CN1823737A - Porous drug matrices and methods of manufacture thereof - Google Patents
Porous drug matrices and methods of manufacture thereof Download PDFInfo
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- CN1823737A CN1823737A CN 200510136940 CN200510136940A CN1823737A CN 1823737 A CN1823737 A CN 1823737A CN 200510136940 CN200510136940 CN 200510136940 CN 200510136940 A CN200510136940 A CN 200510136940A CN 1823737 A CN1823737 A CN 1823737A
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Abstract
Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solutions, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral admisnistration. Paclitaxel or docetaxel can be provided in a porous matrix form, which allows the drug to be formulated without solubilizing agents and administered as a bolus. rocessed using standard techniques into tablets or capsules for oral administration. Paclitaxel or docetaxel can be provided in a porous matrix form, which allows the drug to be formulated without solubilizing agents and administered as a bolus.
Description
The application is N.00808161.1 dividing an application of (PCT/US00114578) of Chinese patent application.
Background of invention
Present invention relates in general to medicine, particularly have the preparation of low solubility drug, more specifically, relate to make this type of medicine preparation to strengthen the method for its rate of dissolution.
After the administration, the bioavailability that the bad dissolving of medicine in aqueous body fluid may limit drug.Therefore this rate-limiting step is crucial for reaching the levels of drugs with curative effect apace.
Parenteral comprises diluent water, solubilizing agent, cleaning agent, nonaqueous solvent or the non-physiologic pH solution that use is a large amount of for the traditional method with the bad medicine of dissolving.Yet these preparations can increase the general toxicity of pharmaceutical composition or the bodily tissue of infringement medicine-feeding part.
For example, paclitaxel is a kind of natural product with cytotoxin and anti-tumor activity that is proved to be.But when also whether uncertain its had huge treatment potentiality, paclitaxel had some shortcomings relevant with the patient as a kind of healing potion.These shortcomings partly are to derive from its dissolubility extremely low in water, and this makes and is difficult to provide the proper dosage form.Because paclitaxel has relatively poor dissolubility in water, (U.S. FDA) clinical preparation of checking and approving at present contains the paclitaxel of 6m grams per milliliter at the ethylating Oleum Ricini (CREMOPHOREL of 50% polyoxy
TM) and 50% dehydrated alcohol in solution.United States Hospital Acta Pharmaceutica Sinica (Am.J.Hosp.Pharm.),
48: 1520-24 (1991).In some cases, can take place and be used for compensating paclitaxel at the low solubility of water and combine CREMOPHOR to usefulness
TMRelevant severe reaction comprises hypersensitivity.Because hypersensitivity reaction can appear in the commodity formulation for paclitaxel, and paclitaxel has sedimentary probability takes place in patient blood, so said preparation must inject in several hrs.In addition, before injecting, patient must treat with steroid and hydryllin preliminary election.Because CREMOPHOR takes place
TMRelevant hypersensitivity to the continuous approval of paclitaxel as a kind of antineoplastic agent likely, and must be injected paclitaxel loathsomely in several hrs, therefore still need to develop improved formulation for paclitaxel, can be used as pill and injects to usefulness.Similarly, inject to the Ramulus et folium taxi cuspidatae terpene rather than resemble the present method medicine dissolution back in 100% polysorbate80 injected and have advantage with pill.
Other parenteral is given the physical form that concentrates on medicine itself with the method for the bad medicine of dissolubility.To can be used to the surface area that contacts with water-bearing media at medicine-feeding part or absorption site directly related because the rate of dissolution of drug particle is with it, therefore developed the method for the medicine of preparation nanoparticle form, try hard to make its surface area maximization, the United States Patent (USP) 5 of authorizing De Castro for example, 534,270 and authorize description in the United States Patent (USP) 5,587,143 of Wong.But nanoparticle may be difficult to make, and because nanoparticle has when not having absorption on flocculation or the accumulative tendency, particularly microgranule or wrapping the surface modifier of quilt, is difficult to make it to keep stable form.In addition, the grinding or the wet milling techniques that are generally used for nanorize may be also undesirable, because only handle a collection of time that have to spend several days, mill on a large scale or milled processed may be very difficult and/or expensive, this process also is difficult to carry out under aseptic condition, and is difficult to remove the abrasive media that is shed in the product.
Other effort that is intended to strengthen rate of dissolution concentrate on medicine be formed in a kind of can be water-soluble or biodegradable substrate in the dispersion administration, normally with polymeric particulate form.For example, it is reported, can improve its rate of dissolution (Genta etc., S.T.P. pharmaceutical science (PharmaSciences) by dexamethasone being clipped in the chitan microsphere of making by spray drying
5 (3): 202-07 (1995)).Similarly, other bibliographical information by the drug powder that a kind of dissolubility is bad with a kind of it is said the surface hydrophilic that can make medicine, water miscible gelatin mixes and increases its dissolubility (Imai etc., pharmacopathology journal (J.Pharm.Pharmacol.), 42:615-19 (1990)).
Relevant effort is intended to form bigger, the porous matrix of low solubility drug.For example, Roland ﹠amp; Paeratakul, " sphere aggregates of water-insoluble drug ", pharmaceutical science journal (J.Pharma.Sci.),
78 (11): 964-67 (1989) discloses preparation low solubility drug content and has been up to 98% bead, and wherein bead has porous internal structure.But so big bead also is not suitable for parenteral and gives usefulness, and bead is littler and rate of dissolution is low than littler particle surface area.
Therefore, an object of the present invention is to provide the increase medicine, particularly have the compositions of the rate of dissolution of drugs of low aqueous solubility, and this kind of manufacturing method for compositions is provided.
Another object of the present invention provides to be suitable for passing through number of ways, include but not limited to parenteral, mucosa, oral and the local dosage form of giving usefulness, strengthened medicine, the deliquescent compositions of drugs of low aqueous solubility particularly is to produce part, zone or whole body effect.
Another object of the present invention provides to be suitable for by number of ways, includes but not limited to parenteral, mucosa, oral and local deliquescent compositions dosage form, that strengthened paclitaxel of giving usefulness, to produce part, zone or whole body effect.
A further object of the invention provides the paclitaxel that do not contain in the present commercial product preparation solubilizing agent that must existence or the compositions of Ramulus et folium taxi cuspidatae terpene.
Another object of the present invention provides with the pill injection rather than by injecting compositions, particularly paclitaxel or the Ramulus et folium taxi cuspidatae terpene of giving usefulness.
Summary of the invention
Provide medicine with the porous matrix form, wherein when substrate contacted with water-bearing media, the rate of dissolution of medicine increased.In a preferred embodiment, provide the medicine that has than low aqueous solubility with the porous matrix form, when substrate contacted with water-bearing media, porous matrix formed microgranule.When the porous matrix that has drugs of low aqueous solubility contacts with water-bearing media, will produce average diameter between about 0.01-5 μ m, total surface area is greater than about 0.5 square metre/milliliter microgranule.Preferred exsiccant porous matrix is the form of dry powder, has the TAP density that is less than or equal to 1.0 grams per milliliters.
In a preferred embodiment, medicine is taxane (taxane).For example, paclitaxel or Ramulus et folium taxi cuspidatae terpene can provide with the form of porous matrix, when substrate contacts with water-bearing media, form the nanoparticle and the microgranule of medicine.
The method preparation of the porous matrix that preferably comprises medicine by may further comprise the steps: (i) with medicine dissolution in a kind of volatile solvent, form drug solution, (ii) at least a pore creating material is mixed with drug solution, form emulsion, suspension or second solution, (iii) from emulsion, suspension or second solution, remove volatile solvent and pore creating material, form exsiccant, the porous matrix of medicine.The porous matrix that is obtained is compared with the non-porous matrix form of medicine, gives the rate of dissolution after using faster to patient.Pore creating material can be not miscible with drug solvent volatile liquid or volatile solid chemical compound, preferred a kind of volatile salts.If pore creating material is a liquid, then this reagent is by drug solution emulsifying.If pore creating material is a solid, then this reagent (i) is dissolved in drug solution, (ii) be dissolved in not with the miscible solvent of drug solution in, then by drug solution emulsifying, or (iii) in drug solution, suspend with solid particle.Perhaps, hydrophilic excipient, wetting agent and/or isotonic agent (tonicity agent) can be joined in drug solvent, pore creating material solvent or the two.Handle solution, emulsion or suspension that pore creating material forms then in drug solution, remove drug solvent and pore creating material, and any pore creating material solvent.In a preferred embodiment, use spray drying method, optionally carry out lyophilizing, fluid bed drying or vacuum drying then except that desolvating and pore creating material.
In a preferred embodiment, use water-bearing media regeneration porous drug matrices, and through parenteral such as intramuscular, subcutaneous or intravenous administration.As selection, porous drug matrices can use standard technique further to be machined for tablet or the capsule or the rectal suppository of oral administration, use a kind of Diskus to carry carrying out pulmonary administration, or mix/be machined for the emulsifiable paste or the ointment of topical.
Work as medicine, must inject usually when avoiding drug precipitation as paclitaxel, an advantage of porous drug matrices preparation is to can be used as the pill administration.By avoiding medicine to precipitate in vivo, preparation also can pass through in intra-arterial, intravenous, part, the head, in the sheath, if or suitablely directly enter the tumor administration.Another advantage is that preparation can be with the volume administration that reduces.
In one embodiment, substrate also comprises a kind of excipient of PEGization of medicine, as the phospholipid of PEGization.The excipient of PEGization makes medicine avoid being absorbed by macrophage, and this has prolonged the half-life of medicine or has increased bioavailability of medicament.
The accompanying drawing summary
Fig. 1 for the prednisone that do not form preparation and the prednisone that is in the porous matrix form in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 2 for the griseofulvin that do not form preparation and the griseofulvin that is in the porous matrix form in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 3 for the nifedipine that do not form preparation and the nifedipine that is in the porous matrix form in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 4 for the naproxen that do not form preparation and the naproxen that is in the porous matrix form in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 5 for the paclitaxel that do not form preparation and the paclitaxel that is in the porous matrix form in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 6 is that the nifedipine of different porous matrix form is in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 7 is that the griseofulvin of different porous matrix form is in external rate of dissolution curve (dissolving percentage comparison time).
Fig. 8 gives with behind the regenerated nifedipine by vein in the Canis familiaris L. body, and the plasma concentration of nifedipine is to the curve of time.
Fig. 9 represents taxane compounds, comprises the chemical constitution of paclitaxel and Ramulus et folium taxi cuspidatae terpene.
Detailed description of the invention
The rate of dissolution of medicine can improve by medicine being made the porous matrix form, be in fact increased medicine pharmaceutical composition to the surface area that can contact with moisture biofluid with the position. The method of making the medicine porous matrix may further comprise the steps: (a) with medicine dissolving in a kind of volatile solvent, form drug solution, (b) at least a pore creating material is mixed with drug solution, form emulsion, suspension or the second solution, (c) from emulsion, suspension or the second solution, remove volatile solvent and pore creating material, produce the porous matrix of medicine.
In a preferred embodiment, provide and do not contain respectively CREMOPHORTMOr the pharmaceutical composition of the taxol of polysorbate80 solubilizer or DTX, the form that wherein pharmaceutical composition can pill is given and is used. Said composition is the dried powder of porous, when adding water-bearing media, will form the nano particle of medicine or the suspension of particulate.
I. drug matrices composition
The content of the drug matrices Chinese traditional medicine of porous is at least the 1-95 % by weight, preferably is at least about 10 % by weight, more preferably before about 10-70 weight. Can also comprise hydrophilic excipient such as water miscible polymer or sugar, wetting agent such as surfactant and isotonic agent in the matrix.
The form of drug matrices (dry powder) is very crucial to rate of dissolution. Matrix must comprise the particulate of medicine, and preferably its average diameter is between about 0.01-5 μ m, more preferably between about 0.1-5 μ m. In one embodiment, the average diameter of particulate is between about 1-5 μ m. The average total surface area of the particulate that comprises in the porous matrix of typical dry powder form be 0.5 square metre/milliliter or more than, be preferably 0.9 square metre/milliliter or more than. The total surface area value of particulate can Application standard Ku Erte particle collector (Coulter Counter) equipment and technology mensuration.
The hole of drug matrices must be abundant, to guarantee the producing particulate with these parameters when contacting with water-bearing media. The unit of porosity that be used for to characterize drug matrices is for the bulk density of dry porous matrix (dry powder) or stride axial pressure (" TAP ") density and the total surface area (internal surface area and external surface area sum) of dry porous matrix. Preferred TAP density is less than or equal to 1.0 grams per milliliters, is more preferably less than 0.8 grams per milliliter. The porosity of this kind level of the matrix that is characterized by density provides the enough surface areas that promote the moistening of dry porous matrix and increase the solubility of medicine. The total surface area of porous matrix can be measured by for example BET surface area analysis. In some embodiments, the total surface area of preferred porous matrix is greater than 0.1m2/ g, more preferably greater than or equal 0.2m2/ g. The total surface area of this kind level provides the enough surface areas that promote the moistening of dry porous matrix and increase drug solubility.
1. medicine
There is multi-medicament to can be used in the method and composition described herein. In a preferred embodiment, medicine is the medicine of low aqueous solubility. Term used herein " low aqueous solubility " refers to medicine under the condition near physiological temp and pH, and the solubility of medicine in water-bearing media is less than about 10m grams per milliliter, preferably less than about 5m grams per milliliter. Term used herein " medicine " refers to provide in vivo chemistry or the biomolecule for the treatment of, diagnosis or preventive effect. Particularly preferred drug categories is taxane.
(i)
Taxane
Taxane is the anticancer cytotoxin of stabilized cell microtubule. The taxane compounds that can be used on composition as herein described and method comprises taxol and DTX, and has the natural or synthetic analogues of anticancer or anti-angiogenic origin activity. Taxol and DTX have significant activity, and its one or both be widely used as the component for the treatment of carrying out property breast cancer, lung cancer and oophoroma. Taxol is approved for the auxiliary curing of early stage positive knurl breast cancer recently in the U.S.. Represent taxane among Fig. 9, comprised the chemical constitution of taxol and DTX.
(ii)
Other medicines
The other medicines that expection is used for compositions as herein described comprise the optional form of medicine and these medicines of following classification and example, as salt form, free sour form, free alkali form and the hydrate forms selected:
Analgesics/antipyretic(as aspirin, acetaminophen, ibuprofen, naproxen sodium; buprenorphine; regretol; propoxyphene napsylate; hydrochloric acid dolantin; dihydro-morphinone hydrochloride; morphine; oxycodone; codeine; paracodintartrate; pentazocine; Hycodan; left promise coffee; diflunisal; triethanolamine Salicylate; nalbuphlne hydrochloride; mefenamic acid; Bu Tuonuo coffee; choline salicylate; butalbital; phenyltoloxamine citrate; diphenhydramine citrate; methotrimeprazine hydrochloride and meprobamate);
Anti-asthmatic(as ketotifen and bent promise);
Antibiotic(as neomycin, streptomycin, chloromycetin, cephamycin, ampicillin, penicillin, tetracycline and ciprofloxacin);
Antidepressant(, imipramine embonate bright, isocarboxazid, trimeprimine and protriptyline) as nefopam and oxypertine, doxepin, amoxapine, trazodone, amitriptyline, maprotiline, phenelzine, desipramine, nortriptyline, tranylcypromine, fluoxetine, doxepin, miboplatin;
The anti-diabetic medicament(for example biguanide and sulphur urea derivative);
Antifungal(for example griseofulvin, ketoconazole, itraconazole, amphotericin B, nystatin and gram oidiomycin);
Antihypertensive agents(for example PR, Propafenone, oxyprenolol, nifedipine, blood pressure lowering are flat, arfonad, phenoxybenzamine, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulphate, minoxidil, rescinnamine, sodium nitroprusside, raudixin, alseroxylon and phentolamine);
The antibiotic medicine(for example (on-steroidal) indomethacin, ketoprofen, flurbiprofen, naproxen, ibuprofen, ramifenazone, piroxicam, (steroidal) cortisone, dexamethasone, Fluazacort, celecoxib, rofecoxib, hydrocortisone, prednisolone and prednisone);
Antineoplastic agent(for example cyclophosphamide, D actinomycin D, rich rice mycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl isophthalic acid-lomustine, cisplatin, etoposide, camptothecine and derivant, phenesterine, vinblastine, vincristine, tamoxifen and piposulfan);
Antianxiety drug(for example lorazepam, buspirone, prazepam, chlorine nitrogen , oxazepam, chlorine nitrogen dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone and dantrolene);
The immunosuppressant medicament(for example cyclosporin, azathioprine, mizoribine and FK506 (immunosuppressant));
The migraine medicament(for example ergotaminine, PR, isometheptene mucate and dichloralphenazone);
Tranquilizer/hypnotic(for example barbiturates such as pentobarbital and quinalbarbitone; With benzodiazepine class example hydrochloric acid flurazepam, triazolam and midazolam);
The antianginal medicament(beta-adrenaline blocker for example; Calcium channel blocker such as nifedipine and diltiazem ; With nitrate such as nitroglycerin, isosorbidi dinitras, pentaerythritol tetranitrate and cardilate);
Antipsychotic agent(for example haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, Thioridazine Hydrochloride, tiotixene, fluphenazine, fluphenazin decanoate, Amatansol, trifluoperazine, chlorpromazine, perphenazine, lithium citrate and prochlorperazine);
The antimanic drugs agent(for example lithium carbonate);
The arrhythmia medicament(for example bromine west ammonium tosilate, esmolol, verapamil, amiodarone, encainide, digoxin, digitophyllin, mexiletine, disopyramide phosphate, procainamide, quinidine sulfate, quinidine gluconate, Cardioquin (Purdue Frederick), flecainide acetate, tocainide and lignocaine);
The arthritis medicament(for example Phenylbutazone, sulindac, penicillamine, salsalate, sieve former times health, azathioprine, indomethacin, Meclofenamate, sodium aurothiomalate, ketoprofen, auranofin, aurothioglucose and tolmetin sodium);
The gout medicament(for example colchicine and other purine);
Anticoagulant(for example heparin, heparin sodium and tintorane);
Thrombolytic agent(for example urokinase, streptokinase and alteplase);
The fibrinolysis agent(for example aminocaproic acid);
The hemorheology medicament(for example pentoxifylline);
Anti-platelet agents(for example aspirin);
The convulsion medicament(for example valproic acid, divalproex sodium, phenytoin, phenytoin Sodium, clonazepam, primidone, phenobarbital, carbamazepine, amobarbital sodium, mesuximide, metharbital, enphenemal, mephenytoin, phensuximide, paramethadione, ethotoin, phenacal, barbose, chlorine nitrogen dipotassium and trimethadione);
The antiparkinsonian drug agent(for example ethosuximide);
Antihistamine medicament/pruritus(for example hydroxyzine, diphenhydramine, chlorphenamine, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexbrompheniramine maleate and methdilazine);
The Calcium Metabolism Regulation medicament(for example calcitonin and parathyroid hormone);
Antibacterial(for example amikacin sulfate, aztreonam, chloromycetin, chloramphenicol palmitate, ciprofloxacin, clindamycin, clindamycin palmitate, clindamycin phosphate, metronidazole, hydrochloric acid metronidazole, gentamycin sulfate, lincomycin hydrochloride, tobramycin sulfate, Lyphocin (Fujisawa), aerosporin, colistimethate sodium and polymyxin E sulfate);
Antiviral agent(for example interferon-ALPHA, β or γ, zidovudine, hydrochloric acid Aminodiamantane, ribavirin and acyclovir);
The antimicrobial medicament(for example cephalosporin such as Cefazolin sodium, cefradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, Cefotetan Disodium, cefuroxime e zaotil, cefotaxime sodium, cefadroxil monohydrate, cefalexin, cephalothin sodium, cefalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cefradine and Cefuroxime Sodium; Penicillins such as ampicillin, amoxicillin, benzathine penicillin G, cyclacillin, ampicillin, scotcil, potassium v calcium, avocin, oxacillin sodium, bacampicillin hydrochloride, cloxacillin sodium, licarcillin sodium, azlocillin sodium, carbapen, neoproc, dimethoxyphenyl penicillin sodium and sodium nafcillin; Erythromycin such as pediamycin, erythromycin, erythromycin propionate lauryl sulfate, erythromycin lactobionate, erythromycin stearate and erythromycin ethylsuccinate; And Tetracyclines example hydrochloric acid tetracycline, doxycycline hyclate and minocycline hydrochloride, Azithromycin, clarithromycin);
Anti-infectives(for example granulocyte-macrophage colony-stimulating factor);
The bronchiectasis medicament(for example intend neat sense neurologic agent example hydrochloric acid epinephrine, orciprenaline sulfate, terbutaline sulphate, neoisuprel, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfuric ester, albuterol, bitolterol mesilate, isoprenaline, terbutaline sulphate, adrenaline acid tartrate, orciprenaline sulfate, epinephrine and adrenaline acid tartrate; Anticholinergic agents such as ipratropium bromide; Xanthine such as aminophylline, neutraphylline, orciprenaline sulfate and aminophylline; Mast cell stabilizers such as sodium cromoglicate; Corticosteroid inhalant such as beclomethasone (BDP) and beclomethasone monohydrate; Albuterol; Ipratropium bromide; Budesonide; Ketotifen; Salmaterol; Xinafoate; Terbutaline sulphate; Triamcinolone; Theophylline; Sodium nedocromil; Orciprenaline sulfate; Albuterol; Flunisolide; Fluticasone propionate;
Steroid and hormone(for example androgen such as danazol, depo-testosterone, fluoxymesterone, second testosterone (ethyltestosterone), testosterone enanthatas, methyltestosterone, fluoxymesterone and depo-testosterone; Estrogen such as estradiol, piperazine estrone sulfate and conjugated estrogen hormone; Progesterone such as medroxyprogesterone acetate and norethindrone acetate; Corticosteroid such as triamcinolone, betamethasone, betamethasone dosium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acefurate, prednisone, the methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone phosphate sodium, solu-medrol, hydrocortisone 21-sodium succinate, triamcinolone hexacetonide, hydrocortisone, the hydrocortisone cipionate, prednisolone, acetic acid fluorine hydrogen can be loose, paramethasone acetate, prednisone uncle fourth ethyl ester, the meticortelone acetate, prednisolone phosphate sodium and hydrocortisone 21-sodium succinate; With thyroxin such as levothyroxine sodium);
The blood sugar lowering medicament(for example the Iletin II (Lilly) of the bovine insulin of human insulin, purification, purification, glibenclamide, chlorpropamide, glipizide, tolbutamide and sweep tolazamide);
The blood fat reducing medicament(for example chlorine Bei Te, dextrothyroxine sodium, probucol, pravastatin, atorvastatin, lovastatin and nicotinic acid);
Protein(for example deoxyribonuclease, alginase, superoxide dismutase and lipase);
Nucleic acid(protein of any pharmaceutically useful of for example encoding comprises any proteinic synonym as herein described or antisensenucleic acids);
Erythrocyte generates stimulates reagent(for example erythropoietin);
Antiulcerative/anti-reflux reagent(for example Famotidine, cimetidine and ranitidine hydrochloride);
Bendectin/anti-the medicine of vomitting(for example meclozine hydrochloride, nabilone, prochlorperazine mesylate, dimenhydrinate, promethazine hydrochloride, thiethylperazine and scopolamine);
Fat soluble vitamin(for example vitamin A, D, E, K etc.);
And other medicines such as mitotane, halo nitroso ureas (halonitrosoureas), anthracycline (anthrocyclines) and ellipticine.Tabulation to the description of these and other useful drug categories and each apoplexy due to endogenous wind various kinds of drug can be at " pharmacopeia supplementary issue " (The Extra Pharmacopoeia) of Martindale, the 30th edition (The Pharmaceutical Press, London, 1993) find in.
Other exemplary agents that can be used for compositions as herein described and method comprises ceftriaxone, ketoconazole, ceftazidime Evil promazine, albuterol, valaciclovir, Urofollitropin, famciclovir, flutamide, enalapril, metformin (mefformin), itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, Fen Laxi dissolves, follicle stimulating hormone, glipizide, omeprazole, fluoxetine, lisinopril, nemicide (tramsdol), levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, ZL-101, amfebutamone, perindopril, erbumine, adenosine, Alendronate sodium, Alprostadil, benazepril, betaxolol, Bleomycin Sulphate, dexfenfluramine, diltiazem , fentanyl, flecainide, gemcitabine, acetic acid glatiramer, granisetron, lamivudine, the mangafodipir trisodium, aminosallcylic acid, Metoprolol fumarate, metronidazole, the Mi Gelie urea, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, growth hormone, the succinic acid sumatriptan, tacrine, verapamil, nabumetone, trovafloxacin, dolasetron, zidovudine, Fei Nasi carries, tobramycin, isradipine, tolcapone, the Yi Nuo heparin, fluconazol, lansoprazole, terbinafine, silks rice hydrochlorate, didanosine, diclofenac, cisapride, literary composition traction therapy star, troglitazone, fluvastatin, Losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin and ipratropium bromide.It is water miscible that these medicines are considered to usually.
Preferred medicine comprises albuterol or salbutamol sulfate, adapalene, budesonide, Carclura, momestasone furoate, ursodesoxycholic acid glycol (ursodiol), amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogen hormone, medroxyprogesterone acetate, Licardipine Hydrochloride, Zolpidemtar Trate, amlodipine benzenesulphonate, ethinylestradiol, omeprazole, rubitecan, amlodipine benzenesulphonate, benazepril hydrochloride, etodolac, paroxetine hydrochloride, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, vitamin D
3With relevant analog, Fei Nasi carries, fumaric acid quetiapine, Alprostadil, Candesartan, cilexetil, fluconazol, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbamazepine (carbemazepine), carbidopa, levodopa, ganciclovir, Saquinavir, amprenavir, carboplatin, glibenclamide, sertraline hydrochloride, rofecoxib, carvedilol, halobetasol propionate, citric acid sidenafil, celecoxib, urine thiophene ketone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, the cisapride monohydrate, lansoprazole, hydrochloric acid tamsulosin, mofafinil, Azithromycin, clarithromycin, letrozole, terbinafine HCl, maleic acid rosiglitazone, diclofenac sodium, lomefloxacin hydrochloride, hydrochloric acid tirofiban, telmisartan, diazepam, loratadine, FC-1157a, Thalidomide, row prostatitis, ground ketone, Mefloquine Hydrochloride, trandolapril, the Ramulus et folium taxi cuspidatae terpene, mitoxantrone hydrochloride, tretinoin, etodolac, Ledercort A, estradiol, the ursodesoxycholic acid glycol, Viracept, indinavir, beclomethasone Evil promazine, flutamide, famotidine, nifedipine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, the citric acid zitazonium, nimodipine, amiodarone and alprazolam.
2. excipient
Substrate can comprise hydrophilic excipient such as water-soluble polymer or saccharide, and they can serve as filler or wetting agent; Wetting agent such as surfactant or saccharide; And isotonic agent.In case contact with water-bearing media, water will the penetration height porous matrix, and the water soluble excipient in the dissolved matrix.For the medicine of low aqueous solubility, keep drug particles in water-bearing media, to be in suspended state.The total surface area of the drugs of low aqueous solubility microgranule of gained increases to some extent with respect to unprocessed medicine, and the rate of dissolution of medicine increases.
Those skilled in the art can be according to multiple factor, as treat to usefulness medicine, give with approach, dosage and preferred rate of dissolution, select to be used for the suitable excipient of drug matrices compositions.For example, excipient can serve as filler, release regulator, wetting agent, isotonic agent or its combination.Preferred excipient comprises hydrophilic polymer, wetting agent and sugar.Based on the weight of drug matrices, the content of excipient in drug matrices is more preferably less than about 80% less than about 95%.
In making the process of substrate, added hydrophilic excipient, wetting agent and isotonic agent in drug solution, pore creating material or the two in the past.
(i) hydrophilic polymer
The polymer that can be used for substrate as herein described comprises synthetic and natural polymer, and promptly can right and wrong biodegradable also can be biodegradable.Representational synthetic polymer comprises Polyethylene Glycol (" PEG "), polyvinylpyrrolidone, polymethacrylates, polylysine, poloxamer, polyvinyl alcohol, polyacrylic acid, poly(ethylene oxide) and Ju ethyl oxazoline.Representational natural polymer comprises albumin, alginate, gelatin, Radix Acaciae senegalis, chitan, cellulose glucosan, water-soluble poly-sucrose, starch, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hyaluronic acid, carboxyethyl cellulose, carboxymethyl cellulose, the chitin that takes off acetyl, dextran sulfate and derivant thereof.Preferred hydrophilic polymer comprises PEG, polyvinylpyrrolidone, poloxamer, hydroxypropyl cellulose and hydroxyethyl-cellulose.
The selected hydrophilic polymer that is used for special drug matrices preparation is based on multiple factor, as the molecular weight of polymer, the hydrophilic of polymer and the intrinsic viscosity of polymer.Hydrophilic polymer can be used as filler or wetting agent.
(ii) sugared
The representational steamed bun stuffed with sugar that can be used for drug matrices is drawn together mannitol, Sorbitol, xylitol, glucitol, galactitol, inositol, 1,2,3,4,5-pentanepentol, arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, allose, dextrose, Ah 's sugar, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose and Raffinose.Preferred steamed bun stuffed with sugar is drawn together mannitol, lactose, sucrose, Sorbitol, trehalose, glucose, and if through parenteral, sugar can be adjusted to provide osmolality, perhaps make to make porous drug matrices or drug microparticles moistening in the substrate.
(iii) wetting agent
Wetting agent can be used for promoting water to enter in the substrate, and for promoting dissolving, drug particles is moistening.The example of representational wetting agent comprises gelatin, casein, lecithin (phospholipid), acacin, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, the pure emulsifing wax of poly-third holder, sorbitan, polyoxyethylene alkyl ether (for example polyglycol ether is as the poly-third holder alcohol 1000), polyoxyethylene castor oil derivant, polyoxyethylene sorbitan fatty acid ester (TWEEN for example
TMSeries), Polyethylene Glycol, Myrj 45, silica sol, phosphate ester, sodium lauryl sulphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, amorphous cellulose element, Magnesiumaluminumsilicate, triethanolamine, polyvinyl alcohol and polyvinylpyrrolidone (PVP).Alevaire (a kind of alkyl aryl polyether alcohol type liquid polymers of nonionic is also referred to as alevaire (superinone) or Qu Litong (triton)) is another kind of useful wetting agent.Major part in these wetting agents is known pharmaceutical excipient, and by American Medical Association (American PharmaceuticalAssociation) and Britain medicine association (The Pharmaceutical Society of Great Britain) combined publication " pharmaceutical excipient handbook (Handbook of PharmaceuticalExcipients) has a detailed description in (medicine publishing house (The Pharmaceutical Press), 1986).
Preferred humectants comprises polyvinylpyrrolidone, Polyethylene Glycol, alevaire, poloxamer such as PLURONIC
TMF68, F127 and F108, it is end-capped copolymer and the polyxamines such as the TETRONIC of oxirane and expoxy propane
TM908, it is derived from expoxy propane and oxirane dialkyl such as the AEROSOL to the four-functional group end-capped copolymer (can buy from BASF AG) of the continuous addition of ethylenediamine, glucosan, lecithin, sodium sulfo-succinate
TMOT, it is dioctyl ester (can buy from U.S. Cyanimid company), the DUPONOL of sodium sulfo-succinate
TMP, it is sodium lauryl sulphate (can buy from Dupont company), TRITON
TMX-200, it is alkyl aryl polyether sulphonic acid ester (can buy from Rohm ﹠ Haas Corp), TWEEN
TM20 and TWEEN
TM80, it is polyoxyethylene sorbitan fatty acid ester (can buy from ICI special chemical article company), Carbowax 3550 and 934, it is Polyethylene Glycol (can buy from associating carbide (Union Carbide) company), Crodesta F-110, it is mixture and the Crodesta SL-40 (all can buy from Croda company) and the SA90HCO of sucrose stearate and sucrose distearate, and it is C
18H
37CH
2(CON (CH
3) CH
2(CHOH)
4CH
2OH)
2
Find that useful especially wetting agent comprises Tetronic 908, Tweens, Pluronic F-68 and polyvinylpyrrolidone.Other useful wetting agent comprises capryl-N-methyl Portugal amide; Positive decyl-β-D-glucopyranoside; Positive decyl-β-D-pyranoid form maltoside; Dodecyl-β-D-glucopyranoside; Dodecyl-β-D-maltoside; Heptanoyl group-N-methyl Portugal amide; N-heptyl-β-D-glucopyranoside; N-heptyl-β-D-thioglycoside; N-hexyl-β-D-glucopyranoside; Nonyl-N-methyl Portugal amide; Positive pelargonyl group-β-D-glucopyranoside; Caprylyl-N-methyl Portugal amide; N-octyl-β-D-glucopyranoside; And octyl group-β-D-pyranoid form thioglycoside.Another kind of preferred humectants is to different Nonylphenoxy poly epihydric alcohol, is also referred to as Olin-10G or surfactant 10-G (can buy the 10G product of OlinChemicals company).Two or more wetting agents can be used in combination.
(iv) isotonic agent or osmolality reagent
Porous drug matrices can comprise that one or more grades ooze reagent, ooze hypotonic drug solution is adjusted to etc. as salt (for example sodium chloride or potassium chloride) or sugar (as mannitol, glucose, sucrose or trehalose), thereby it is when making medicine in being in solution, compatible with patient's bodily tissue cell physiological.The consumption of the type of isotonic agent can use known technology to select by one of skill in the art.
(the v) excipient of PEGization
In one embodiment, substrate also comprises a kind of excipient of PEGization.The excipient of this type of PEGization includes, but are not limited to the phospholipid of PEGization, the protein of PEGization, the peptide of PEGization, the sugar of PEGization, the polysaccharide of PEGization, the end-capped copolymer with the end capped PEGization of PEG and the hydrophobic compound of PEGization such as the cholesterol of PEGization.The excipient of PEGization can surround or avoid the macrophage ingestion of drugs effectively, and this has prolonged the half-life of medicine or has strengthened bioavailability of medicament.
The example of the phospholipid of representational PEGization comprises 1; 2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Macrogol 2000] (" PEG2000PE ") and 1; 2-diacyl-sn-oxygen three bases-3-phosphoethanolamine-N-[Polyethylene Glycol 5000] (" PEG5000PE "), acyl group wherein for example is selected from two myristoyl, two palmityls, distearyl acyl group, dioleoyl and 1-palmityl-2-oleoyl.
Can replace polyethylene with other polyalkylene oxide.
II. volatile solvent
According to the medicament selection volatile solvent.In a preferred embodiment, this solvent is the organic volatile solvent, and it has lower boiling point, or can remove under vacuum, and to give when using in the human body with trace be acceptable.Representational solvent comprises acetic acid, the acetaldehyde dimethylacetal, acetone, acetonitrile, chloroform, chlorofluorocarbon, dichloromethane, dipropyl ether, diisopropyl ether, N, dinethylformamide (DMF), Methanamide, dimethyl sulfoxine (DMSO), dioxane, ethanol, ethyl acetate, Ethyl formate, ethyl vinyl ether, methyl ethyl ketone (MEK), glycerol, heptane, hexane, isopropyl alcohol, methanol, isopropyl alcohol, butanols, triethylamine, Nitrocarbol., octane, pentane, oxolane (THF), toluene, 1,1, the 1-trichloroethane, 1,1, the 2-trichloroethylene, water, dimethylbenzene and combination thereof.In general, medicine dissolution is between the 0.01-80 weight/volume % (w/v) to form drug level in volatile solvent, more preferably the drug solution between 0.025-30% (w/v).
Can use the mixture of aqueous solvent or water and organic solvent, as the water-alcohol mixture dissolved substance.
III. pore creating material
Pore creating material is a volatile material, is used for this procedure to produce hole in final substrate.Pore creating material can be volatilizable liquid or volatilizable solid.
1. liquid pore creating material
The liquid pore creating material must can not be miscible with drug solvent, and can volatilize under the treatment conditions compatible with medicine.For realizing the formation in hole, pore creating material is at first by drug solvent emulsifying.Then, further handle emulsion, use the combination while of evaporation, vacuum drying, spray drying, fluid bed drying, lyophilizing or these technology or remove drug solvent and pore creating material in succession.
The selection of liquid pore creating material will depend on drug solvent.Representational liquid pore creating material comprises water; Dichloromethane; Alcohol is as ethanol, methanol or isopropyl alcohol; Acetone; Ethyl acetate; Ethyl formate; Dimethyl sulfoxine; Acetonitrile; Toluene; Dimethylbenzene; Dimethyl formamide; Ether such as THF, diethyl ether or dioxane; Triethylamine; Methanamide; Acetic acid; Methyl ethyl ketone; Pyridine; Hexane; Pentane; Furan; Water and cyclohexane extraction.
The liquid pore creating material accounts for the consumption of drug solvent emulsion between 1-50 volume %, preferably between 5-25 volume %.
2. solid pore creating material
The solid pore creating material must be able to volatilize under the treatment conditions of not damaging pharmaceutical composition.The solid pore creating material can (i) be dissolved in the drug solution, (ii) be dissolved in not with the miscible solvent of drug solvent in, form solution, this solution and drug solution emulsifying then, (iii) the form with solid particle joins in the drug solution.Combination by evaporation, spray drying, fluid bed drying, lyophilizing, vacuum drying or these technology then, solution, emulsion or the suspension that further processing pore creating material forms in drug solution is with the while or remove drug solvent, pore creating material in succession, if with suitable, the solvent that pore creating material uses.
In a preferred embodiment, the solid pore creating material is a volatile salts, the salt that forms as volatility alkali and volatile acid chemical combination.Volatile salts is for can be by solid-state or liquidly change gasiform material under heating and/or vacuum condition.The example of volatility alkali comprises ammonia, methylamine, ethamine, dimethylamine, diethylamine, methyl ethylamine, trimethylamine, triethylamine and pyridine.The example of volatile acid comprises carbonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propanoic acid, butanoic acid and benzoic acid.Preferred volatile salt comprises ammonium bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate and composition thereof.
The example of other solid pore creating material comprises iodine, phenol, benzoic acid (with sour form rather than salt), and naphthalene.
The solid pore creating material accounts for amount of drug between 0.5-1000% (w/w w/w), preferably between 10-600% (w/w), more preferably between 1-100% (w/w).
IV. make the method for porous drug matrices
The preferred manufacturing step of porous drug matrices is: (i) with medicine, preferred a kind of medicine dissolution with low aqueous solubility forms drug solution in a kind of volatile solvent; (ii) at least a pore creating material and drug solution are merged formation emulsion, the suspension or second solution and (iii) remove volatile solvent and pore creating material from emulsion, suspension or second solution.In a preferred embodiment, use spray drying, optionally use lyophilizing or vacuum drying to remove then and desolvate and pore creating material.The removal of pore creating material can with enough solvent simultaneously or carrying out thereafter so that droplet solidification.Can use continuously, intermittently or the semi-continuous process manufacturing.
At first, with selected medicine dissolution in a kind of suitable solvent.The concentration of medicine in final drug solution between about 0.01-80% (w/v), is preferably between about 0.025-30% (w/v) usually.
Then, normally under mixing condition, drug solution and pore creating material or its solution are merged.If what use is the liquid pore creating material, then at first with drug solution with its emulsifying so that pore creating material forms the drop that is dispersed in the whole drug solution.If use the solid pore creating material, then it directly is dissolved in the drug solution forming drug solution/pore creating material, or it at first is dissolved in a kind of second solvent.If second solvent is not miscible with drug solution, then with drug solution with the pore creating material emulsifying soln, pore creating material is formed be scattered in the drop in the whole drug solution.If second solvent and drug solution are miscible, then two solution are mixed to form single drug solution.Can the form of a kind of solid pore creating material with solid particle directly be added in the drug solution selectivity, grain sizes is between about 100nm-10 μ m, to form the suspension of pore creating material in drug solution.Subsequently, can use for example known in the art homogenizing or ultrasonic technique, the suspension by further processing gained reduces the particulate size of solid pore creating material.
The further Treatment Solution of combination, suspension or the emulsion of use evaporation then,, spray drying, fluid bed drying, lyophilizing, vacuum drying or these technology is with the while or remove drug solvent and pore creating material in succession.In a preferred embodiment, spray drying soln, emulsion or suspension." spray drying " used herein is meant solution, emulsion or suspension atomization to form the drop (drug solution that contains dispersed solids or liquid pore creating material) of fine mist, these drops enter in the hothouse (for example vessel, jar, pipe or tube) immediately, and drop contacts with a kind of dry gas there.Solvent and pore creating material evaporate from drop and enter in the dry gas so that drop solidifies, and form simultaneously to spread all over this solid hole.Separating solids (normally with powder, particle form) and collection from dry gas then.
Can control the temperature that hothouse goes out inbound port, and the flow velocity of feedstock solution, atomization gas and dry gas is to make needed product.In an especially preferred embodiment, authorize the spray drying process of describing in people's such as Straub the United States Patent (USP) 5,853,698 and be fit to make drug matrices.
The medicine that is present in product solid or the powder can be crystal or amorphous state, or the mixture of these states.Its state depends on the drying means of drop and the excipient of existence usually.
Emulsion stability
Be added in the embodiment that forms emulsion in the liquid medicine at least a pore creating material, can add a kind of surfactant or emulsifying agent to improve the stability of emulsion.In this course, can add the kinds of surface activating agent, preferred addition is 0.1-5 weight %.The example of operable emulsifying agent and surfactant comprises acceptable emulsifying agent on most of physiology, for example lecithin or soybean lecithin, or synthetic lecithin, as saturated synthetic lecithin, for example, two myristoyl lecithin, DPPC or distearoylphosphatidylcholine, or unsaturated synthetic lecithin, for example two oil base lecithin or two inferior oil base lecithin.Other hydrophobic or amphoteric compounds can be used to replace phospholipid, for example cholesterol.Emulsifying agent also comprises surfactant such as free fatty, the formed ester of fatty acid and polyoxyalkylene compounds such as polypropylene glycol and Polyethylene Glycol; The formed ether of aliphatic alcohol and poly alkylene glycol; The formed ester of the sorbitan of fatty acid and poly-alkoxylation; Soap; The polyalkylene tristerin; Polyoxyethylene castor oil glyceride; The homopolymer of poly alkylene glycol or copolymer; The soybean oil of polyethoxylated or Oleum Ricini and hydroderivating thing; The formed ester of fatty acid, aliphatic alcohol or the ether of sucrose or other carbohydrates and selectivity poly-alkoxylation; Saturated or unsaturated fatty acid single, two and triglyceride, the glyceride of soybean oil and sucrose.
Other emulsifying agents comprise natural and bile salt or bile acid synthesized form, and the two is all gripped altogether with aminoacid or non-ly grips altogether, for example taurodeoxycholate and cholic acid.
V.
The application of porous drug matrices
Porous drug matrices described herein is used to prepare preparation, to the patient's administration that needs medicine." patient " described herein is meant and comprises mammal by animal, and be preferred human.Said preparation treats or prevents the medicine of effective dose to the patient.
In a preferred embodiment, in preparation, used paclitaxel or Ramulus et folium taxi cuspidatae terpene substrate to be used for patient's administration to needs.The pharmaceutical composition of preferred these medicines is with the form administration of pill and do not contain CREMOPHOR
TM, polysorbate80, or other solubilizing agents.Said composition is porous dry powder, when adding water-bearing media in this powder, forms the suspension of medicament nano particle or microgranule.
Porous matrix or its preparation are fit to by different administrations, for example injection, mucosa, oral, local/via percutaneous drug delivery, thus part, the effect of zone or whole body obtained.The example of injecting pathway comprises in the intravenous, intra-arterial, heart, in the film, in the bone, in the intraarticular, synovial membrane, Intradermal, subcutaneous and intramuscular administration.The example of mucosal route comprises pulmonary's (in respiratory system), oral cavity, Sublingual, intranasal, rectum and vagina administration.Porous matrix can also be used in ophthalmic, conjunctiva, ear, urethra, intracranial, the pathological changes and administration in the tumor.
In a preferred embodiment, drug matrices is a form of powder, this powder can with aqueous medium, normal saline for example, regeneration and drug administration by injection are as intramuscular, subcutaneous or intravenous injection.An advantage of preparation described herein is that it can be used to change the medicine (for example, being to avoid pill to inject the deposition of back medicine) that must inject pellet-formulation, avoids medicine unacceptably sedimentation or be used for topical in vivo.
Perhaps, can use standard technique further this substrate to be processed into tablet or capsule is used for oral administration, is processed into rectal suppository, is processed into that Foradil Aerolizer formoterol fumarate is used for pulmonary administration or mixing/be processed into Emulsion or ointment is used for topical.These standard techniques are at " pharmaceutical dosage form and drug delivery system (Pharmaceutical Dosage Forms and DrugDelivery Systems) " the 6th edition (Williams ﹠amp of people such as for example Ansel; Wilkins 1995) in description is arranged.
In conjunction with non-limiting example hereinafter, can further understand the present invention.
General introduction
Embodiment 1-10 uses the production of different pore creating materials, different medicine and different solvent demonstration porous drug matrices.Embodiment 1-8 uses emulsifying agent preparation production substrate, and embodiment 9 and 10 uses pharmaceutical solutions production substrate.Embodiment 11-13 has described the analytical method of the feature of the porous drug matrices that is used for confirming that embodiment 1-10 is produced.These features comprise the integrity and the solubility property of density, medicine.
Embodiment 14 described to the particle size analysis and the surface area analysis of the bonded drugs of low aqueous solubility particle of porous drug matrices.Embodiment 15-17 has described the experiment of the internal surface area that the porous drug matrices that confirms to use pore creating material production improved.Embodiment 18-21 has described the needs that contain the wetting agent component in porous drug matrices or the experiment of its advantage.Embodiment 22 has described and has confirmed the experiment of porous drug matrices with the form administration of intravenous pill.Embodiment 23 and 24 has described with the phospholipid of pore creating material and PEGization and has produced porous drug matrices.
Material and facility
Used following material and facility: PEG3350 in an embodiment, PEG8000, polyvinylpyrrolidone K-15, nifedipine, naproxen, prednisone, SPAN
TM40, lecithin, TWEEN
TM80, PLURONIC
TMF127, ammonium chloride, ammonium bicarbonate and ammonium acetate from Spectrum Chemicals (Gardena, CA).Griseofulvin from AldrichChemicals (Milwaukee, WI).Paclitaxel from Hauser (Boulder, CO).1,2-two myristoyls-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-5000] (PEG 5000PE) and 1,2-two myristoyls-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-2000] (PEG 2000 PE) from Avanti Polar Lipids Inc. (Alabaster, AL).Dichloromethane from EM Science (Gibbstown, NJ).All emulsifying agents all use Virtis IQ
2Homogenizer (Virtis, Gardiner, NY) preparation.All preparations all use pneumatic atomizing nozzle spray drying on the spray dryer of bench top.
Embodiment 1: use ammonium bicarbonate as pore creating material, SPAN
TM40 and PEG8000 as wetting agent production porous prednisone substrate
With 5.46g PEG8000,0.545g prednisone and 0.055g SPAN
TM40 are dissolved in the 182mL dichloromethane.The 3.27g ammonium bicarbonate is dissolved in 18.2mL deionization (DI) water prepares aqueous solution.Aqueous solution added (be in a ratio of 1: 10) in the organic solution and with revolutions per minute (RPM) 16,000 homogenize 5 minutes.With the emulsion spray drying on the aerosol apparatus of bench top that is obtained, the condition of spray drying operation is solution flow rate 20mL/min, dry gas speed 60kg/hr, 36 ℃ of outlet temperatures as dry gas for use pneumatic atomizing nozzle and nitrogen.
Embodiment 2: use ammonium bicarbonate as pore creating material, PEG8000, TWEEN
TM80 and lecithin as wetting agent production porous prednisone substrate
With 5.46g PEG8000,0.545g prednisone and 0.003g TWEEN
TM80 and 0.003g lecithin be dissolved in the 182mL dichloromethane.Prepare aqueous solution according to the method among the embodiment 1.Aqueous solution added (be in a ratio of 1: 10) in the organic solution and according to the description homogenize among the embodiment 1 15 minutes.With the emulsion spray drying that is obtained, the condition of spray drying operation is flow of solution speed 20mL/min, dry gas speed 60kg/hr, 35 ℃ of outlet temperatures according to the description among the embodiment 1.
Embodiment 3: use ammonium acetate as pore creating material, PEG8000, TWEEN
TM80 and lecithin as wetting agent production porous prednisone substrate
The organic solution for preparing a kind of load prednisone according to the description of embodiment 2.The 3.27g ammonium acetate is dissolved in the 18.2mL deionized water prepares aqueous solution.According to the description among the embodiment 2 with aqueous solution and organic solution homogenize and spray drying.
Embodiment 4: use ammonium chloride as pore creating material, PEG8000, TWEEN
TM80 and lecithin as wetting agent production porous prednisone substrate
The organic solution for preparing a kind of load prednisone according to the description of embodiment 2.The 3.27g chloride leach is prepared aqueous solution in the 18.2mL deionized water.According to the description of embodiment 1 with aqueous solution and organic solution homogenize.According to the description of embodiment 2 with the emulsion spray drying that is obtained.
Embodiment 5: use ammonium bicarbonate as pore creating material, PEG3350, TWEEN
TM80 and lecithin as wetting agent production porous griseofulvin substrate
With 9.09g PEG3350,4.55g griseofulvin, 0.01g TWEEN
TM80 and 0.01g lecithin be dissolved in the 182mL dichloromethane.3.27g ammonium bicarbonate and 1.09g PEG3350 be dissolved in the 18.2mL deionized water prepare aqueous solution.According to the description of embodiment 1 with aqueous solution and organic solution homogenize.According to the emulsion that the description spray drying of embodiment 1 is obtained, the condition of spray drying operation is solution flow rate 20mL/min, dry gas speed 80kg/hr, 12 ℃ of outlet temperatures.
Embodiment 6: use ammonium bicarbonate as pore creating material, PEG3350 and lecithin are as wetting agent production porous nifedipine substrate
With 9.09g PEG3350,2.27g nifedipine and 0.009g lecithin are dissolved in the 182mL dichloromethane.The 3.27g ammonium bicarbonate is dissolved in the 18.2mL deionized water prepares aqueous solution.Description homogenize aqueous solution and organic solution according to embodiment 1.According to the emulsion that the description spray drying of embodiment 1 is obtained, employed operating condition is flow of solution speed 20mL/min, dry gas speed 60kg/hr, 20 ℃ of outlet temperatures.
Embodiment 7: use ammonium chloride as pore creating material, PEG3350 and lecithin are as wetting agent production porous naproxen substrate
With 10.91g PEG3350,2.73g naproxen and 0.109g lecithin are dissolved in the organic solution of preparation load naproxen in the 182mL dichloromethane.Description according to embodiment 4 prepares aqueous solution.Description homogenize aqueous solution and organic solution according to embodiment 1.The emulsion that uses following operating condition spray drying to be obtained, solution flow rate 20mL/min, dry gas speed 100kg/hr, 20 ℃ of outlet temperatures.
Embodiment 8: use ammonium bicarbonate as pore creating material, PEG3350 and lecithin are as wetting agent production porous paclitaxel substrate
With the 3.0g paclitaxel, 15.0g PEG3350 and 15.7mg lecithin are dissolved in the 100mL dichloromethane.The aqueous solution that will contain the 10mL deionized water of 1.8g ammonium bicarbonate and 0.6g PEG3350 adds in the organic solution (being in a ratio of 1: 10).16, under the 000RPM with mixture homogenization 5 minutes.Use following operating condition with the emulsion spray drying that is obtained, solution flow rate 10mL/min, dry gas speed 60kg/hr, 25 ℃ of outlet temperatures.
Embodiment 9: use ammonium bicarbonate as pore creating material, PEG3350 and TWEEN
TM80 as wetting agent, and polyvinylpyrrolidone is as filler, and ethanol is as solvent production porous nifedipine substrate
With the 0.76g nifedipine, 0.28g PEG3350 and 2.72g polyvinylpyrrolidone K-15 are dissolved in and prepare the organic solution that contains nifedipine in the 170mL ethanol.Will be by 1.62g ammonium bicarbonate and 3mg TWEEN
TMThe aqueous solution of the solution composition of 80 30mL deionized water adds in the alcoholic solution and mixes.Use following operating condition with the solution spray drying that is obtained: solution flow rate 20mL/min, dry gas speed 100kg/hr, 36 ℃ of outlet temperatures.
Embodiment 10: use ammonium bicarbonate as pore creating material, PEG3350 and PLURONIC
TMF127 is as wetting agent, and polyvinylpyrrolidone is as filler, and ethanol is as solvent production porous nifedipine substrate
With the 0.76g nifedipine, 0.28g PEG3350 and 2.72g polyvinylpyrrolidone K-15 are dissolved in the organic solution that obtains to contain nifedipine in the 170mL ethanol.To contain 1.62g ammonium bicarbonate and 3mg PLURONIC
TMThe aqueous solution that the 30mL deionized water solution of F127 is formed adds in the alcoholic solution and mixes.Use following operating condition with the solution spray drying that is obtained: solution flow rate 20mL/min, dry gas speed 100kg/hr, 36 ℃ of outlet temperatures.
Embodiment 11: the dissolution in vitro of porous drug matrices
With the dissolution in vitro speed of embodiment 1-10 gained powder and the rate of dissolution contrast of corresponding loose medicament.
Analytical method
All solubility studies all among at room temperature the PBS (phosphate buffered saline (PBS)), are used top to be stirred in the glass beaker and are carried out.Employed agitator is IKARW16 BasicMixer, and its R1342 impeller shaft is with stir speed (S.S.) 5 runnings.Pipette sample by pipet, filter 0.22 micron CA injection filter, filter then and analyze.On Hewlett-Packard's 8453 type instruments, carry out the ultraviolet-visible spectrum analysis.With consoluet scale solubility curve.
For griseofulvin, in the material in an amount of test of PBS (600mL) adding, make and contain the 2.4mg griseofulvin in the sample.Under 291nm, carry out ultra-violet analysis.
For naproxen, in the material in an amount of test of PBS (600mL) adding, make and contain the 100mg naproxen in the sample.All contain the equal lucifuge of container of naproxen solid or solution.Under 332nm, carry out ultra-violet analysis.
For nifedipine, in the material in an amount of test of PBS (600mL) adding, make and contain the 2.4mg nifedipine in the sample.All contain the equal lucifuge of container of nifedipine solid or solution.Under 237nm, carry out ultra-violet analysis.
For prednisone, in the material in an amount of test of PBS (250mL) adding, make and contain the 5mg prednisone in the sample.Under 244nm, carry out ultra-violet analysis.
For paclitaxel, containing 0.08%TWEEN
TMStudy among 80 the PBS (T80/PBS).T80/PBS (10mL) is added in the material in an amount of test, make in the sample that is contained in the 15mL polypropylene conical flask and contain the 5mg paclitaxel, with suspension vortex 3-4 minute.Then suspension (0.25mL) is added among the 250mLT80/PBS in the 600mL glass flask and be used for the dissolving analysis.Using embodiment 13 described paclitaxel high performance liquid chromatography (HPLC) methods that the aqueous solution that leaches is directly carried out HPLC analyzes.
The result
The dissolution in vitro speed of the porous drug matrices that embodiment 1-10 is prepared is represented in Fig. 1-6.Dissolution in vitro and corresponding loose medicine contrast with porous drug matrices.In all cases, the porous drug matrices required time of dissolving 80% is all than dissolving short 4-50 of required time of 80% loose medicine doubly.In the contrast of the rate of dissolution that is approximately equal to the slope of curve, the porous drug matrices of embodiment 1-10 than the high 10-1400 of corresponding loose medicine doubly.
Embodiment 12: the density of porous drug matrices
The prepared dry powder density of embodiment 1-7 is listed in the table 1.With a Micromeritics Geopac1360 instrument that uses 8 newton's compaction force, by striding axial pressure (TransaxialPressure) (" TAP ") density measurement.In all cases, the density of substrate all is lower than initial loose medicine, shows that porous drug matrices has more hole than the loose medicine that can buy on the market.
Table 1: grain density analysis
| Material | Density (grams per milliliter) |
| The loose medicament of prednisone | 0.68 |
| | 0.48 |
| | 0.55 |
| | 0.51 |
| Embodiment 4 | 0.49 |
| The loose medicament of griseofulvin | 0.80 |
| | 0.55 |
| The loose medicament of nifedipine | 1.01 |
| | 0.56 |
| The loose medicament of naproxen | 0.69 |
| | 0.58 |
Embodiment 13: the medicine integrity in the porous drug matrices
Analytical method
Use high pressure lipuid chromatography (HPLC) (" HPLC ") (the series 1100HPLC of Hewlett-Packard) to analyze the integrity of processing back medicine.Prednisone, naproxen, nifedipine and griseofulvin are used the chromatographiccondition of American Pharmacopeia (USP).The container and the phial that contain naproxen or nifedipine solution keep in Dark Place.For paclitaxel, chromatographiccondition comprise the Nucleosil post (5:m, C18,100A, 250 * 4.6mm), mobile phase is 2mM H
3PO
4/ acetonitrile (2: 3), flow velocity are 1.5mL/min, carry out ultraviolet detection at 227nm, and the working time is 25 minutes.
The result
Among the embodiment 1-9, the integrity that machines the back medicine is listed in table 2 with the form of purity.The course of processing that medicine is formed porous matrix seems not change the purity of medicine.
Table 2: medicine integrity analysis
| Material | Purity (%) |
| The | 100 |
| | 99.8 |
| | 99.8 |
| | 99.8 |
| Embodiment 4 | 99.8 |
| The loose medicament of griseofulvin | 95.7 |
| | 95.7 |
| The loose medicament of | 100 |
| | 100 |
| | 100 |
| | 100 |
| The loose medicament of | 100 |
| | 100 |
| The loose medicament of | 100 |
| Embodiment 8 | 100 |
Embodiment 14: be in the particle size analysis and the surface area analysis of the drug particle in the wetted porous drug matrices
Analytical method
Coulter Multisizer II with 50 micron pore size carries out particle size analysis in the mode of siphon.Use corresponding medicine to make the electrolyte presaturation, before adding is used to analyze in batches, filter 0.22 micron filter, to guarantee in this batch, not having medicine in analytic process, to dissolve.
The result
The average particle size and the total surface area of the drug particle that is obtained during reconstruct in water-bearing media when porous drug matrices prepared among the embodiment 1-7 are listed in the table 3.
Table 3: particle size and total surface area analysis
| Material | Size (micron) | Surface area (square metre/milliliter microgranule) |
| The prednisone powder | 2.07 | 1.43 |
| | 1.58 | 1.66 |
| | 1.39 | 2.53 |
| | 1.39 | 3.02 |
| Embodiment 4 | 1.24 | 3.36 |
| The loose medicament of griseofulvin | 2.42 | 0.88 |
| | 2.16 | 1.28 |
| The loose medicament of nifedipine | 2.64 | 0.57 |
| | 1.78 | 1.98 |
| The loose medicament of naproxen | 2.89 | 0.66 |
| | 1.34 | 2.79 |
In all cases, reduce 10-54% by the particle size of the drug particle that wetted porous drug matrices obtained with respect to initial loose medicament, the total surface area of particle increases about 16-320% with respect to initial loose medicament.
Embodiment 15: the nifedipine drug matrices that contains wetting agent that uses and do not use the pore creating material preparation
With the 2.0g nifedipine, 8.0g PEG3350 and 8mg lecithin are dissolved in preparation nifedipine/PEG solution in the 200mL dichloromethane (embodiment 15A).Prepare second part of same organic solution that contains nifedipine.To add in first part of nifedipine organic solution (being in a ratio of 1: 10) by the aqueous solution that the 1.8g ammonium bicarbonate is formed in the 20mL deionized water.The homogenize mixture is 5 minutes under 16,000 rev/mins rotating speed.Use following operating condition respectively with nifedipine solution (embodiment 15A) and nifedipine emulsion (embodiment 15B) spray drying: solution flow rate 20mL/min, dry air rate 60kg/hr, 21 ℃ of outlet temperatures.
Embodiment 16: the griseofulvin drug matrices that contains wetting agent that uses and do not use the pore creating material preparation
With the 5.0g griseofulvin, 11.2g PEG3350,11mgTWEEN
TM80 and 11mg lecithin be dissolved in preparation griseofulvin/PEG solution in the 200mL dichloromethane (embodiment 16A).Prepare second part of same organic solution that contains griseofulvin.To add in first part of organic solution (being in a ratio of 1: 10) by the aqueous solution that the 1.8g ammonium bicarbonate is formed in the 20mL deionized water.The homogenize mixture is 5 minutes under 16,000 rev/mins rotating speed.Use following operating condition on long table face workbench respectively with griseofulvin solution (embodiment 16A) and griseofulvin emulsion (embodiment 16B) spray drying: solution flow rate 20mL/min, dry air rate 80kg/hr, 13 ℃ of outlet temperatures.
Embodiment 17: the internal surface area of using and do not use the porous drug matrices that contains wetting agent of pore creating material preparation
Use the internal surface area of the drug matrices of preparation in krypton BET methods analyst embodiment 15 and 16.Use the analysis of multiple spot surface area to carry out the BET specific surface area analysis with krypton as gas.Before the analysis, under 20 ℃ with sample degasification to 20 micron vacuum.The result who is shown in table 4 shows that the internal surface area of using pore creating material to make the drug matrices that is obtained improves 2.3 to 3.5 times.
Table 4: the internal surface area of drug matrices
| Substrate (embodiment numbering) | Surface area (m 2/ g substrate) |
| Use the nifedipine (15A) of wetting agent | 0.40 |
| Use the nifedipine (15B) of wetting agent and ammonium bicarbonate | 1.4 |
| Use the griseofulvin (16A) of wetting agent | 0.41 |
| Use the griseofulvin (16B) of wetting agent and ammonium bicarbonate | 0.95 |
Embodiment 18: the nifedipine drug matrices that does not use the preparation of pore creating material or wetting agent
The 10.0g nifedipine is dissolved in the nifedipine solution of preparation 5% in the 200mL dichloromethane.Use following operating condition on director's work top spray dryer with the solution spray drying: solution flow rate 20mL/min, dry air rate 60kg/hr, 22 ℃ of outlet temperatures.
Embodiment 19: the griseofulvin drug matrices that does not use the preparation of pore creating material or wetting agent
The 16.2g griseofulvin is dissolved in the griseofulvin solution of preparation 8.1% in the 200mL dichloromethane.Use following operating condition on director's work top spray dryer with the solution spray drying: solution flow rate 20mL/min, dry air rate 80kg/hr, 13 ℃ of outlet temperatures.
Embodiment 20: the dissolution in vitro that use/does not use the nifedipine drug matrices of pore creating material and wetting agent preparation
The dissolution in vitro speed of embodiment 15 and 18 prepared nifedipine substrate is shown in Fig. 6., use wetting agent or use wetting agent simultaneously and pore creating material drug prepared substrate improves at external rate of dissolution by medicine drug prepared matrix phase ratio with only.Use the prepared substrate of wetting agent and pore creating material to have the highest rate of dissolution simultaneously.
Embodiment 21: the dissolution in vitro that use/does not use the griseofulvin drug matrices of pore creating material and wetting agent preparation
The dissolution in vitro speed of embodiment 16 and 19 prepared griseofulvin substrate is shown in Fig. 7., use wetting agent or use wetting agent simultaneously and pore creating material drug prepared substrate improves at external rate of dissolution by medicine drug prepared matrix phase ratio with only.Use the prepared substrate of wetting agent and pore creating material to have the highest rate of dissolution simultaneously.
Embodiment 22: with the form of vein pill Canis familiaris L. is given and used porous drug matrices
With 9.09g PEG3350,2.27g nifedipine and 0.009g lecithin are dissolved in and prepare the organic solution that contains nifedipine in the 182mL dichloromethane.3.27g ammonium bicarbonate and 0.91gPEG3350 be dissolved in the 18.2mL deionized water prepare aqueous solution.According to description homogenize aqueous solution and the organic solution of embodiment 1, use following operating condition with the emulsion spray drying that is obtained: solution flow rate 20mL/min, dry gas speed 60kg/hr, 20 ℃ of outlet temperatures.
Preparation concentration is the suspension of the porous nifedipine drug matrices of 2.5m grams per milliliter in 5% glucose solution.With suspension (2mL) with the form of pill to of the beagle administration of four body weight at 8-10kg.Gather the blood sample of the time point between 1 minute to 24 hours.Sample is processed into blood plasma, and freezing preservation is also kept in Dark Place before the liquid chromatography-mass spectrography analysis up to carrying out.All animals all can tolerate to give with the form of pill uses suspension.The average plasma levels of intravenously administrable suspension is shown among Fig. 8.
Embodiment 23: use the phospholipid of PEGization, and 1,2-two myristoyl-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-5000] preparation porous nifedipine substrate
With the 2.0g nifedipine; 30.0g PEG3350; 4mg lecithin and 4mg1,2-two myristoyl-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-5000] (PEG 5000 PE) be dissolved in the organic solution that preparation in the 202mL dichloromethane contains nifedipine.To add in the organic solution (being in a ratio of 1: 10) by the aqueous solution that the 1.8g ammonium bicarbonate is formed in the 20mL deionized water.The homogenize mixture is 5 minutes under 16,000 rev/mins rotating speed.Use following operating condition with the emulsion spray drying that is obtained: solution flow rate 20mL/min, dry air rate 60kg/hr, 21 ℃ of outlet temperatures.
Embodiment 24: use the phospholipid of PEGization, and 1,2-two myristoyl-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-2000] preparation porous nifedipine substrate
With the 2.0g nifedipine; 30.0g PEG3350; 4mg lecithin and 4mg1,2-two myristoyl-sn-glyceryl-3-phosphoethanolamine-N-[gathers (ethylene glycol)-2000] (PEG 2000 PE) be dissolved in the organic solution that preparation in the 202mL dichloromethane contains nifedipine.To add in the organic solution (being in a ratio of 1: 10) by the aqueous solution that the 1.8g ammonium bicarbonate is formed in the 20mL deionized water.The homogenize mixture is 5 minutes under 16,000 rev/mins rotating speed.Use following operating condition with the emulsion spray drying that is obtained: solution flow rate 20mL/min, dry air rate 60kg/hr, 21 ℃ of outlet temperatures.
Detailed description is above improved and change obtains improvement of the present invention and change scheme is conspicuous to those skilled in the art.This type of improvement and change are also in the protection domain of claims.
Claims (13)
1. pharmaceutical composition, it comprises the porous matrix that is formed by wetting agent, hydrophilic excipient and taxane microgranule,
Wherein said hydrophilic excipient is a polyvinylpyrrolidone,
Wherein said wetting agent is a polyoxyethylene sorbitan fatty acid ester,
Wherein said porous matrix is the dry powder form, and wherein said porous matrix will provide through contacting with water-bearing media that to have average diameter be that 0.01-5 micron and total surface area are greater than 0.5m
2The drug microparticles of/mL.
2. the compositions of claim 1, wherein said wetting agent is a polysorbate80.
3. the compositions of claim 1 further comprises sugar.
4. the compositions of claim 3, wherein said sugar is mannitol.
5. the compositions of claim 1, wherein said taxane is a paclitaxel.
6. claim 1,2,4 or 5 compositions, wherein said substrate prepares by the following method,
(a) the described taxane of dissolving forms taxane solution in a kind of organic volatile solvent;
(b) at least a pore creating material, wetting agent and hydrophilic excipient are mixed formation emulsion, suspension or second solution with taxane solution; And
(c) from emulsion, suspension or second solution, remove organic volatile solvent and pore creating material, obtain described porous matrix.
7. the described compositions of claim 6, wherein said pore creating material is an ammonium bicarbonate.
8. the described compositions of claim 6, wherein said step (b) further comprise add sugar in described taxane solution.
9. the described compositions of claim 8, wherein said sugar is mannitol.
10. a method for preparing the taxane porous matrix comprises
(a) the described taxane of dissolving forms taxane solution in a kind of organic volatile solvent;
(b) at least a pore creating material, wetting agent and hydrophilic excipient are mixed formation emulsion, suspension or second solution with taxane solution;
(c) from emulsion, suspension or second solution, remove organic volatile solvent and pore creating material, obtain described porous matrix;
Wherein said hydrophilic excipient is a polyvinylpyrrolidone, and
Wherein said wetting agent is a polyoxyethylene sorbitan fatty acid ester.
11. the described method of claim 10, wherein said pore creating material are ammonium bicarbonate.
12. further comprising, the described method of claim 10, wherein said step (b) in described taxane solution, add sugar.
13. the described method of claim 12, wherein said sugar are mannitol.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13632399P | 1999-05-27 | 1999-05-27 | |
| US60/136,323 | 1999-05-27 | ||
| US60/158,659 | 1999-10-08 | ||
| US09/433,486 | 1999-11-04 | ||
| US60/186,310 | 2000-03-02 |
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| CNB008081611A Division CN1240373C (en) | 1999-05-27 | 2000-05-25 | Porous drug matrices and methods of manufacture thereof |
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| CN102762202A (en) * | 2010-02-19 | 2012-10-31 | 帝国制药美国公司 | Taxane pro-emulsion formulations and methods making and using the same |
| CN113081971A (en) * | 2021-05-14 | 2021-07-09 | 江西中医药大学 | Traditional Chinese medicine porous core-shell type composite particle powder and preparation method and application thereof |
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| GB1265615A (en) * | 1970-09-10 | 1972-03-01 | ||
| IL82245A (en) * | 1986-04-25 | 1990-07-26 | Basf Ag | Preparation of spray-dried granules of active ingredients |
| US6423345B2 (en) * | 1998-04-30 | 2002-07-23 | Acusphere, Inc. | Matrices formed of polymer and hydrophobic compounds for use in drug delivery |
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| CN102762202A (en) * | 2010-02-19 | 2012-10-31 | 帝国制药美国公司 | Taxane pro-emulsion formulations and methods making and using the same |
| CN113081971A (en) * | 2021-05-14 | 2021-07-09 | 江西中医药大学 | Traditional Chinese medicine porous core-shell type composite particle powder and preparation method and application thereof |
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