active agents ".
United States Patent (USP) 6,506,405 require the preparation of protection paclitaxel, and said preparation is used for treating experimenter's primary tumo(u)r, and it has realized the high local concentrations of said paclitaxel at tumor locus, and said preparation is substantially free of polyoxyethylene castor oil.According to 6,506,405 inventor, their preparation that comprises albumin and do not contain polyoxyethylene castor oil shows brain toxicity or neurological's toxicity of the reduction of comparing with the commercially available Taxol compositions that comprises polyoxyethylene castor oil.
United States Patent (USP) 6; 749; 868 provide drug delivery system; The part of the molecule of pharmacologically active agents is combined with protein (for example human serum albumin) and therefore mammal is given after immediately for biological available, and another part of pharmacologically active agents is included in by in the nanoparticle of protein coating.Preparation by the medicament nano particle of protein coating is carried out as follows: in the presence of the surfactant that does not have routine, use high shear force; Obtain diameter less than about 1 micron particle; Then with its aseptic filtration, so that the sterile solid that can be used for intravenous injection dosage form to be provided.
In the above-mentioned patent that relates to
; The method of the paclitaxel that scribbles protein (like albumin) is provided; Wherein said protein coat also has bonded free protein within it, makes a part of activating agent be comprised in the protein coat and combines with free protein so that available for biology immediately when giving with a part of activating agent.The average diameter of the said particle of in the invention of described prior art, describing is not more than about 1 micron; Wherein compositions comprises the particle of the particle size range of 10-200nm, and particularly these small particle diameter particles can carry out aseptic filtration through 0.22 micron filter and obtain.Basically through using albumin bound type drug particle (albumin is biocompatible substance); The inventor proposes; With available comprise polyoxyethylene castor oil and relate to anaphylactic reaction compare with other toxic Taxol, the toxicity of pharmacologically active agents such as paclitaxel such as bone marrow depression and/or neurotoxicity reduce.
But preparation paclitaxel method for compositions is described or provided to neither one in the above-mentioned patent; Wherein said composition is in specific narrow particle size range and does not contain free drug in fact, so that the inductive alopecia of the chemotherapy treatment of cancer that (it is one of traumatic side effect of tool for the cancer patient) reduces in fact is provided.The product of the above-mentioned patent that relates to commercially available prod
through avoiding emulsifying agent such as polyoxyethylene castor oil to provide avoiding causing allergic reaction; And microgranule or the nanoparticle delivery system stable, the warp sterilization that are used for water-insoluble in fact activating agent such as paclitaxel are provided, but they fail to provide the formulation for paclitaxel of being free from side effects like alopecia or hair forfeiture or said side effect minimizing.
product advertising in the Patient Information (PATIENT? INFORMATION) mentioned in the hair loss is about taking
The study of patients observed in one important side effect.It is mentioned hair forfeiture completely or alopecia almost always takes place when using
.
By people such as Yang, Front Biosci.2005Sep 1; 10:3058-67 discloses research paper; Be about the temperature that is used for sending in the born of the same parents paclitaxel, the research of pH sensitivity core-core/shell nanoparticles; It has been described with temperature, pH sensitivity amphiphilic polymers N-Isopropylacrylamide-acrylic acid-cholesteryl acrylate copolymer (P (NIPAAm-Co-AA-Co-CHA)) envelope paclitaxel, to form nanoparticle.Yet this research paper is not discussed or is mentioned the method for these particle compositions of preparation and particle is classified as specific clear and definite particle size range and do not contain free drug in fact and makes it be suitable for being provided at and have the method for compositions that the inductive alopecia of chemotherapy reduces in fact among the cancer patient.
United States Patent (USP) 5; 399; 363 relate to the anticancer nano particle of surface modification; Wherein particle mainly is made up of the crystallization anticarcinogen with surface modifier, and said surface modifier is preferably absorption from the teeth outwards with the nonionic and the anionic surfactant of effective mean diameter of keeping below about 1000nm.The Usage of Surfactant itself promotes the toxicity of compositions.5,399, not only there is not proof but also do not predict that the particular range of the particle diameter that uses the taxol nanometer particle compositions that comprises biodegradable polymers reduces like alopecia to realize that the inductive side effect of specific chemotherapy reduces in 363 inventions.5,399,363 concrete invention is the noncrosslinking surface modifier of absorption on the surface of crystallization anticarcinogen.
United States Patent (USP) 6,136,846 require protection to be used for sending in the body compositions of paclitaxel, said composition comprise paclitaxel, solvent such as ethanol or propylene glycol and can with the miscible solubilizing agent of water such as the d-alpha-tocopherol acid succinate of esterification.Because 6; Researchs before 316,846 inventions efforts be made so that with 50% polyoxyethylene castor oil and 50% anhydrous alcohol preparation insoluble drugs such as paclitaxel, and these preparations precipitate when diluting with infusion liquid, instability and cause unsuitable adverse reaction when storing; So 6; 316,846 inventions efforts be made so that with what be different from polyoxyethylene castor oil can provide the preparation with improved long-time stability and safety with the miscible solubilizing agent of water, thereby improved formulation for paclitaxel is provided.
The open WO 2004/084871 of PCT relates to lactic-co-glycolic acid polymer and polylactic acid (PLA) nanoparticle, and it is sealed low-molecular-weight water soluble drug and this medicine is delivered to the target location, and wherein particle discharges medicine gradually in time expand.In essence; The interaction that the WO2004/084871 invention relates to through low-molecular-weight, water miscible and non-peptide medicament and metal ion is translated into hydrophobic drug; Then with the hydrophobization drug encapsulation in PLGA or PLA nanoparticle, and on the surface of particle the absorption surface activating agent.This patent does not relate to or mentions like paclitaxel and other anticarcinogen, and the chemotherapy compositions that inductive side effect is able to reduce is not provided.
By people such as Fonseca; The research of in " Journal of Controlled Release 83 (2002) 273-286 ", announcing relates to the polymeric medicine delivery system of developing paclitaxel; For example be loaded with (lactic-co-glycolic acid) polymer nano-particle of paclitaxel; The therapeutic index that it is used for intravenous administration and can improves medicine, and the side effect that does not cause by polyoxyethylene castor oil EL.In this paper and other prior art document of aforementioned great majority, the particle diameter of the particle that obtains is less than 200nm.Authors do not provide not containing free drug and being in the compositions (it has surprising advantage) in specific definite particle size range of inventor's discovery of the present invention.
U. S. application 20060041019 requires protection to be used to suppress the medicine of the hair forfeiture that caused by antitumor agent, and wherein said medicine is that condensation degree is 3 to 20 the ring-type and/or the mixture of straight chain poly lactic acid.Preferably, the mixture of described ring-type of the inventor of U. S. application 20060041019 and/or straight chain poly lactic acid is the poly-lactic acid mixture through the lactide polymerization is produced: formula (3) is Me-N (R
1) (R
2), wherein Me representes alkali metal, R
1And R
2Represent aliphatic group or aromatic group independently of one another.
Therefore, can find out, the compositions of anticarcinogen that the alopecia related side effects reduces in fact such as paclitaxel, docetaxel and other anticarcinogen all is not provided in these prior art documents and prepare this method for compositions.Improved the anti-cancer compsn of rendeing a service although before carried out various trials to provide to have; But these compositionss all do not show low clinical side effects; Especially, these compositionss all do not provide the method for distressful especially alopecia of minimizing or hair forfeiture side effect.
Therefore; Need comprise the compositions of anticarcinogen and use these compositionss to overcome the Therapeutic Method of the stability problem and the various clinical side effects of the preparation that alleviates present known listing; The most important thing is to reduce inductive alopecia of treatment or hair forfeiture, and these preparation of compositions methods.Have demand for medicine such as 5-fluorouracil, doxorubicin, docetaxel, paclitaxel, its derivant and/or its analog.
Goal of the invention
The objective of the invention is:
1. provide treatment of cancer to use compositions, it has inductive side effect of chemotherapy such as the alopecia that reduces in fact.
2. provide treatment of cancer to use compositions, it comprises the particle of at least a anticarcinogen and at least a polymer, and wherein because particle exists with the particle size range of confirming, said composition produces inductive side effect of chemotherapy such as the alopecia that reduces in fact.
3. provide aforesaid treatment of cancer to use compositions, wherein additionally, compositions does not contain free drug in fact; Medicine in fact fully combines with polymer.
4. provide treatment of cancer to use compositions, comprise the particle of at least a anticarcinogen and at least a polymer, the D10>=80nm of particle wherein, D50 is about 200nm, D90≤450nm; Compositions is to make it that the inductive side effect of chemotherapy such as the alopecia of minimizing are provided.
5. provide the treatment of cancer described in top the 4th to use compositions, the D10>=120nm of particle wherein, D50 is about 200nm and D90≤350nm.
6. provide the treatment of cancer described in top the 5th to use compositions, the D10>=140nm of particle wherein, D5 is about 200nm and D90≤260nm.
7. provide treatment of cancer as stated to use compositions, wherein anticarcinogen is selected from alkylating agent, antimetabolite class medicine, antibiotics anticarcinogen, vegetable alkaloids medicine, amerantrone class medicine, natural product, hormone, hormone antagonist, other medicines (miscellaneous agent), radiosensitizer, platinum coordination complex, adrenal cortex inhibitor, immunosuppressant, functional therapeutic agent, gene therapeutic agents, antisense therapy agent, tyrosine kinase inhibitor, monoclonal antibody, immunotoxin, radioimmunity conjugate, cancer vaccine, interferon, interleukin, substituted urea class, taxanes and cox 2 inhibitor.
8. provide the treatment of cancer described in top the 7th to use compositions, wherein anticarcinogen is preferably selected from derivant (like paclitaxel, docetaxel), 5-fluorouracil and the doxorubicin of taxane.
9. provide aforesaid treatment of cancer to use compositions, the paclitaxel of anticarcinogen wherein for existing to the amount of about 99.5 weight % with about 0.5 weight % of compositions, and comprise the polymer that about 2.0 weight % arrive about 99.0 weight %.
10. provide aforesaid treatment of cancer to use compositions, the biodegradable polymer of polymer wherein for existing to the amount of about 99.0 weight % with about 2.0 weight % of compositions, like human serum albumin, d, l-poly lactic coglycolic acid etc.
11. being provided in addition, above-mentioned treatment of cancer uses compositions; It has second polymer of temperature of being selected from and/or pH sensitive polymer, as gathers N-acetyl group acrylamide, poly-N-isopropyl acrylamide, N-Isopropylacrylamide-acrylamide copolymer, polyvinyl alcohol, Polyethylene Glycol, polyacrylamide, PMAm etc. and derivant thereof.
12. provide like top the 11st described treatment of cancer and use compositions; Wherein second polymer is a poly-N-isopropyl acrylamide, uses to be selected from following amount: the about 2.0 weight %s of about 0.5 weight % of compositions to about 1.0 weight % of about 99.0 weight %, compositions to about 95.0 weight % and compositions are to about 90.0 weight %.
13. provide like top the 11st described treatment of cancer and use compositions; Wherein in the presence of second polymer; To the mammal administration time; The size of the particle of compositions is increased to about twice of its original size in blood plasma, and is increased to about ten times of its original size at tumor locus, thus the inductive side effect of chemotherapy such as the alopecia that targeting are provided and reduce in fact.
14. provide like top the 1st described treatment of cancer and use compositions; Wherein compositions comprise about 0.5 weight % of accounting for compositions to the paclitaxel of about 99.5 weight %, account for about 2.0% to about 99.0 weight % d of compositions; L poly lactic coglycolic acid and about 2.0 weight % of accounting for compositions are to the optional poly-N-isopropyl acrylamide of about 90.0 weight % and account for one or more pharmaceutically acceptable excipient, carrier or its combination of about 0.01 weight % of compositions to about 99.9 weight %.
15. provide like top the 1st described treatment of cancer and use compositions; Wherein compositions comprise about 0.5 weight % of accounting for compositions to the paclitaxel of about 99.5 weight %, about 2.0% to about 99.0 weight % the albumin that accounts for compositions and optional about 2.0 weight % that account for compositions to about 90.0 weight % poly-N-isopropyl acrylamide and account for one or more pharmaceutically acceptable excipient, carrier or its combination that about 0.01 weight % of compositions arrives about 99.9 weight %.
16. provide preparation aforesaid method for compositions; May further comprise the steps: (i) in solvent with at least a anticarcinogen and at least a polymer mixed; (ii) randomly in the presence of one or more pharmaceutically suitable carrier, carry out step (i); (iii) obtain nanoparticle and (iii) make nanoparticle, (iv) remove any free drug from compositions through the particle screening through removing to desolvate; Said composition is to make it that inductive side effect of chemotherapy such as alopecia that reduces in fact is provided.
17. the method for treatment mammalian cancer is provided; Comprise the step of this mammal being treated the said compositions of effective dose; Said compositions comprises the particle of at least a anticarcinogen and at least a polymer; D10>=the 80nm of particle wherein, D50 is about 200nm and D90≤450nm, and said composition is to make it not contain free drug in fact and inductive side effect of chemotherapy such as the alopecia that reduces in fact is provided.
18. be provided at experience with reducing the inductive side effect of chemotherapy of treatment of cancer such as the method for alopecia in the mammal of anticancer drug therapy; Said method comprises the said compositions of treating effective dose; Said compositions comprises the particle of at least a anticarcinogen and at least a polymer; D10>=the 80nm of particle wherein, D50 is about 200nm and D90≤450nm, and said composition is for making it not contain free drug in fact.
Summary of the invention
The present invention relates to treatment of cancer and use compositions, it has the inductive side effect of chemotherapy that reduces in fact.
The present invention relates to the anticarcinogen compositions, the anticarcinogen that anticarcinogen is preferably poorly soluble, said preparation of compositions method and the method for using these combination treatments cancer patient, said compositions has the inductive side effect of chemotherapy such as the alopecia of minimizing.
Importance of the present invention is devoted to provide the colloidal state delivery system such as the nanoparticle compositions of anticarcinogen such as taxanes (for example paclitaxel or docetaxel) and at least a biodegradable polymer; Make said composition have definite particle size range; Wherein the D10 of particle is more than or equal to 80nm, and D50 is less than or equal to 450nm for about 200nm and D90.This definite specific effective size of grain scope provides such compositions, when giving the patient with said composition and be used to treat cancer, has the inductive side effect of chemotherapy such as the alopecia that reduce in fact.Said composition is preferably and makes it not contain free drug in fact; Medicine in fact fully combines with polymer.
Another aspect of the present invention is devoted to the nanoparticle compositions that provides such, and this nanoparticle compositions comprises second polymer and optional other pharmaceutically suitable carrier and the excipient of any other expectation of temperature and pH sensitivity in addition.This compositions provides such particle; When giving this particle to mammal; The size of particle is increased to about twice of its original size in blood plasma; And be increased to about ten times of its original size, thereby the inductive side effect of chemotherapy such as the alopecia that the targeting of tumor locus are provided and reduce in fact at tumor locus.
The present invention discloses the method for preparing this nanoparticle compositions in addition; May further comprise the steps: in the presence of solvent with at least a anticarcinogen and at least a polymer mixed; Said solvent randomly has one or more pharmaceutically suitable carrier and any desired excipient; Except that desolvating and sieving to obtain confirming the particle of granularity, be about 200nm and D90≤450nm like D10>=80nm, D50 through particle.The nanoparticle with definite particle size range that so obtains is further through removing any free drug.When giving the patient, this compositions provides inductive side effect of chemotherapy such as the alopecia that reduces in fact.
Therefore, the present invention relates to provide Therapeutic Method, comprise the nanoparticle compositions of the present invention of the mammal that needs are arranged being treated effective dose, said composition provides inductive side effect of chemotherapy such as the alopecia that reduces in fact.The present invention provides through giving the effective nanoparticle compositions of the present invention of said treatment and in experiencing with the mammal of anticancer drug therapy, reduces the inductive side effect of chemotherapy of treatment of cancer such as the method for alopecia.
Aforesaid general remark and following detailed description are exemplary with illustrative, and are intended to the present invention who requires to protect provided and further specify.Through following detailed description of the invention, other purpose, advantage and novel characteristics it will be apparent to those skilled in the art that.
Detailed description of the invention
The present invention provides treatment of cancer to use compositions.
The anticarcinogen of developing many renewals is used to treat mammiferous tumor, but the major defect of anticarcinogen or antineoplastic agent is that they can not specificity and optionally influence tumor cell; They also influence normal cell and have side effects thus.
Send at medicine and to make great efforts in the field so that improve rendeing a service, and is making great efforts to provide multiple medicines thing therapy to improve the effectiveness of anticarcinogen at increasing these anticarcinogen targeting positions.Yet the problem of side effect is still main worry, and it is not also solved fully, and one of these major side effects of chemotherapy are alopecia or hair forfeiture.
Hair forfeiture or alopecia are distressful side effect for the individuality that carries out chemotherapy.Great majority have experienced alopecia significantly in the patients undergoing chemotherapy.Hair regeneration after the chemotherapy needs 3 to 6 months, and has the patient of certain percent to fail to recover fully.The inductive alopecia of chemotherapy has special destructiveness, because it is the external sign of the disease otherwise hidden, causes some patients to refuse systemic chemotherapy.
Therefore, the most preferred aspect according to the present invention provides the treatment of cancer with the side effect that reduces in fact to use compositions.Said side effect is inductive side effect of chemotherapy such as alopecia preferably.Compositions of the present invention comprises at least a anticarcinogen and at least a polymer.
The treatment of cancer that can use in the present invention is selected from alkylating agent with anticarcinogen; Antimetabolite class medicine; The antibiotics anticarcinogen; The vegetable alkaloids medicine; Amerantrone class medicine; Natural product; Hormone; Hormone antagonist; Other medicines; Radiosensitizer; The platinum coordination complex; The adrenal cortex inhibitor; Immunosuppressant; The functional therapeutic agent; Gene therapeutic agents; The antisense therapy agent; Tyrosine kinase inhibitor; Monoclonal antibody; Immunotoxin; The radioimmunity conjugate; Cancer vaccine; Interferon; Interleukin; Substituted urea class; Taxanes and cox 2 inhibitor.
Last group comprises: alkylating agent; Comprise: alkyl sulfonates is busulfan for example; The Ethylenimine derivant is for example filled in for group; Nitrogen mustards is chlorambucil, cyclophosphamide, estramustine, ifosfamide, chlormethine, melphalan and uracil mustard for example; Nitrosoureas is carmustine, lomustine and streptozocin for example, and triazines is dacarbazine, procarbazine and temozolomide and platinum compounds cisplatin, carboplatin, oxaliplatin, Satraplatin JM216 BMS 182751 and (SP-4-3)-(cis)-amine two chloro-[2-picoline] platinum (II) for example for example; Antimetabolite class medicine; Comprise: antifolate is methotrexate, permetrexed, Raltitrexed and trimetrexate for example; Purine analogue is cladribine, chlorine deoxyadenosine, clofarabine, fludarabine, mercaptopurine, pentostatin and thioguanine for example, and pyrimidine analogue is azacitidine, capecitabine, cytosine arabinoside, edatrexate, azauridine, fluorouracil, gemcitabine and troxacitabine for example; Natural product; Comprise: AGPM is bleomycin, actinomycin D, mithramycin, mitomycin, mitoxantrone, porfiromycin for example; With anthracene nucleus class for example daunorubicin (comprising the liposome daunorubicin), doxorubicin (comprising the liposome doxorubicin), epirubicin, idarubicin and valrubicin; Enzyme is altheine enzyme and PEG-L-asparaginase for example; Microtubule polymerization thing stabilizing agent is taxanes, paclitaxel and docetaxel for example; Mitotic inhibitor is vinca alkaloids vinblastine, vincristine, vindesine and vinorelbine for example, and the topoisomerase I inhibitor is for example amsacrine, etoposide and teniposide of camptothecine, irinotecan and TPT and topoisomerase II inhibitor for example; Hormone and hormone antagonist; Comprise: androgen is fluoxymesterone and Testolactone for example; Androgen antagonist is bicalutamide, cyproterone, flutamide and nilutamide for example; Aromatase inhibitor is aminoglutethimide, Anastrozole, exemestane, formestane and letrozole for example, and cortical steroid is dexamethasone and prednisone for example, and estrogen is diethylstilbestrol for example; Antiestrogen is fulvestrant, raloxifene, tamoxifen and toremifene for example; LHRH agonist and antagonist for example buserelin, goserelin, bright in Rayleigh and triptorelin, progestational hormone is for example levothyroxine and liothyronine of medroxyprogesterone acetate and megestrol acetate and thyroxin for example; And other medicines; Comprise for example methoxsalen and porfimer sodium and proteasome inhibitor bortezomib for example of altretamine, arsenic trioxide, Ganite (Fujisawa)., hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, Thalidomide, photodynamics chemical compound.Molecular targeted therapeutic agent comprises: the functional therapeutic agent; Comprise: gene therapeutic agents, antisense therapy agent; Tyrosine kinase inhibitor is Erlotinib hydrochloride, gefitinib, imatinib mesylate and Si Mashani (semaxanib) for example; With gene expression regulator for example tretinoin and xanthoplane class (rexinoids), for example adapalene, bud salol fourth, trans retinoic acid, 9-cis-retinoic acid and N-(4-hydroxyphenyl) VAAE; The therapeutic agent of epi-position guiding; Comprise: for example Ah coming organizes monoclonal antibody (alemtuzumab), bevacizumab, Cetuximab, ibritumomab tiuxetan (ibritumomnab tiuxetan) to monoclonal antibody, sharp appropriate Xidan is anti-and Herceptin; The for example lucky trastuzumab of immunotoxin azoles rice difficult to understand star, the radioimmunity conjugate for example
131The lucky trastuzumab of I-azoles rice difficult to understand star, and cancer vaccine.Biology, therapeutic agent comprised: interferon is interferon-' alpha ' for example
2aAnd interferon-' alpha '
2bAnd interleukin for example aldesleukin, diphtheria toxin, diphtherotoxin/IL-2 gene recombinant fusion protein (denileukindiftitox) and oprelvekin (oprelvekin).Except being directed against acting these medicines of cancerous cell; Treatment of cancer comprises and utilizes protectiveness or auxiliary medicaments; Comprise: cytoprotective is amifostine, dexrazoxane (dexrazonxane) and mesna for example; Phosphonic acid ester for example pamldronate and zoledronic acid and stimulating factor for example according to Bo Ting, Da Beiting (darbeopetin), filgrastim, PEG-filgrastim and Sargramostim.Preferably, anticarcinogen is poorly soluble anticarcinogen.
(for example be used for anticarcinogen of the present invention and be taxanes and derivant thereof; Paclitaxel, docetaxel and derivant thereof etc.), but other anticarcinogens do not got rid of like (for example doxorubicin, methotrexate, cisplatin, daunorubicin, doxorubicin, cyclophosphamide, D actinomycin D, bleomycin, epirubicin, mitomycin, methotrexate, 5-fluorouracil, carboplatin, carmustine (BCNU), Semustine, cisplatin, etoposide, interferon, camptothecine, phenylacetic acid chlormethine, tamoxifen, piposulfan and derivant thereof etc.).Preferred anticarcinogen is the medicine that is selected from taxanes, 5-fluorouracil and doxorubicin, most preferably is taxanes.
The term that uses among this paper " taxanes " comprises chemotherapeutics Taxol (common name: paclitaxel; Chemical name 5 β, 20-epoxy-1,2a; 4,7 β, 10; 13a-six hydrogen Ramulus et folium taxi cuspidatae-11-alkene-9-ketone; 4, docetaxel), other semi-synthetic derivant of second filial generation taxanes such as Ortataxel and taxanes 10-diacetate esters 2-benzoic acid 13-ester and (2R, 3S)-N-benzoyl-3-(-)-Eseroline phenylcarbamate) and Taxotere (common name:.Taxol; Described anticarcinogen is also arranged in background technology; General by name " paclitaxel (paclitaxel) " is originally from the diterpene (complex polyoxygenated diterpene) in polyoxy generation of the isolating complicacy of bark of Pacific yew tree (mountain mahogany) by the trade name
of Bristol-Myers Squibb Company registration.It is used to treat breast carcinoma, ovarian cancer and pulmonary carcinoma and the relevant Kaposi sarcoma of AIDS by the FDA approval.
(docetaxel) is similar with paclitaxel; Also be the material that derives from the yew tree needle, be used to treat the breast carcinoma and nonsmall-cell lung cancer in late period that other anticarcinogen is not replied by FDA approval.Paclitaxel and docetaxel intravenous administration.But the two all has the comparison serious adverse paclitaxel and docetaxel.Paclitaxel is water insoluble, uses CremophorEL (polyethoxy Oleum Ricini) and ethanol as excipient that paclitaxel is formulated as Taxol; It causes serious adverse.Anaphylaxis and the high rate of other allergy when using Taxol have been reported.Recently; New protein bound type nanoparticle paclitaxel injectable suspensions has been proposed; It has avoided the use of polyoxyethylene castor oil and has not contained solvent brand name for
, therefore the not side effect relevant with polyoxyethylene castor oil and solvent.Even but this compositions also shows the inductive side effect of another kind of chemotherapy, one of them is traumatic side effect alopecia of tool or hair forfeiture.Therefore; Although it is the maximum progress of oncology's drug world that paclitaxel has that good clinical efficacy and its occur, for the better safety and the pharmacokinetics characteristic that have in the patient being provided, avoiding the paclitaxel compositions of traumatic side effect of tool such as alopecia to still have increasing needs.
The most preferred taxanes that selection is used for this research is a paclitaxel; But should be appreciated that; This research also can extend to other anticarcinogen, and its details provides in this article, and paclitaxel is present in the compositions of the present invention to the amount of about 99.5 weight % with about 0.5 weight % of compositions; Be preferably the amount of about 2.0 weight %, most preferably be about 5.0 weight % to about 90.0 weight % to about 95.0 weight %.
Anticarcinogen can use separately, perhaps uses with one or more other medicines combinations of the present invention.They can be unbodied, crystallization or its mixture, and preferred agents is unbodied in fact.
Place like this is described and run through the application, uses several definition to describe the present invention among this paper.
" pharmaceutically useful " as using among this paper is meant those chemical compounds, material, compositions and/or dosage form; They are fit to contact human and animal's tissue and do not have too much toxicity, zest, allergy or other problem or complication in rational medical judgment scope, match with rational interests/risk ratio.
" treatment effective dose " is meant effective realization desired therapeutic result's amount.
Like the term " polymer " of using among this paper " be meant the molecule that comprises a plurality of covalently bound monomeric units, comprise side chain, dendroid and star polymer and straight chain polymer.This term also comprises homopolymer and copolymer, for example, and random copolymer, block copolymer and graft copolymer, and uncrosslinked polymer and be linked to appropriately crosslinked polymer to significant cross linking a little.
The term " biodegradable " polymer " be meant this polymer through each process of health be degraded to can be easily by health handle and can be in health cumulative product, and term " biocompatible " but described that this material does not change with any disadvantageous mode perception ground or the biosystem of said material is not wherein introduced in influence.
Like what use among this paper, " poorly soluble " is meant that activating agent at room temperature has the dissolubility that is lower than about 10mg/ml in water, and is preferably lower than 1mg/ml.
Like what use among this paper; " granularity " is used for representing the size of compositions particle; Its by one of skill in the art the particle size analyzer of known routine measure for example sedimentation FFF, photon correlation spectroscopy method, laser light scattering or kinetics light scattering technique and through using transmission electron microscope (TEM) or scanning electron microscope (SEM) to measure.Automatically light scattering technique adopts Horiba LA laser light scattering particle size analyzer or similarly installs easily.This analysis typically provides the volume fraction (frequency normalization) of the discrete sized of particle, comprises one-level particle, aggregate (aggregates) and aggregation.In this manual, grain size characteristic often is meant the representation of Dn type, and wherein n is 1 to 99 numeral; This representation is represented the cumulative distribution of granularity, and promptly the particle of n% (by volume) is less than or equal to said size.Typically, to be expressed as with nm be D10, D50 (intermediate value) and the D90 value of unit to granularity.The ratio of D90/D10 is the suitable characteristic of identifying the size distribution curve width.In various aspects of the present invention, narrow particle size distribution, the ratio of preferred D90/D10 is more preferably less than 3, even is more preferably less than 2.0 less than 4.
Like what use among this paper, term " nm " is meant nanometer, and than 1 micron littler unit, micron is the measurement unit of one thousandth millimeter.
Like what use among this paper, " pact " should be that those skilled in the art can understand, and it is to a certain extent with the environment change of its use.If the situation that has the use of this term that those skilled in the art are not still removed under the situation of known its environment for use, then " pact " means that particular term adds and deduct maximum 10%.This implication is applicable to term " about " is used in the situation that the application describes percent or amount in anticarcinogen, carrier, excipient and other situation except particle size of the present invention; When describing particle size of the present invention, word " pact " expression particular term adds or deducts maximum 25% value.This means that D50 is that about 200nm is meant the particle size range of 150nm to 250nm.
Be meant owing to give the unfavorable symptom that anticarcinogen produces in mammal like the term " the inductive side effect of chemotherapy " that uses in the text.The example comprises hair forfeiture, bone marrow depression, vomiting, digestive pathologies, liver toxicity, nephrotoxicity, brain toxicity, cardiac toxicity, lung toxicity, stomatitis, dermatosis and neurotoxicity.Preferably provide compositions of the present invention to be used to suppress or reduce the hair forfeiture (or alopecia) of one of above-mentioned side effect.
The forfeiture of " alopecia " or hair in this article refers to preferred relevant with drug-induced alopecia, and it damages the hair follicle of health.Should be appreciated that; Hair follicle on the head has optimum growth speed and its trophophase is long; Owing to have higher biological activity with the hair organ that the hair organ of other position in health is compared on scalp; Hair organ on the scalp receives the influence of anticarcinogen more easily, causes the infringement to matrix cells in the hair follicle.Therefore, the growth of hair matrix cell function is affected or the hair organ develops resting stage and hair rapidly and comes off with the form of atrophic hair.
The previous effort that is used to suppress the hair forfeiture that chemotherapy causes comprise anticarcinogen made up with antagonist give, blocking blood flow gives and alternate manner to scalp, intra-arterial, but these work all do not provide any significant effect so far.Attempt among the present invention, realize this task through safety, effective, simple and novel technology.
System and detailed research for the compositions of the various particulate forms that comprise anticarcinogen and at least a polymer has disclosed surprising and very useful discovery, and the geometry of physical chemical factor such as particle is providing the side effect with minimizing such as the treatment of cancer of alopecia to play important effect with Composition Aspects.Said factor comprises granularity, shape, quality, surface character such as surface charge, surface hydrophobic, weight, molecular weight, volume, fraction, any morphology etc., and wherein the granularity of representing with diameter as one of most important factor studies in great detail in the present invention.When the compositions that comprises particle with definite particle size range as treatment during mammiferous cancer treatment method; Said compositions experiences optionally bio distribution, makes it provide more targeting in site of action and reduce side effect such as alopecia in fact.
It is reported the particle of nano particle size scope when giving in blood circulation and since the vascular system of seepage arrive tumor cell and in the tumor epithelial cell, keep; But also report in the document greater than the particle of 200nm diameter preferentially by the reticuloendothelial system of cell (RES) identification and thus targeting and from blood circulation, leave in organ such as liver, lung, spleen, lymph circulation etc.The major part (90%) of the nanosystems that intravenous injects is lost to reticuloendothelial system usually after the proteinic opsonic action that blood flow exists, mainly be in the fixed macrophage in liver and the spleen.Therefore, opsonic action or remove the major obstacle that the nanoparticle pharmaceutical carrier is considered to drug targeting from health through mononuclear phagocyte system (MPS is called reticuloendothelial system (RES) again).One piece of paper (Current Nanoscience, 2005,1,47-64) in, mention possess hydrophilic property surface≤less relatively opsonic action and the removing through the RES picked-up take place in the particle of 100nm.Therefore, preparation better with the aforementioned effort great majority of effective antitumor compositions concentrate on make compositions particle less than 1 micron, preferably less than 200nm or 100nm, be in the circulation to keep particle, avoid by RES absorption and target tumor position.But great majority remain and are lower than any size of 1 micron in these prior art combinations, preferably are lower than the 200nm diameter, and it possibly comprise also that diameter is lower than the particle of about 70nm.In these previous effort any one all do not recognize particle less than about 70nm through the normal blood capillary percolation to skin and Rhizoma Imperatae, and so this anticarcinogen that comprises particle when being used to treat mammal, can cause inductive side effect of chemotherapy such as alopecia.Therefore the tumor microvasculature is discontinuous and has high osmosis, and on average, the internal diameter of the interior hole skin of tumor is 108 ± 32nm, is the capillary tube depression of 58 ± 9nm and more inhomogeneous greater than internal diameter significantly in size.Therefore, the particle greater than 70nm can not and can reduce the hair forfeiture in fact through normal blood capillary infiltration.
In the present invention, successfully attempt, use compositions so that treatment of cancer to be provided, it comprises the particle of at least a anticarcinogen and at least a polymer; Wherein the diameter of particle is less than 1 micron.Preferably; D10>=the 80nm of particle, D50 are about 200nm and D90≤450nm, that is, and and the particle size range of particle sd so; Make 90% particle size less than 450nm and have only 10% particle size less than 80nm and littler, 50% particle is big or small for about 200nm.More preferably, the D10>=120nm of particle, D50 are about 200nm and D90≤350nm, and most preferably, the D10>=140nm of particle, D50 are about 200nm and D90≤260nm.All of a sudden observing the particle that is about 220nm to the maximum is not absorbed by reticuloendothelial system and is used for circulation with the target tumor position; Particle is not in the size that is lower than 70nm; Thereby prevent that them from penetrating into hair follicle, produce the inductive side effect of chemotherapy such as the alopecia that reduce in fact.Be surprised to find that particle of the present invention gathers in being different from the tissue that comprises RES with remarkable bigger level; Said for example prostate, pancreas, testis, breast, seminiferous tubule, the bone etc. organized; And provide alopecia to reduce, therefore be illustrated in the minimizing of gathering like skin and hair follicle position.
Should be appreciated that each hair follicle passes through three phases continuously: the anagen (growth), catagen (decline) and telogen (static).The anagen succeeded by catagen and finally when hair shaft is ripe when be club hair hair follicle entering stage telogen, finally come off from hair follicle.At any given time point, in the stage anagen that the great majority of finding hair follicle being in, have only less percentage ratio to be in stage telogen and have only minority to be in stage catagen.The spherical stromal cell of this rapid propagation the anagen that anticarcinogen destroying in the phase process.As a result, the hair generation stops and hair shaft becomes thinner, and hair breaks off and comes off subsequently.In the present invention, the anticarcinogen compositions prevents the hair forfeiture thus for making medicine be prevented from penetrating into hair follicle.
Of the present invention preferred aspect; The compositions that comprises anticarcinogen and at least a polymer is the colloidal state delivery system, and this system comprises liposome, microemulsion, micelle, polymer-drug conjugate, Nano capsule, nanometer spheroid, microgranule and nanoparticle, solid-lipid nanometer particle.These delivery systems provide following advantage: targeting, profile adjustment and preparation and have polymer architecture flexibly, it can be to be suitable for expecting that the mode of purpose is designed and produces.Compositions can be sent through any route of administration described in this paper; As in oral, intravenous, subcutaneous, intraperitoneal, the sheath, in the intramuscular, intracranial, suction, part, transdermal, rectum, vagina, mucosa etc.; And can discharge immediately medicine or through various known methods through regulate, keep, pulse, delay or control medicine discharge and in a period of time, discharge medicine from delivery system, it all is included in the scope of the invention.The colloidal state delivery system can be whole, wherein polymer is disperseed with medicine, and perhaps it can be coating, and wherein polymer-coated is on medicine or the polymeric encapsulate medicine.Preferred systems is the nanosystems that comprises nanoparticle; And the newer nanosystems of developing, comprise nanocages (nanocages), nanogel (nanogels), nanofiber (nanofibers), nanoshell (nanoshells), nanometer rods (nanorods), nano container (nanocontainers) etc.
The preferred delivery system of anticarcinogen is a nanoparticle compositions; It can provide many advantages; Comprise: be suitable for parenterai administration, can be formulated as the dried forms of easy redispersion; For the activating agent particle that is present in the nanoparticle compositions provides high redispersibility, improve targeting, increase bioavailability, reduce dosage, improve pharmacokinetic properties and reduce side effect at site of action.Preferred nanoparticle is to be encapsulated in the polymeric matrix or absorption or be conjugated to the polymeric colloid particle of the sub-micron of lip-deep anticarcinogen, and it also allows through the release characteristic of selective polymer control of material medicine suitably and keeps levels of drugs for a long time.
According to embodiment of the present invention; Improved anticarcinogen compositions is provided, and wherein compositions is the nanoparticle compositions of anticarcinogen and polymer, for having the colloidal state delivery system like the specified particle size scope that limits among this paper; This particle can be used for treating primary tumor and metastatic tumor; The cancer and other cancer that comprise prostate, testis, breast, lung, kidney, pancreas, bone, spleen, liver, brain etc. have the inductive alopecia of side effect, particularly chemotherapy that reduces in fact.Preferably, compositions comprises about 0.5 weight % of accounting for compositions at least a anticarcinogen and at least a polymer of the about 2.0 weight % that account for compositions to about 99.0 weight % to about 99.5 weight %.In preferred embodiments, anticarcinogen is a paclitaxel, and it is as comprising that about 2.0 weight % of accounting for compositions nanoparticle compositions form at least a polymer of about 99.0 weight % is provided.
Be used for biodegradable polymer of the present invention and comprise natural, synthetic and semisynthetic material.
The instance of natural polymer (for example comprises protein, peptide, polypeptide, oligopeptide, polynucleic acid, polysaccharide; Starch, cellulose, dextran, alginate, chitosan, pectin, hyaluronic acid etc.), fatty acid, fatty acid ester, glyceride, fat, lipid, phospholipid, proteoglycan, lipoprotein etc. and their variant.Protein comprises albumin, immunoglobulin, casein, insulin, hematochrome, lysozyme, a-2-macroglobulin, Fibronectin, vitronectin, Fibrinogen, lipase etc.If desired, protein, peptide, enzyme, antibody and combination thereof can also be used used as stabilizers in the present invention, to improve stability.Preferred protein is albumin, and preferably the about 2.0 weight % with compositions use to the amount of 99.0 weight %, and more preferably 5.0 weight % of compositions are to 95.0 weight %, and about 10.0 weight % of most preferred group compound are to about 90.0 weight %.
Synthetic polymer comprises polyamino acid such as gelatin, polyvinyl alcohol, polyacrylic acid, polyvinyl acetate, polyester, polyacrylate, polyvinyl pyrrolidone, polyethoxyzoline, polyacrylamide, polyvinylpyrrolidone, PAG, polyactide, gathers Acetic acid, hydroxy-, bimol. cyclic ester, PCL or its copolymer etc.; With any two or more suitable combination; Particularly ∝-hydroxy carboxylic acid, poly-hydroxyethyl methacrylate, poly-epsilon-caprolactone, gather the beta-cyano butyrate, gather hydroxyl valerate and beta-hydroxy-butanoic acid ester-hydroxyl pentanoate copolymer, polymalic acid, polylactic acid, polyglycolic acid, d, the block copolymer of the both sexes block polymer of l-poly lactic coglycolic acid, polylactic acid-polyethylene glycol oxide, PAG, polyethylene glycol oxide, polyethylene glycol oxide-PPOX, gather anhydride, poe, polyphosphazene, Pullulan amylopectin (pullulan).
Preferably, delivery system of the present invention uses biodegradable/biocompatible polymeric encapsulate anticarcinogen.These biodegradable first polymer can be when giving, discharge the active anticancer agent immediately those or postpone the release of active anticancer agent and keep nanoparticle compositions to be beneficial to those of curative effect for more time in the target location.Preferred first polymer is d, l-poly lactic coglycolic acid or PLGA, and it is biodegradable polymer, is permitted for preparation and changes the galenical that discharges.PLGA is a hydrophobic copolymer, and it produces two kinds of common substrates biology by the degraded that hydrolysis causes, lactic acid and hydroxyacetic acid, and metabolism was CO2 and H2O when the two finished in aerobic glycolysis.The biodegradation rate of PLGA depends on lactic acid and hydroxyacetic acid ratio separately, and 50: 50 ratio is preferred.PLGA has biocompatibility completely and causes the foreign body reaction of moderate.Be used for PLGA of the present invention and preferably account for the amount of about 2.0 weight % of compositions to 99.0 weight %, the 5.0 weight % that more preferably account for compositions are to 95.0 weight %, and the about 10.0 weight % that most preferably account for compositions are to about 90.0 weight %.
According to another aspect of the present invention; It comprises through various technology makes the anticarcinogen targeting in site of action; This comprises puts together targeting part and medicine or the nanoparticle compositions that comprises medicine to guide them to arrive their target location; Perhaps combine with temperature and/or pH sensitive polymer coating/compositions or with it, and other technology.
According to this above-mentioned aspect; In order to realize that active component discharges at the targeting of tumor locus; Through the nanoparticle of sealing anticarcinogen such as paclitaxel is applied thermally sensitive copolymer complex preparation temperature responsive with the nanoparticle of outer surface through modification; Said thermally sensitive copolymer complex can show heat and reply in aqueous solution, as gathers N-acetyl group acrylamide, poly-N-isopropyl acrylamide, N-Isopropylacrylamide-acrylamide copolymer, polyvinyl alcohol, Polyethylene Glycol, polyacrylamide, PMAm.The nanoparticle on this possess hydrophilic property surface can in blood, circulate reach the longer time and owing to the thermal sensitivity of particle (promptly; In aqueous solution, show upper critical solution temperature (UCST) or lower critical solution temperature (LCST)); When in 37 ℃ of bodies, injecting, granularity increases; Because when the difference particle of physiological conditions is accumulated in the tumor in the tumor microenvironment, granularity further increases several times and the active medicine sealed and discharges at tumor locus.Spendable PH sensitive polymer comprises polyacrylate, CAP etc.
The nanoparticle of entrapped drug of the present invention is through design; Make that under vitro conditions at room temperature D10>=the 80nm of particle, D50 are about 200nm and D90≤450nm, preferred D10>=120nm, D50 are about 200nm and D90≤350nm, and more preferably D10>=140nm, D50 are about 200nm and D90≤260nm; But what is interesting is; Because the temperature sensitivity of particle, in the time of in these particles inject body, granularity is increased to the twice of its original size in blood plasma.Therefore, though scale enlarge and industrial processes in, comprise in the compositions particle of medicine and polymer there are not several particle size ranges that can not fall into qualification; In vivo; Particle always is in the particle size range, and it prevents from the normal blood capillary percolation to skin, and is penetrated into Rhizoma Imperatae thus; But remain on for a long time in the blood circulation, final targeting is in site of action.When these particles arrive tumor; They are increased to about ten times of its original size and permeate the tumor microvasculature through seepage property and high osmosis at tumor locus; Particle is held (that is, improving permeability and retention effect) and discharges medicine therein.This finally causes alopecia to reduce when administering such compositions is treated various cancer.Compositions does not almost have free drug therein, and it is in the advantage that has increase aspect the minimizing alopecia related side effects.Preferred second polymer that is used for compositions of the present invention is temperature and/or pH sensitive polymers such as poly-N-isopropyl acrylamide; About 0.5 weight % with said compositions arrives about 95.0 weight % to about 99.0 weight % use, preferred about 1.0 weight %, and most preferably from about 2.0 weight % are to about 90.0 weight %.
Therefore; According to the preferred embodiments of the invention; Provide to prepare this temperature sensitive and the outer surface method through the nanoparticle of modification, said nanoparticle is sealed anticarcinogen such as paclitaxel, is used for sending immediately or controlling and send and site specific delivery at tumor locus; Thereby the maximum hospital benefit of medicine is provided, and the active component under low dosage more produces minimal side effect.
The pharmaceutical composition of anticarcinogen of the present invention comprises above-described nanoparticle compositions, and it comprises medicine and pharmaceutically suitable carrier thereof.The pharmaceutically suitable carrier that is fit to is well known to a person skilled in the art.These comprise nontoxic physiology's acceptable carrier, excipient or auxiliary agent or vehicle, be used for the injection of non-intestinal, with solid or liquid form be used for oral administration, be used for rectally, nose administration, intramuscular administration, subcutaneous administration etc.Preferably, compositions is as intravenous bolus injection or the non-intestinal injectable composition through subcutaneous or intramuscular administration.
The compositions that is suitable for the injection of non-intestinal can comprise acceptable aseptic aqueous or non-aqueous dispersions, suspension or the Emulsion of physiology and be used to be reconstructed into the sterile powder of sterile injectable dispersion or suspension.Suitable aqueous and non-aqueous carrier, diluent, solvent or vectorial instance comprise water; Aliphatic or aromatic alcohols such as dehydrated alcohol, capryl alcohol; Alkyl halide or aryl halide such as dichloromethane; Ketone such as acetone; Aliphatic, cyclic aliphatic or aromatic hydrocarbon such as hexane, cyclohexane extraction, toluene, benzene; And polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.); N-hydroxy-succinamide, carbodiimide, its mixture, vegetable oil (for example soybean oil, mineral oil, Semen Maydis oil, Oleum Brassicae campestris, Oleum Cocois, olive oil, safflower oil, cotton seed wet goods) and injectable organic ester that is fit to be ethyl oleate for example; Alkyl, aryl or cyclic ether such as ether, oxolane; Acetonitrile and aqueous buffer solution, chloroform etc.Can through for example use coating for example lecithin, through keeping the expectation in dispersion or the suspension granularity and through utilizing surfactant to keep suitable flowability.
The nanoparticle pharmaceutical composition can also comprise excipient or auxiliary agent except that activating agent and solvent; For example antiseptic, wetting agent, emulsifying agent, surface stabilizer, surfactant and dispersant are that all instances are known in the art and comprise within the scope of the present invention.Under any suitable situation, can prevent growth of microorganism, for example parabens, chlorobutanol, phenol, sorbic acid etc. through various antibacterial and antifungal agent.Also possibly hope to comprise isotonic agent, like sugar, sodium chloride etc., buffer agent such as phosphate, phthalic acid salt, acetate, citrate, borate etc.
Nanoparticle compositions of the present invention can prepare through aseptic filtration or under aseptic condition in each stage of preparation.This has been avoided the needs to thermal sterilization, and said thermal sterilization can damage or the degrading activity agent, and the crystal growth and the particle accumulation that cause activating agent.Be provided as freeze-dried powder or the form of suspension that is suspended in the biocompatibility waterborne liquid at last as the compositions of colloidal state delivery system.Biocompatible liquid can be selected from water, buffered water-bearing media, saline, BS, the buffer solution of aminoacid, protein, sugar, carbohydrate, vitamin or synthetic polymer, lipid emulsion etc.
In an importance of the present invention; The nanoparticle of sealing anticarcinogen such as paclitaxel, its derivant or its analog is provided; And the nanoparticle that anticarcinogen such as paclitaxel, its derivant or its analog are sealed in preparation makes nanoparticle compositions not contain free drug therein in fact to realize the method for maximum encapsulation efficiency.Therefore; The purpose of this invention is to provide nanoparticle with envelope paclitaxel, its derivant or analog is classified as the method for specific qualification particle size range and the method for nanoparticle through the process of removing any free drug in the compositions that make is provided; Nearly all medicine combines with polymer, the side effect such as alopecia or the hair forfeiture that make compositions when giving mammal and be used to treat, produce to reduce in fact.
Compositions of the present invention (it comprises microgranule, liposome, Nano capsule, nanometer spheroid and nanoparticle and aforesaid other compositions) is produced through the standard normal method of this area; Limit particle size range and make particle but have as required particle is classified as through handling to remove all not by the other step of polymeric encapsulate or the free drug that combines with polymer, illustrated in greater detail in its described in this article embodiment.The method that is used to prepare nanoparticle pharmaceutical composition of the present invention comprises all technology of preparation microgranule/nanoparticle compositions.In preferred aspects of the invention; This method may further comprise the steps: with medicine and polymer dissolution and/or be dispersed in aqueous solution and/or solvent or solvent mixture in, under agitation two kinds of solution are mixed to form emulsion or deposition, randomly mixing under other pharmaceutically suitable carrier or excipient; Under low pressure or high pressure with its homogenize to obtain having the nanoparticle of expectation granularity; Except that desolvating, one of said technology is to utilize decompression, if desired through any technology; Nanoparticle is sieved to obtain qualification particle size range of the present invention through particle; With the nano suspending liquid ultrafiltration through 30 kilodalton films removing all free drugs, and lyophilizing and storage in bottle at last is up to further research.
The mammiferous method of treatment of the present invention comprises that the mammal to the needs treatment gives the said above-mentioned anticarcinogen of effective dose and the compositions of polymer, and said composition provides the inductive alopecia of chemotherapy that reduces in fact.
Therefore; According to preferred especially aspect of the present invention; The method that in the mammal of experience with anticarcinogen treatment treatment of cancer, reduces inductive side effect of chemotherapy such as alopecia is provided; Said method comprises the said compositions of treating effective dose, and said composition comprises at least a anticarcinogen described in this paper and the particle of at least a polymer.Compositions is to make it have the particle that is in the qualification particle size range as herein described, and does not wherein contain free drug in fact.
Embodiment
Embodiment 1: the PLGA nanoparticle of envelope paclitaxel synthetic:
Use dual emulsion process from d through the dual emulsifying of w/o/w, l-poly lactic coglycolic acid (PLGA) synthesizing nano-particle.In typical experiment, the PLGA of 100mg is dissolved in the 2mL dichloromethane and the 10mg paclitaxel is dissolved in the dehydrated alcohol of 1.0mL.Under agitation two kinds of solution are slowly mixed.Through 500 μ L phosphate buffer saline emulsifyings in above-mentioned solution are prepared first Water-In-Oil (w/o) emulsion.Then with first water-in-oil emulsion further in gathering N-acetyl group acrylamide solution emulsifying to form W/O/W (w/o/w emulsion).With the w/o/w emulsion homogenize that so prepares, after evaporating solvent, form the nanoparticle that has loaded paclitaxel.Then solution centrifugal is also optionally separated the nanoparticle that is in the expectation particle size range.Be dispersed in nanoparticle in the sterilized water then and lyophilizing immediately in order to the usefulness in future.
Embodiment 2:PLGA is covalently bonded in the loading of Pullulan amylopectin micelle nano aggregate and paclitaxel:
Through PLGA being covalently bonded in the Pullulan amylopectin with N-hydroxy-succinamide activation PLGA.Pullulan amylopectin-PLGA complex carries out purification through gel filtration and characterizes through FTIR, H-NMR and mass spectrum.To and remain the usefulness of Deep-Frozen through the Pullulan amylopectin solution lyophilizing of hydrophobic treatment in order to future.
With the hydrophobization Pullulan amylopectin of 100mg be dissolved in 10mL water and with the solution vortex to form micelle.The paclitaxel solution that will in ethanol, prepare slowly joins in the micellar solution and dissolving, up to the solution clarification, shows that drug encapsulation is in micellar preparation.Preferential separate the loading that is in the expected range medicine particle and with the solution lyophilizing.
Use HPLC to pass through measured by standard techniques encapsulation efficiency or load capability and paclitaxel and measure granularity from the release behavior and the conventional particle size analyzer of use of nanoparticle.
Use the thermosensitive polymer coated nanoparticles:
The nanoparticle that has loaded medicine is suspended in the water-containing buffering liquid (pH 4-5).In this solution, add the solution of carbodiimide and with solution vortex that obtains and continuous stirring 4 hours at room temperature.Separate nanoparticle through centrifugal (or through filtering or dialysis) then.To the aqueous solution of nanoparticle suspension dropping polymer poly N-acetyl group acrylamide and with the mixture vortex.Then solution is further stirred, with particle purification and lyophilizing usefulness in order to future.
Be in the classification of the nanoparticle in the specified particle size scope:
Under the help of sonication with the loading of 10.0mg the freeze-dried powder of nanoparticle of paclitaxel be suspended in the water-containing buffering liquid.With solution filter through 0.2 μ m Millipore filter element and use the manufacturer be used to use this technology to make filtrating through asymmetric flow field-flow fractionation to the fractionated standard schedule of particle.Collect different fractions and use standard technique to carry out grain size analysis, to measure granularity and particle size distribution.
Embodiment 3: the preparation of paclitaxel-human serum albumin's nanoparticle:
The 1800mg human serum albumin is dissolved in sterile water for injection.The 200mg paclitaxel is dissolved in ethanol individually.Under high-speed stirred, alcoholic solution is slowly joined in human serum albumin's the aqueous solution.The emulsion that makes formation is through high pressure homogenizer, and its time is enough to the nanoparticle size that obtains expecting.Remove ethanol from the nanoparticle decompression, thereafter it is sieved through particle, at first through 0.2 micron filter, subsequently through 0.1 micron filter.0.2 micron filter, ultrafiltration are passed through in nanoparticle aseptic filtration after the classification, and lyophilizing in bottle.The various parameters of measure moving particle.
Table 1:
Embodiment 4: the preparation of paclitaxel-human serum albumin's nanoparticle:
The 675mg human serum albumin is dissolved in sterile water for injection.The 75mg paclitaxel is dissolved in ethanol individually.Under agitation alcoholic solution is slowly joined in human serum albumin's the aqueous solution.Through homogenizer, its time is enough to the nanoparticle size that obtains expecting to the emulsion that makes formation with low-pressure.Remove ethanol from nanoparticle decompression, thereafter with its through 30 in dalton's membrane ultrafiltration to remove free drug, lyophilizing in bottle then.The various parameters of the particle that measures.
Table 2:
Embodiment 5: the preparation with paclitaxel-human serum albumin's nanoparticle of LCST polymer:
1800mg human serum albumin and 200mg poly-N-isopropyl acrylamide (LCST polymer) are dissolved in sterile water for injection.The 200mg paclitaxel is dissolved in ethanol individually.What provide in further step subsequently and the foregoing description 3 is similar.
The particle that in the experiment of using the LCST polymer, obtains is through classification, to obtain the particle in expected range.In a this experiment, the granularity of the particle that research obtains under all temps condition changes, and its result provides in following table 3, with its instance that increases along with the increase of temperature as the proof granularity.
Table 3:
| Temperature | 25℃ | 30℃ | 35℃ | 37℃ | 38℃ |
| Particle mean size | 90.0nm | 92.8nm | 98nm | 130nm | ＜1000nm |
The result shows; In the presence of second polymer such as LCST polymer; Comprise that paclitaxel and albuminous particle show granularity and increase when experience all temps condition, 37 ℃ (for example blood plasma temperature), particle is increased to about twice of its original size; 38 ℃ (for example tumor temperature), particle is increased to about ten times of its original size.
The preparation of embodiment 6:PLGA-paclitaxel-LCST polymer nano-particle:
With paclitaxel and d, l-poly lactic coglycolic acid (PLGA) is dissolved in acetone.Poly-N-isopropyl acrylamide is dissolved in water for injection, adds polyvinyl alcohol to this water subsequently.Under agitation paclitaxel-PLGA solution is slowly joined aqueous phase.Remove acetone from this emulsion decompression.The nanoparticle that so obtains is through particle screening, the processing and the lyophilization of removing free drug respectively.
Embodiment 7: the preparation of paclitaxel-PLGA-human serum albumin nanoparticle:
The 900mg human serum albumin is dissolved in sterile water for injection.To be dissolved in chloroform individually to paclitaxel and the PLGA of the 100mg that does for oneself.Under mixed at high speed stirs, paclitaxel-PLGA solution is joined in human serum albumin's aqueous solution, to form oil-in-water (O/W) emulsion.Through homogenizer, its time is enough to the nanoparticle size that obtains expecting to the emulsion that makes formation with low-pressure.Remove remaining ethanol from nanoparticle decompression, thereafter with its through 30 kilodalton membrane ultrafiltration removing free drug, and lyophilizing.The various parameters of the particle that measures.
Table 2:
Embodiment 8: chemotherapy is to the influence of mice hair growth pattern
The male BALB/c mouse in seven ages in week that will be used for studying is supported at cage and is allowed ad lib and water inlet.Hold them under the standard conditions (25 ℃ of room temperatures, illumination in 12 hours and 12 hours dark cycle).
The sample that injection is used to study is: reference appearance: (commercially available albumin bound type paclitaxel injectable suspensions), test appearance: (deriving from the sample of embodiment 3), and control samples: saline (vehicle).
Form mouse model with the inductive alopecia of research chemotherapy.In anesthesia down, the anagen of inducing entering through mice telogen that makes hair shaft depilation telogen will experience birth back several times hair cycle.This is to carry out through using electric hair clipper subsequently commercially available hair ablation emulsion to be applied to skin of back.Through using this technology, and all hair follicles (Phase I is to the VI) telogen of being lost hair or feathers, hair follicle began to change into immediately the anagen (with reference to people such as Paus, American Journal of Pathology, 144,719-734 (1994).Carry out above-mentioned steps and be being used for mice induce with spontaneous anagen the stage of development be in a ratio of high level of synchronization anagen the stage of development.The anagen VI stage (depilation after the 9th day), three group intravenouss of every group of four mices tests appearance and with reference to the control samples of kind (20mg/kg) and equivalent, are studied.
After handling, the hair growth of all animals of visual observation and the sign of alopecia and carry out the digital filming record.Different time after chemotherapy and vehicle processing is described below at interval, carries out the score of hair growth pattern based on the hair growth index:
Hair growth index score:
0=does not have hair growth
The hair growth of 1=appropriateness is with serious alopecia
The hair growth that 2=is medium is with sparse alopecia
Good and the uniform hair growth of 3=does not have the alopecia sign
The hair growth of each processed group gets separate index number and in following table 4, provides.
Table 4:
The higher better hair growth of hair growth score exponential representation.
Above-mentioned data show, the mice of handling with test appearance show than with reference to the better hair growth and have more the numerical value near control samples of appearance.
Embodiment 9: chemotherapy is to the influence of mice hair growth pattern
Another test specimen that use derives from embodiment 4 carries out research same as described above.
The sample that injection is used to study is: reference appearance: (commercially available albumin bound type paclitaxel injectable suspensions), test appearance: (deriving from the sample of embodiment 4), and control samples: saline (vehicle).
The hair growth of each processed group that in this research, obtains gets separate index number and in following table 5, provides.
Table 5:
Above-mentioned data show, a mice of handling with test appearance show than with reference to the much better hair growth of appearance, and have more near the score of control samples, have minimum hair growth with a mice of handling with reference to appearance and get separate index number.Between the hair growth index score of matched group and reference group, statistically significant difference (p≤0.05 is arranged; T=1.964, df=6, n=4).These data show that further test appearance shows the inductive side effect of chemotherapy such as the alopecia of minimizing.
Embodiment 10: the research in having the mice of tumor
The sample that is used to study is: (a) with reference to appearance: (commercially available albumin bound type paclitaxel injectable suspensions), (b) a test appearance I: (deriving from the sample of embodiment 4) and (c) test appearance II: (deriving from the sample of embodiment 5).
The purpose of this experiment is research and the tumor retentivity (retentiveness) and (leakiness) behavior of leakage of comparing nanoparticle of the present invention (test appearance) with reference to appearance.Get the ICRC mice (mammary neoplasms has spontaneity) that has tumor, be divided into three groups (n=5) and use reference appearance and test kind dosed administration (0.06mg/100mm through path in the tumor based on the big young pathbreaker mice of average tumor
3).After 8 hours Fixed Time Interval, mice is put to death results tumor and blood plasma and analysis paclitaxel.
Calculate the tumor blood plasma ratio of paclitaxel in test appearance and the reference appearance, find that embodiment 4 is 71.61, embodiment 5 is 355.7, is 19.96 with reference to appearance.This data show is compared with reference appearance, and the paclitaxel that the test appearance of embodiment 4 keeps is 3.58 times, and the paclitaxel that the test appearance of embodiment 5 keeps is 17.80 times.This further show test appearance with compare with reference to appearance generation still less leakage and help to reduce side effect such as alopecia, shown in the test appearance of embodiment 4.Because particle expand into the granularity of the present invention's qualification and has the leakage of much less thus; Test appearance in compositions like embodiment 5 illustrated provides much better retentivity with other temperature sensitive polymer, and it can produce side effect such as the alopecia that reduces in fact.
Claims (26)
1. compositions is used in the treatment of cancer that has the inductive side effect alopecia of chemotherapy of minimizing; Comprise at least a anticarcinogen and at least a particle of sealing, adsorbing or put together said anticarcinogen to lip-deep polymer; Wherein said at least a anticarcinogen is selected from paclitaxel and docetaxel and said at least a polymer and is selected from albumin and d, the l-poly lactic coglycolic acid; D10>=the 120nm of wherein said particle, D50 are 200nm and D90≤350nm.
2. compositions is used in the treatment of cancer of claim 1, and wherein said compositions does not contain free drug, and wherein said medicine fully combines with polymer.
3. compositions is used in the treatment of cancer of claim 1, the particle size distribution of wherein said particle than D90/D10 less than 4.0.
4. compositions is used in the treatment of cancer of claim 1, the particle size distribution of wherein said particle than D90/D10 less than 3.0.
5. compositions is used in the treatment of cancer of claim 1, the particle size distribution of wherein said particle than D90/D10 less than 2.0.
6. compositions is used in the treatment of cancer of claim 1, and wherein said compositions comprises the said polymer of 0.5 weight % to the said anticarcinogen of 99.5 weight % and 2.0 weight % to 99.0 weight %.
7. compositions is used in the treatment of cancer of claim 1, and wherein anticarcinogen is that paclitaxel and polymer are albumin.
8. compositions is used in the treatment of cancer of claim 1; Comprise temperature and/or pH sensitive polymer in addition, said temperature and/or pH sensitive polymer are selected from and gather N-acetyl group acrylamide, poly-N-isopropyl acrylamide, N-Isopropylacrylamide-acrylamide copolymer, polyacrylamide, PMAm.
9. compositions is used in the treatment of cancer of claim 8, and wherein said temperature and/or pH sensitive polymer are poly-N-isopropyl acrylamides.
10. compositions is used in the treatment of cancer of claim 6, comprises second polymer in addition, and its amount accounts for 0.5 weight % of said compositions to 99.0 weight %.
11. compositions is used in the treatment of cancer of claim 6, the amount of second polymer accounts for 1.0 weight % of said compositions to 95.0 weight %.
12. compositions is used in the treatment of cancer of claim 6, the amount of second polymer accounts for 2.0 weight % of said compositions to 90.0 weight %.
13. compositions is used in the treatment of cancer of claim 1, wherein said compositions is the colloidal state delivery system.
14. compositions is used in the treatment of cancer of claim 13, wherein the colloidal state delivery system is a lyophilized form.
15. compositions is used in the treatment of cancer of claim 13, wherein the colloidal state delivery system is for making particle suspension in the biocompatibility waterborne liquid.
16. compositions is used in the treatment of cancer of claim 1; Wherein compositions comprise the 0.5 weight % that accounts for compositions to the paclitaxel of 99.5 weight %, account for the d of 2.0% to 99.0 weight % of compositions; L-poly lactic coglycolic acid and optional 2.0 weight % that account for compositions are to the poly-N-isopropyl acrylamide of 90.0 weight % and account for one or more pharmaceutically useful carriers or its combination of 0.01 weight % of compositions to 99.9 weight %.
Use compositions 17. have the treatment of cancer of the inductive side effect alopecia of the chemotherapy of minimizing; Comprise at least a anticarcinogen and at least a particle of sealing, adsorbing or put together said anticarcinogen to lip-deep polymer; Wherein said at least a anticarcinogen is selected from taxane, 5-fluorouracil, doxorubicin, daunorubicin, cisplatin, carboplatin and oxaliplatin; Be selected from albumin, d with said at least a polymer; L-poly lactic coglycolic acid, poly-epsilon-caprolactone, gather beta-hydroxy-butanoic acid ester, gather hydroxyl valerate, the block copolymer and the polyacrylate of the both sexes block polymer of beta-hydroxy-butanoic acid ester-hydroxyl pentanoate copolymer, polylactic acid-polyethylene glycol oxide, poe, polyamino acid, polyethylene glycol oxide-PPOX; D10>=the 120nm of wherein said particle, D50 are 200nm and D90≤350nm.
18. the compositions of claim 17, the D10>=140nm of wherein said particle, D50 are 200nm and D90≤260nm.
19. the compositions of claim 17, wherein said anticarcinogen is selected from taxane.
20. the compositions of claim 17, wherein said taxane is selected from paclitaxel and docetaxel.
21. the compositions of claim 17, wherein said polymer is an albumin.
22. the compositions of claim 17, wherein said taxane are paclitaxel and polymer is albumin.
23. the compositions of claim 17; Wherein compositions comprise the 0.5 weight % that accounts for compositions to the paclitaxel of 99.5 weight %, account for the d of 2.0% to 99.0 weight % of compositions; L-poly lactic coglycolic acid and optional 2.0 weight % that account for compositions are to the poly-N-isopropyl acrylamide of 90.0 weight % and account for one or more pharmaceutically useful carriers or its combination of 0.01 weight % of compositions to 99.9 weight %.
24. method for compositions is used in the treatment of cancer of preparation claim 1 or 17; May further comprise the steps: (i) in solvent with at least a anticarcinogen and at least a polymer mixed, (ii) randomly in the presence of one or more pharmaceutically suitable carrier, carry out step (i), (iii) obtain nanoparticle through removing to desolvate; And (iv) make nanoparticle through the particle screening; Make the D10>=80nm of gained particle, D50 is 200nm and D90≤450nm, and does not contain free drug; Compositions is to make it that inductive side effect alopecia of chemotherapy of minimizing is provided.
25. the compositions of claim 1 or 17 is used for treating the application of the medicine of mammiferous cancer in preparation; Comprise the said compositions of treating effective dose, wherein said compositions does not contain free drug and wherein said medicine fully combines with polymer.
26. being used for the compositions of claim 1 or 17 is used in the application of experience with the medicine of the inductive side effect alopecia of chemotherapy of the mammal minimizing treatment of cancer of anticancer drug therapy in preparation; Comprise the said compositions of treating effective dose, wherein said compositions does not contain free drug and wherein said medicine fully combines with polymer.
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| IN1081/MUM/2006 | 2006-07-10 | ||
| PCT/IN2006/000427 WO2007069272A2 (en) | 2005-10-21 | 2006-10-19 | Pharmaceutical composition comprising at least one anticancer drug and at least one polymer |
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| CN103202812B (en) * | 2010-08-09 | 2015-10-28 | 南京大学 | A kind of method of protein nano grain for the preparation of sending pharmacological active substance in body |
| CN102697735A (en) * | 2012-06-18 | 2012-10-03 | 南京大学医学院附属鼓楼医院 | Polymer nanoparticles for loading alkaline antitumor drugs |
| CN103520728B (en) * | 2013-10-25 | 2015-10-07 | 扬州大学 | The preparation method of arsenic trioxide invisible immunity targeting anti-tumor preparation |
| CN103705469B (en) * | 2014-01-03 | 2016-01-20 | 中国医学科学院药用植物研究所 | A kind of honokiol nanoparticle and preparation method thereof |
| CN104490764B (en) * | 2014-12-03 | 2017-05-10 | 中国人民解放军第九八医院 | Camptothecin nano-gel |
| CN107163255B (en) * | 2017-04-21 | 2020-10-20 | 四川大学 | Redox and pH dual-response random-graft type drug carrier and method |
| PE20210047A1 (en) * | 2018-06-12 | 2021-01-08 | Farm Rovi Lab Sa | INJECTABLE COMPOSITION |
| CN110051653A (en) * | 2019-06-03 | 2019-07-26 | 辽宁大学 | A method of preparing piperlongumine albumin nano granular and freeze-dried powder |
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