COMPOSITION THAT UNDERSTANDS UNIFORM, RIGID, SPHERICAL, NANOPOROUS CALCIUM Phosphate MICRO SIZE PART

专利摘要:
calcium phosphate particle compositions and methods of making them. the present invention relates to uniform, rigid, spherical, nanoporous calcium phosphate particles that define an internal space and an amount of active agents present in the internal space are provided. topical delivery compositions are also provided which include particles loaded with active agent, as well as methods of making the particles and topical compositions. the particles and their compositions find use in a variety of different applications, including active agent delivery applications.
公开号:BR112012006635B1
申请号:R112012006635-8
申请日:2009-09-23
公开日:2021-04-06
发明作者:Tetsuro Ogawa；Akira Yamamoto
申请人:Laboratory Skin Care, Inc.；
IPC主号:

专利说明:

[0001] [001] In accordance with 35 U.S.C. §119 (e), the present application claims priority from the filing date of the provisional patent application US 61 / 099,500 filed on September 23, 2008; the disclosure of whose order is incorporated herein by reference. INTRODUCTION
[0002] [002] A variety of different active agents have been and continue to be developed for use in the treatment of a variety of different conditions, including both disease and non-disease conditions. For such applications, an effective amount of the active agent must be provided to those in need. A variety of different delivery formulations and routes have been developed, where such routes may vary depending on the nature of the active agent, the identity of the individual to whom the active agent is to be administered, etc. typically, less invasive routes of distribution are better tolerated and are therefore more desirable.
[0003] [003] A type of distribution route that is of great interest due to its minimally invasive nature is dermal distribution. In dermal delivery, an active agent composition is applied to a location on the skin to deliver the active agent to the individual. Many dermal distribution technologies currently in use or being evaluated are not entirely satisfactory. For example, certain dermal distribution technologies can disrupt the integrity of the stratum corneum (Sc) and / or depend on the presence of permeation enhancers, which can cause undesirable damage and / or irritation. In addition, certain dermal delivery technologies can be polymer and / or liposome based technologies, none of which truly deliver through Sc. In addition, these technologies cannot be applied to bioactive products with large molecular weight.
[0004] [004] As such, there remains a need for the development of new dermal delivery technologies that overcome one or more of the disadvantageous experiences with current dermal delivery approaches. SUMMARY
[0005] [005] Uniform, rigid, spherical nanoporous calcium phosphate particles that define an internal space and an amount of active agent present in the internal space are provided. Topical delivery compositions are also provided which include particles loaded with active agent, as well as methods of making the particles and topical compositions. Their particles and compositions find use in a variety of different applications, including active agent delivery applications. BRIEF DESCRIPTION OF THE FIGURES
[0006] [006] Figures 1A to 2B provide scanning electron microscope images of uniform, rigid, spherical, nanoporous calcium phosphate particles that find use in inventive delivery compositions.
[0007] [007] Figure 3 provides a graphical representation of the particle size distribution of uniform, rigid, spherical, nanoporous calcium phosphate particles that find use in the distribution compositions of the invention.
[0008] [008] Figure 4 provides a graphical representation of the particle size distribution of uniform, rigid, spherical, nanoporous nanoporous particles complexed with resveratrol, according to one aspect of the invention.
[0009] [009] Figure 5 shows a microscopic view of uniform, rigid, spherical, nanoporous calcium phosphate particles complex with resveratrol, according to one aspect of the invention. DETAILED DESCRIPTION
[0010] [0010] Uniform, rigid, spherical, nanoporous calcium phosphate particles that define an internal space and an amount of active agent present in the internal space are provided. Topical delivery compositions are also provided which include particles loaded with active agent, as well as methods of making the particles and topical compositions. Their particles and compositions find use in a variety of different applications, including active agent delivery applications.
[0011] [0011] Before the present invention is further described, it should be understood that that invention is not limited to the specific described modalities, as these may vary. It should also be understood that the terminology used here is for the purpose of describing specific modalities only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0012] [0012] Where a range of values is provided, it is understood that each intervening value, up to the tenth of the lower limit unit, unless the context clearly determines otherwise, between the upper and lower limit of that range and any other mentioned value or intervening in that mentioned range, is covered in the invention. The upper and lower limits of these smaller ranges can be independently included in the smaller ranges and are also covered in the invention, subject to any limit specifically excluded in the mentioned range. Where the mentioned range includes one or both of the limits, the ranges excluding either or both of these included limits are also included in the invention.
[0013] [0013] Certain ranges are shown here with numerical values being preceded by the term "approximately". The term "approximately" is used here to provide literal support for the exact number that precedes as well as a number that is close to or approximately the number that the term precedes. In determining whether a number is close to or is approximately a specifically cited number, the unmentioned nearby or approaching number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically mentioned number.
[0014] [0014] The methods mentioned here can be performed in any order of the mentioned events that is logically possible, as well as the mentioned order of the events.
[0015] [0015] Unless otherwise defined, all technical and scientific terms used here have the same meaning as commonly understood by a person with common knowledge in the technique to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.
[0016] [0016] All publications mentioned here are incorporated here for reference to reveal and describe the methods and / or materials with respect to which the publications are cited.
[0017] [0017] It should be noted that as used here and in the appended claims, the singular forms "a", "an" and "o, a" include plural referents unless the context clearly determines otherwise. It is further noted that the claims can be traced to exclude any optional elements. As such, this statement is intended to serve as an antecedent basis for the use of such exclusive terminology as "exclusively", "only" and similar with respect to the recitation of elements of claim or use of a "negative" limitation.
[0018] [0018] The publications discussed here are provided solely for your disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to predate such publication by virtue of the previous invention. In addition, the publication dates provided may differ from the actual publication dates which may need to be independently confirmed. UNIFORM, RIGID, SPHERICAL, NANOPOROUS CALCIUM Phosphate PARTICLES LOADED WITH ACTIVE AGENT
[0019] [0019] As summarized above, aspects of the invention include uniform, rigid, spherical, nanoporous particles loaded with active agent. The active agent charged particles are calcium phosphate particles that include a porous structure, as described in more detail below. The porous structure of the particles is such that for each particle, the porosity of the particle defines an internal space. The internal space is an empty area or volume located within the particle and is configured in such a way that it can contain an amount of active agent. In particles loaded with active agent of the invention, an amount of active agent is present in the internal space, such that the amount of active agent is located inside the particle, as opposed to present on the external surface of the particle. The particles of the invention having an internal amount of active may or may not include an active agent that is present, for example, absorbed, on the surface of the particle.
[0020] [0020] The amount of internal active agent present in particles of the composition can vary. In certain embodiments, the amount of internal active agent is 2% or more, for example, 4% or more, 5% or more, 7.5% or more, 10% or more, 15% or more, including 20% or more by weight of the particle that includes the internal active agent. As such, in some cases the amount of active agent present in the internal space of a given particle is 10% by weight or more of the calcium phosphate particle.
[0021] [0021] Uniform, rigid, spherical, nanoporous calcium phosphate particles are spherical and uniform in shape. By "uniform" we mean that the shape of the particles does not vary substantially, so that the particles have substantially the same spherical shape. By "rigid" we mean that the particles are hard, in such a way that they are not flexible. The term "spherical" is used in its conventional sense to mean a round body whose surface is at all points substantially equidistant from the center. Of interest are calcium phosphate particles in which the median diameter is 20 µm or less, such as 10 µm or less, including 5 µm or less, where in some cases the average diameter is 4 µm or less, such as 3 µm or less , including 2 µm or less.
[0022] [0022] The particles are nanoporous. By "nanoporous" is meant that the particles have a porosity or 30% or more, such as 40% or more, including 50% or more, where the porosity can vary from 30% to 85% as from 40% to 70% including from 45% to 55%, as determined using a mercury intrusion porosimeter porosity determination protocol as described in ASTM D 4284-88 "Standard Test Method for Determining Pore Volume Distribution of Catalysts by Mercury Intrusion Porosimetry". Porosity is also described by "pore volume (ml / g)" and in such cases it can vary from 0.1 ml / g to 2.0 ml / g. in some cases, the particles have a porosity such that their internal surface area varies from 10 m2 / g to 150 m2 / g, as from 20 m2 / g to 100 m2 / g, including 30 m2 / g to 80 m2 / g, as determined using a BET gas adsorption surface area determination protocol as described in Standard Test Method ASTM D3663-03 for surface area of catalysts and catalyst carriers. The pore diameter can vary, ranging in certain cases from 2 to 100 nm, such as 5 to 80 nm, including 10 to 60 nm. In addition, the particles can have a varying density from 0.2 g / cm3 to 0.5 g / cm3, such as from 0.25 g / cm3 to 0.45 g / cm3, including 0.3 g / cm3 at 0.4 g / cm3. The tap density can be measured by using standard ASTM WK13023 - New Determination of Tap Density of Metallic Powders by a Constant Volume Measuring Method.
[0023] [0023] The particles are, in some cases, chemically pure. By chemically pure it is meant that the particles are substantially composed of a type of calcium phosphate mineral. In some cases, the calcium phosphate particles are composed of a calcium phosphate that is described by the molecular formula Ca10 (PO4) 6 (OH) 2.
[0024] [0024] In some cases, the particles are ceramic particles. By ceramics we mean that the particles are produced using a method that includes a step of subjecting the particles to conditions of high temperature, where such conditions are illustrated below. Elevated temperatures can range from 200 to 1000 ° C, such as 300 to 900 ° C, and including 300 to 800 ° C. In some embodiments, the particles have a compressive breaking strength ranging from 20 to 200 MPa, such as 50 to 150 MPa, and including 75 to 90 MPa, as determined using a test machine particle strength determination protocol micro-compression system SHIMADZU MCT-W500 with a particle sintered at a temperature of 400 ° C to 900 ° C, as described in European patent EP 1840661. In some embodiments, the particles are biodegradable, so we mean that the particles degrade in some so, for example, they dissolve over time under physiological conditions. As the particles of these modalities are biodegradable under physiological conditions, at least they begin to dissolve at a detectable rate under conditions of pH of 6 or less, such as 5.5 or less including 5 or less.
[0025] [0025] The uniform, rigid, spherical, nanoporous calcium phosphate particles of the delivery compositions of the invention can be prepared using any convenient protocol. In a protocol of interest, the particles are manufactured by spray drying a paste that includes nano crystals of calcium phosphate (eg hydroxyapatite) (which can vary in size range from 2 nm to 100 nm) to produce particles of uniform, spherical, nanoporous calcium phosphate. The resulting particles are then sintered for a period of time sufficient to provide mechanically and chemically stable, rigid spheres. In this step, sintering temperatures can vary from 200 ° C to 1000 ° C, such as 300 ° C to 900 ° C and including 300 ° C to 800 ° C for a period of time ranging from 1 hour to 10 hours, as 2 hours to 8 hours and including 3 hours to 6 hours.
[0026] [0026] As summarized above, uniform, rigid, spherical, nanoporous particles of active agent loaded calcium include an amount of an active agent component (made from a single type of active agent or two or more different types of agents active) present in an internal space of the particle, as described above. The term "active agent" refers to any compound or mixture of compounds that produces a physiological result, for example, a beneficial or useful result, after contact with a living organism, for example, a mammal, such as a human being. Active agents are distinguishable from other components of the distribution compositions, such as vehicles, thinners, lubricants, binders, coloring substances, etc. The active agent can be any molecule, as well as a binding portion or fragment thereof, which is capable of modulating a biological process in a living individual. In certain modalities, the active agent can be a substance used in the diagnosis, treatment or prevention of a disease or as a component of a medication.
[0027] [0027] The active agent is a compound that interacts with a target in a living individual. The target can be a number of different types of naturally occurring structures, where targets of interest include both intracellular and extracellular targets. Such targets can be proteins, phospholipids, nucleic acids and the like. The active agent can include one or more functional groups necessary for structural interaction with the target, for example, groups necessary for hydrophobic, hydrophilic, electrostatic or even covalent interactions, depending on the specific active agent and its intended target, where functional groups of interest include groups that participate in hydrogen bonding, hydrophobic-hydrophobic interactions, electrostatic interactions, etc., and may include at least one amine, amide, sulfhydryl, carbonyl, hydroxyl or carboxyl group, as at least two of the functional chemical groups.
[0028] [0028] Active agents of interest may include heterocyclic or cyclic carbon structures and / or aromatic or polyaromatic structures substituted by one or more of the above functional groups. Also of interest as fractions of active agents are structures found between biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Such compounds can be selected to identify those of interest, where a variety of different selection protocols are known in the art.
[0029] [0029] The active agents can be derived from a naturally occurring or synthetic compound that can be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. For example, numerous means are available for random and targeted synthesis of a wide variety of organic compounds and biomolecules, including the preparation of randomized olignucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. In addition, natural or synthetically produced libraries and compounds are readily modified by conventional chemical, physical and biochemical means, and can be used to produce combination libraries. Known pharmacological agents can be subjected to random or targeted chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogues.
[0030] [0030] As such, the active agent can be obtained from a library of synthetic or naturally occurring molecules, including a library of compounds produced by means of combining, i.e., a compound of diversity combining library. When obtained from such libraries, the active agent employed will have demonstrated some desirable activity in an appropriate selection trial for the activity. Combination libraries, as well as methods for producing and selecting such libraries, are known in the art and described in: 5,741,713; 5734,018; 5,731,423; 5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696; 5,684,711; 5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698; 5,565,324; 5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564; 5,440,016; 5,438,119; 5,223,409, the disclosures of which are hereby incorporated by reference.
[0031] [0031] Broad categories of active agents of interest include, but are not limited to: cardiovascular agents; pain relieving agents, for example, analgesics, anesthetics, anti-inflammatory agents, etc .; agents that act on nerves; chemotherapeutic agents (for example, anti-neoplastic), etc. Active agents of interest include, but are not limited to:
[0032] [0032] antibiotics, such as: aminoglycosides, for example, amicacin, apramicin, arbecacin, bambermicins, butirosin, dibecacin, diidrostreptomycin, fortimycin, gentamicin, isepamycin, kanamycin, micronomcin, neomycin, netilomycin, paromycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, Tobramycin, trospectomycin; amphenicols, for example, azidamphenicol, chloramphenicol, florfenicol, and teimafenicol; ansamycins, for example, rifamide, rifampin, rifamycin, rifapentin, rifaximin; b-lactams; for example, carbacefens, carbapenens, cephalosporins, cephamycins, monobactams, oxafens, penicillins; lincosamides, for example, ciinamycin, lincomycin; macrolides, for example, ciarithromycin, dirtromycin, erythromycin, etc .; polypeptides, for example, amphomycin, bacitracin, capreomycin, etc .; tetracyclines, for example, apicycline, chlortetracycline, cytocycline, minocycline, etc .; synthetic antibacterial agents, such as 2,4-diaminopyrimidines, nitrofurans, quinolones and analogues thereof, sulfonamides, sulfones;
[0033] [0033] antifungal agents, such as: polyenes, for example, amphotericin B, candicidin, dermostatin, filipin, fungicromin, hachimycin, hamicin, lucensomicin, mepartricin, natamicin, nystatin, pecilocin, perimicin; synthetic antifungals, such as allylamines, for example, butenafine, naphthifine, terbinafine; imidazois, for example, bifonazole, butoconazole, chlordantoin, chlormidazole, etc., thiocarbamates, for example, tolcyclate, triazoles, for example, fluconazole, itraconazole, terconazole;
[0034] [0034] anthelmintics, such as: arecoline, aspidin, aspidinol, dichlorophene, embelin, kosin, naphthalene, niclosamide, pelletierine, quinacrine, alantolactone, amocarzine, amoscanate, ascaridole, behen, bitoscanate, tetrachlorol, carbonate, tetrachlorol , etc.;
[0035] [0035] anti-malarials, such as: acedapsone, amodiaquin, arteter, artemeter, artemisinin, artesunate, atovaquone, bebeerine, berberine, chirata, chlorguanide, chloroquine, chlorprogaunil, cinchona, cinchonidine, cinchonine, cycloguanil, chlorohydrin, hydroquinone mefloquine, 3-methyl arsacetin, pamaquine, plasmocid, primaquine, pyrimethamine, quinacrine, quinidine, quinine, quinocide, quinoline, dibasic sodium arsenate;
[0036] [0036] anti-protozoan agents, such as: acranyl, tinidazole, ipronidazole, etilstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, suramin;
[0037] [0037] cardioprotective agents, for example, Zinecard (dexrazoxane); blood modifiers, including anticoagulants (eg, coumadin (sodium warfarin), fragmin (dalteparin sodium), heparin, innohep (sodium tinzaparin), lovenox (enoxaparin sodium), orgaran (danaparoid sodium)) antiplatelet agents (eg tirofiban hydrochloride), aggrenox (aspirin / extended release dipyridamol), agrilin (anagrelide hydrochloride), ecotrin (acetyl salicylic acid), folan (epoprostenol sodium), halfprin (enteric coated aspiridine), integrlilin (eptifibatide), persidine (dipentine) ), plavix (clopidogrel bisulfate), pletal (cilostazol), reopro (abciximab), ticlid (ticiopidine hydrochloride)), thrombolytic agents (activase (aiteplase), retase (reteplase), streptase (streptocinase)); adrenergic blockers, such as cardura (doxazosin mesylate), dibenzyline (phenoxy benzamine chloridate), hitrin (terazosin hydrochloride), minipress (prazosin hydrochloride), minizide (prazosin hydrochloride / polythiazide); adrenergic stimulants, such as aldochlor (methyldopa - chlorothiazide), aldomet (methyldopa, methyldopate HCI), aldoril (methyldopa - hydrochlorothiazide), catapres (clonidine hydrochloride USP, clonidine), chlorpres (clonidine hydrochloride and chlorididone) / chlortalidone), tenex (guanfacine hydrochloride); alpha / beta adrenergic blockers, such as coreg (carvedilol), normodine (labetalol hydrochloride); angioiensin converting enzyme (ACE) inhibitors, such as acupril (quinapril hydrochloride), aceon (perindopril erbumine), altace (ramipril), captopril, lotensin (benazepril hydrochloride), mavik (trandolapril), monopril (phosinopril sodium tablets ), prinivil (lisinopril), univasc (moexipril hydrochloride), vasotec (enalaprilat, enalapril maleate), zestril (lisinopril); angiotensin converting enzyme (ACE) inhibitors with calcium channel blockers, such as lexxel (enalapril maleate - felodipine ER), lotrel (amlodipine and benazepril hydrochloride), tarka (trandolapril / verapamil hydrochloride ER); angiotensin converting enzyme (ACE) inhibitors with diuretics, such as accuretic (quinapril HCI / hydrochlorothiazide), lotensin (benazepril hydrochlorothiazide USP), prinizide (lisinopril-hydrochlorothiazide), uniretic (hydrochloride / hydrochloride) enalapril maleate - hydrochlorothiazide), zestoretic (lisinopril and hydrochlorothiazide); angiotensin II receptor antagonists, such as Atacand (candesartan cilexetil), avapro (irbesartan), cozaar (losartan potassio), diovan (valsartan), micardis (telmisartan), teveten (eprosartan mesylate); angiotensin II receptor antagonists with diuretics, such as avalide (irbesartan - hydrochlorothiazide), diovan (valsartan and hydrochlorothiazide), hyzaar (losartan potassium-hydrochlorothiazide); antiarrhythmics, such as Group I (for example, mexitil (mexiletine hydrochloride, USP), norpace (disopyramide phosphate), procanbid (procainamide hydrochloride), quinaglute (quinidine gluconate), quinidex (quinidine sulfate), quinidine (injection of quinidine gluconate, USP), ritmol (propafenone hydrochloride), tambocor (flecainide acetate), tonocard (tocainide HCl)), group II (eg betapace (sotalol HCl), brevibloc (esmolol hydrochloride), inderal (hydrochloride propranolol), sectral (acebutolol hydrochloride)), group III (for example, betapace (sotalol HCl), cordarone (amiodarone hydrochloride), corvert (ibutilide fumarate injection), pacerone (amiodarone HCl), tikosin (dofetilide) ), group IV (for example, calan (verapamil hydrochloride), cardizem (diltiazem HCl), as well as adenocard (adenosine), lanoxicaps (digoxin), lanoxin (digoxin)); antilipemic acids, including bile acid scavengers (eg, colestid (micronized colestipol hydrochloride), welchol (colesevelam hydrochloride)), fibric acid derivatives (eg, atromid (clofibrate), lopid (gemfibrozal tablets, USP), tricor (fenofibrate capsules)), HMG-CoA reductase inhibitors (eg baicol (cerivastatin sodium tablets), lescol (sodium fluvastatin), lipitor (atorvastatin calcium), mevacor (iovastatin), pravachol (pravastatin sodium), zocor ( simvastatin)), nicotinic acid (for example, Niaspan (extended-release niacin tablets)); beta-adrenergic blocking agents, for example, betapace (sotalol HCl), blocadren (timolol maleate), brevibloc (esmolol hydrochloride), cartrol (carteolol hydrochloride), inderal (propranolol hydrochloride), cerlone (betaxolol hydrochloride), nadolol, sectral (acebutolol hydrochloride), tenormin (atenolol), toprol (metoprolol succinate), zebeta (bisoprolol fumarate); beta-adrenergic blocking agents with diuretics, for example, corzide (nadolol and bendroflumethiazide tablets), undertone (propranolol hydrochloride and hydrochlorothiazide), tenoretic (atenolol and chlortalidone), timolide (timolol maleate - hydrochlorothiazide), ziac and hydrochlorothiazide); calcium channel blockers, for example, adalat (nifedipine), caian (verapamil hydrochloride), cardene (nicardipine hydrochloride), cardizem (diltiazem HCi), covera (verapamil hydrochloride), isoptin (verapamil hydrochloride), nimotop ( nimodipine), norvasc (amlodipine besylate), plendil (felodipine), procardia (nifedipine), sular (nisoldipine), tiazac (diltiazem hydrochloride), vascor (bepridil hydrochloride), verelan (verapamil hydrochloride); diuretics, including carbonic anhydrase inhibitors (eg, daranide (dichlorphenamide)), combination diuretics (eg, aldactazide (spironoiacton with hydrochlorothiazide), diazide (triamterene and hydrochlorothiazide), maxzide (trianterene and hydrochloride) hydrochlorothiazide)), loop diuretics (demadex (torsemide), edecrin (ethacrynic acid, sodium ethacrinate), furosemide), low potassium diuretics (aldactone (spironoiacton)), direnium (trianterene), midamor (amiloride HCl) & tiaz related (for example, diucardin (hydroflumethiazide), diuryl (chlorothiazide, sodium chlorothiazide), enduron (methiciotiazide), hydrodiuryl hydrochlorothiazide), indapamide, microzide (hydrochlorothiazide) mykrox (metolazone tablets), renese (tal), renese ), zaroxolin (metolazone)); inotropic agents, for example ,egask (digoxin), dobutrex (dobutamine), lanoxicaps (digoxin), lanoxin (digoxin), primacor (milrinone lactate); activase (recombinant alteplase); adrenaline chloride (epinephrine injection, USP); denser (metyrosine), inversin (mecamylamine HCl), reopro (abciximab), retavase (reteplase), streptase (streptocinase), tnkase (tenecteplase); vasodilators, including coronary vasodilators (eg, indur (isosorbide mononitrate), ism (isosorbide mononitrate), isordil (isosorbide dinitrate), nitrodur (nitroglycerin), nitrolingual (nitroglycerin lingual spray), nitrostat (nitroglycerin tablets ), sorbitrate (isosorbide dinitrate)), peripheral vasodilators & combinations (eg, corlopam (fenoldopam mesylate), fiolan (epoprostenol sodium), primacor (milrinone lactate)), vasopressors, eg, aramine (metaraminol bitartrate), epipen (EpiPen 0.3 mg self-injecting epinephrine brand, EpiPen Jr. 0.15 mg self-injecting epinephrine brand), proamatine (midodrine hydrochloride); etc.
[0038] [0038] psychopharmacological agents, such as (1) central nervous system depressants, for example, anesthetics in general (barbiturates, benzodiazepines, steroids, cycloxanone derivatives and various agents), sedative hypnotics (benzodiazepines, barbiturates, piperidinedione and trionas, derivatives of quinazoline, carbamates, aldehydes and derivatives, amides, acyclic ureides, benzazepines and related drugs, phenothiazines, etc.), drugs to modify the tone of central voluntary music (anticonvulsants, such as hydantoins, barbiturates, oxazolidinediones, succinimides, acylureides, glutamine, glutamine, glutamine secondary and tertiary alcohols, dibenzazepine derivatives, valproic acid derivatives, GABA analogs, etc.), analgesics (morphine and derivatives, oripavine derivatives, morphinan derivatives, phenyl piperidines, 2,6-methane-3-benzazocaine derivatives, diphenyl propylamines and isoesters, salicylates, p-aminophenol derivatives, 5-pyrazolone derivatives, ar acid derivatives il acetic, phenamates and isoesters, etc.) and antiemetics (anticholinergics, antihistamines, antidopaminergics, etc.), (2) central nervous system stimulants, for example analgesics (respiratory stimulants, convulsive stimulants, psychomotor stimulants), narcotic antagonists (morphine derivatives, oripavine derivatives, 2,6-methane-3-benzphin derivatives of morphinan) nootropic, (3) psychopharmacological, for example, anxiolytic sedatives (benzodiazepines, propanediol carbamates), antipsychotics (phenothiazine derivatives, derivatives of thioxanthine, other tricyclic compounds, butyrophenone derivatives and isosteres, diphenyl butylamine derivatives, substituted benzamides, aryl piperazine derivatives, indole derivatives, etc.), tricyclic compound antidepressants, MAO inhibitors, etc.), (4) respiratory tract, for example, central antitussives (opium alkaloids and their derivatives);
[0039] [0039] pharmacodynamic agents, such as (1) drugs of the peripheral nervous system, for example, local anesthetics (ester derivatives, amide derivatives), (2) drugs that act at neuro-effector or synaptic junction sites, for example, cholinergic agents , cholinergic blocking agents, neuromuscular blocking agents, adrenergic agents, antiadrenergic agents, (3) active smooth muscle drugs, for example, spasmolytics (anticholinergics, musculotropic spasmolytics), vasodilators, smooth muscle stimulants, (4) histamines and anti -histamines, for example, histamine and derivative thereof (betazole), antihistamines (H1 antagonists, H2 antagonists), histamine metabolism drugs, (5) cardiovascular drugs, for example, cardiotonic drugs (plant extracts, butenolides , pentadienolides, erythrofleum species alkaloids, ionophores, adrenoceptor stimulants, etc.), antiarrhythmic drugs, antihypertension agents, antilipidemic agents (d derivatives of clofibric acid, derivatives of nicotinic acid, hormones and analogues, antibiotics, salicylic acid and derivatives), anti-viral drugs, hemostiptics, (6) drugs of the hemopoietic system and blood, for example, anti-anemia drugs, blood clotting drugs , (hemostatics, anticoagulants, antithrombotics, thrombolytics, blood proteins and their fractions), (7) drugs of the gastrointestinal tract, for example, means of digestion (stomatological, choleretic), anti-ulcer drugs, antidiarrheal agents, (8) drugs of local action;
[0040] [0040] chemotherapeutic agents, such as (1) anti-infective agents, for example, ectoparasiticides (chlorinated hydrocarbons, pyrethines, sulfur compounds), anthelmintics, antiprotozoal agents, antimalarial agents, anti-malarial agents, anti-anti-sweating agents, antitriconomic agents, anti-tramal agents, anti-tramal agents; , antimycobacterial drugs, antiviral chemotherapeutics, etc., and (2) cytostatics, that is, antineoplastic agents or cytotoxic drugs, such as alkylating agents, for example, mecloretamine hydrochloride (Nitrogen mustard, Mustagen, HN2), cyclophosphamide (Cytovan, Endoxan), Ifosfamide (IFEX), chlorambucil (Leukeran), Melfalan (Phenyl Alanine Mustard, L-sarcolysin, Alkeran, L-PAM), Busulfan (Mileran), Tiotepa (Triethylenethiofosforamide), Carmustine (BiCNU, BCNU, BCNU, BCNU, BCNU, , CCNU), Streptozocin (Zanosar) and the like; plant alkaloids, for example, Vincristine (Oncovin), Vinblastine (Velban, Velbe), Paclitaxel (Taxol), and the like; antimetabolites, for example, Methotrexate (MTX), Mercaptopurine (Purinethol, 6-MP), Thioguanine (6-TG), Fluoruracil (5-FU), Cytarabine (Citosar-U, Ara-C), Azacitidine (Milosar, 5- AZA) and the like; antibiotics, for example, Dactinomycin (Actinomycin D, Cosmegen), Doxorubicin (Adriamicin), Daunorubicin (duanomycin, Cerubidine), Idarubicin ((damicin), Bleomycin (Blenoxane), Picamycin (Mithramycin, Mitracycin), Mitomycin and similar (Mutamicin) and Mitomycin other anti-cell proliferative agents, for example, Hydroxy urea (Hydrea), Procarbazine (Mutalane), Dacarbazine (DTIC-Dome), cisplatin (Platinol), Caboplatin (Paraplatin), Asparaginase (Elspar) Etoposideo (VePesid, VP-16-213) , Amsarcrine (AMSA, m-AMSA), Mitotane (Lysodren), Mitoxantrone (Novatrone), and the like.
[0041] [0041] Drug compounds of interest are also listed in: Goodman & Gilman's, The Pharmacological Basis of Therapeutics (9th Ed) {Goodman et al. eds) (McGraw-Hill) (1996); and 2001 Physician's Desk Reference.
[0042] [0042] Specific categories and examples of active agents include, but are not limited to: those that appear in the following table:
[0043] [0043] Specific compounds of interest also include, but are not limited to:
[0044] [0044] antineoplastic agents as disclosed in US patents 5880161, 5877206, 5786344, 5760041, 5753668, 5698529, 5684004, 5665715, 5654484, 5624924, 5618813, 5610292, 5597831, 5530026, 5525633, 5525606, 5512, 556 5358952, 5318965, 5223503, 5214068, 5196424, 5109024, 5106996, 5101072, 5077404, 5071848, 5066493, 5019390, 4996229, 4996206, 4970318, 4968800, 4962114, 4927828, 4892833, 48985, 489, 488, 488, 488, 488 and 488 4849563, 4845216, 4833145, 4824955, 4785085, 476925, 4684747, 4618685, 4611066, 4550187, 4550186, 4544501, 4541956, 4532327, 4490540, 4399283, 4391982, 4383994, 4294763, 42433, 424, 424, 424, 434, 434, 424, 434, 434, 424 and 436 4029661, 4012448;
[0045] [0045] psychopharmacological / psychotropic agents, as disclosed in US patents 5192799, 5036070, 4778800, 4753951, 4590180, 4690930, 4645773, 4427694, 4424202, 4440781, 5686482, 5478828, 5461062, 5387593, 5387527, 5387527, 5387527, 5387527, 5387527, 5387527 , 4977167, 4904663, 4788188, 4778800, 4753951, 4690930, 4645773, 4631285, 4617314, 4613600, 4590180, 4560684, 4548938, 4529727, 4459306, 4443451, 4440781, 4427694, 4424202, 4397853, 4358451, 4324787, 4314081, 4313896, 4294828 , 4277476, 4267328, 4264499, 4231930, 4194009, 4188388, 4148796, 4128717, 4062858, 4031226, 4020072, 4018895, 4018779, 4013672, 3994898, 3968125, 3939152, 3928356, 38808341, 38808341
[0046] [0046] Cardiovascular agents as disclosed in US patents 4966967, 5661129, 5552411, 5332737 5389675, 5198449, 5079247, 4966967, 4874760, 4954526, 5051423, 4888335, 4853391, 4906634, 4775757, 4727072, 4542160, 452294, 4524151, 4525479, 4474804 , 4520026, 4520026, 5869478, 5859239, 5837702, 5807889, 5731322 5726171, 5723457, 5705523, 5696111, 5691332, 5679672, 5661129, 5654294, 5646276, 5637586, 5631251, 5612370, 5512, 5523, 5523, 55, 5623, 55, 56, 56, 56, 56, 56, 576, 55, 56, 576, 556 5482925, 5457118, 5414017, 5414013, 5401758, 5393771, 5362902, 5332737, 5310731, 5260444, 5223516, 5217958, 5208245, 5202330, 5198449, 5189036, 5185362, 5140031, 5128349, 524, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5 and 5 5036065, 5026712, 5011931, 5006542, 4981843, 4977144, 4971984, 4966967, 4959383, 4954526, 4952692, 4939137, 4906634, 4889866, 4888335, 4883872, 4883811, 4847379, 4835747, 485, 477, 477, 477, 477, 477 4767756, 4762837, 4753946, 4752616 4749715, 4738978, 4735962, 4734426, 473442 5, 4734424, 4730052, 4727072, 4721796, 4707550, 4704382, 4703120, 4681970, 4681882, 4670560, 4670453, 4668787, 4663337 4663336, 4661506, 4656267, 4656185, 4654357, 46545, 465, 465, 465, 465 and 465 , 4649139, 4647585, 4647573, 4647565, 4647561, 4645836, 4639461, 4638012, 4638011, 4632931, 4631283, 4628095, 4626548, 4614825, 4611007, 4611006, 4611005, 460967, 456049, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4660, 4760 , 4588743, 4588742, 4588741, 4582854, 4575512, 4568762, 4560698, 4556739, 4556675, 4555571, 4555570, 4555523, 4550120, 4542160, 4542157, 4542156, 4542155, 4542151, 45345, 453, 453, 453, 453 and 453 , 4525479, 4524151, 4522949, 4521539, 4520026, 4517188, 4482562, 4474804, 4474803, 4472411, 4466979, 4463015, 4456617, 4456616, 4456615, 4418076, 4416896, 4252815, 42207454, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 and 4 , 4123550, 4083968, 4076834, 4064259, 4064258, 4064257, 4058620, 4001421, 3993639, 3991057, 3982010, 3980652, 3968117, 3959296, 3951950, 3933834, 3925369, 3923818, 3898210, 3897442, 3897441, 3886157, 3883540, 3873715, 3867383, 3873715, 3867383, 3691216, 3624126;
[0047] [0047] antimicrobial agents as disclosed in US patents 5902594, 5874476, 5874436, 5859027, 5856320, 5854242, 5811091, 5786350, 5783177, 5773469, 5762919, 5753715, 5741526, 5709870, 5707705, 56707990, 56961165 5643950, 5610196, 5608056, 5604262, 5595742, 5576341, 5554373, 5541233, 5534546, 5534508, 5514715, 5508417, 5464832, 5428073, 5428016, 5424396, 5399553, 5391544, 53305, 535, 535, 535, 535, 535, 535, 535, 535, 535, 535 and 535 5266567, 5254685, 5252745, 5209930, 5196441, 5190961, 5175160, 5157051, 5096700, 5093342, 5089251, 5073570, 5061702, 5037809, 5036077, 5010109, 4970226, 4916156, 478, 486, 486, 486, 486, 486, 486, 486 4552882, 4492700, 4489098, 4489085, 4487776, 4479953, 4477448, 4474807, 4470994, 4370484, 4337199, 4311709, 4308283, 4304910, 4260634, 4233311, 4215131, 4166122, 406, 466, 4, 6, 6, 6, 6, 6, 6, 6 and 6 4044139, 4002775, 3991201, 3966968, 3954868, 3936393, 3917476, 3915889, 3867548, 38 65748, 3867548, 3865748 3783160, 3764676, 3764677;
[0048] [0048] anti-inflammatory agents as disclosed in US patents 5872109, 5837735, 5827837, 5821250, 5814648, 5780026, 5776946, 5760002, 5750543, 5741798, 5739279, 5733939, 5723481, 5716967, 5688949, 5686488, 5664884949, 5686488, 5664884949 5684031, 5684002, 5677318, 5674891, 5672620, 5665752, 5656661, 5635516, 5631283, 5622948, 5618835, 5607959, 5593980, 5593960, 5580888, 5552424, 5552422, 54, 547, 54, 54, 54, 54, 54, 54, 54, 54, 54 and 54 5470842, 5464856, 5464849, 5462952, 5459151, 5451686, 5444043, 5436265, 5432181, RE034918, 5393756, 5380738, 5376670, 5360811, 5354768, 5348957, 5347029, 5340, 535, 5338, 535, 5319, 535 5298522, 5298498, 5290800, 5290788 5284949, 5280045, 5270319, 5266562, 5256680, 5250700, 5250552, 5248682, 5244917, 5240929, 5234939, 5234937, 5232939, 5225571, 5225417, 522, 52255, 525, 535, 525, 525 , 5191084, 5187175 5185326, 5183906, 5177079, 5171864, 5169963, 5155 122, 5143929, 5143928, 5143927, 5124455, 5124347, 5114958 5112846, 5104656, 5098613, 5095037, 5095019, 5086064 5081261, 5081147, 5081126, 5075330, 5066668, 50596037, 505, 503, 503, 503, 503, 503, 503, 503, 503 500654, 4992448, 4992447, 4988733, 4988728, 4981865, 4962119, 4959378, 4954519, 4945099, 4942236, 4931457, 4927835, 4912248, 4910192, 4904786, 4904685 4904674, 4904484, 495, 486, 495, 486, 496 , 4851412, 4847303, 4847290, 4845242, 4835166, 4826990, 4803216, 4801598, 4791129, 4788205, 4778818, 4775679, 4772703, 4767776, 4764525, 4760051, 4748153, 4725616, 472174, 466, 476, 466, 466, 466, 466, 466 and 463 , 4678802, 4652564, 4644005, 4632923, 4629793, 4614741, 4599360, 4596828, 4595694, 4595686, 4594357, 4585755, 4579866, 4578390, 4569942, 4567201, 4563476, 4559348, 4564545, 455, 456, 456, 456 and 456 , 4514415, 4512990, 4501755, 4495197, 4493839, 4465687, 4440779, 4440763, 4435420, 4412995, 4400534, 4355034, 4335141, 4322420, 4275064, 4244963, 4235908, 4234593, 4226887, 4201778, 4181720, 4173650, 4173634, 4145444, 4128664, 4125612, 4124726, 4124704, 402, 424, 424, 434, 434, 434, 434, 434, 434, 434, 434, 424, 424, 424, 405 4011326, 3998970, 3998954, 3993763, 3991212, 3984405, 3978227, 3978219, 3978202, 3975543, 3968224, 3959368, 3949082, 3949081, 3947475, 3936450, 3934018, 3930005, 3857938, 383, 393, 383, 393, 383, 393, 383 and 395 3694471, 3691214, 3678169, 3624216;
[0049] [0049] immunosuppressive agents as disclosed in US patents 4450159,4450159, 5905085, 5883119, 5880280, 5877184, 5874594, 5843452, 5817672, 5817661, 5817660, 5801193, 5776974, 5763478, 5739169, 57236, 576, 566, 576, 576, 669, 576 5693645, 5691346 5686469, 5686424, 5679705, 5679640, 5670504, 5665774, 5665772, 5648376, 5639455, 5633277, 5624930, 5622970, 5605903, 5604229, 5574041, 5565560, 556, 556, 556, 556, 556 , 5506233, 5506228, 5494895, 5484788, 5470857, 5464615, 5432183, 5431896, 5385918, 5349061, 5344925, 5330993, 5308837, 5290783, 5290772, 5284877, 5284840, 527398, 526678, 524, 525, 525, 525, 525 and 525 , 5219884, 5208241, 5208228, 5202332, 5192773, 5189042, 5169851, 5162334, 5151413, 5149701, 5147877, 5143918, 5138051, 5093338, 5091389, 5068323, 5068247, 5064835, 50628, 506, 506, 496, 6, 6, 6, 6, 6, 6, 6 and 6 , 4317825, 4256766, 4180588, 4000275, 3759921;
[0050] [0050] analgesic agents as disclosed in US patents 5292736, 5688825, 5554789, 5455230, 5292736, 5298522, 5216165, 5438064, 5204365, 5017578, 4906655, 4906655, 4994450, 4749792, 4980365, 4794112, 467049 4719231, 4533671, 4552866, 4539312, 4569942, 4681879, 4511724, 4556672, 4721712, 4474806, 4595686, 4440779, 4434175, 4608374, 4395402, 4400534, 4374139, 4361583, 545545, 545545, 545545, 425545, 4255, 525, 545, 545 5298522, 5216165, 5204365, 5030639, 5017578, 5008264, 4994450, 4980365, 4906655, 4847290, 4844907, 4794110, 4791129, 4774256, 4749792, 4737493, 4721712, 4719231, 4681879, 4670541, 4667039, 4658037, 4634708, 4623648, 4622326, 4608374, 4595686, 4594188, 4569942, 4556672, 4552866, 4539312, 4536512, 4533671, 4511724 4440779, 4434175, 4400534, 4395402, 4391827, 4374139, 4361583, 4322420, 430609, 445, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 424, 434, 434, 434, 434, 424, 430, 434. , 4133819, 4124713, 4117012, 4064272, 4022836, 3966944;
[0051] [0051] cholinergic agents as disclosed in US patents 5219872, 5219873, 5073560, 5073560, 5346911, 5424301, 5073560, 5219872, 4900748, 4786648, 4798841, 4782071, 4710508, 5482938, 5464842, 5378198, 534, 538, 738, 538, 738, 538, 738, 538, 738, 538 and 778 5084281, 5073560, 5002955, 4988710, 4900748, 4798841, 4786648, 4782071, 4745123, 4710508;
[0052] [0052] adrenergic agents as disclosed in US patents 5091528, 5091528, 4835157, 5708015, 5594027, 5580892, 5576332, 5510376, 5482961, 5334601, 5202347, 5135926, 5116867, 5091528, 5017618, 48356867, 489, 466, 466, 469, 466 and 469 4395559, 4381309, 4363808, 4343800, 4329289, 4314943, 4311708, 4304721, 4296117, 4285873, 4281189, 4278608, 4247710, 4145550, 4145425, 4139535, 4082843, 4011321, 4001440, 3824, 3924, 3924, 3924
[0053] [0053] antihistamine agents, as disclosed in US patents 5874479, 5863938, 5856364, 5770612, 5702688, 5674912, 5663208, 5658957, 5652274, 5648380, 5646190, 5641814, 5633285, 5614561, 5602183, 493289 , 3965257, 3946022, 3931197;
[0054] [0054] steroidal agents, as disclosed in US patents 5863538, 5855907, 5855866, 5780592, 5776427, 5651987, 5346887, 5256408, 5252319, 5209926, 4996335, 4927807, 4910192, 4710495, 4049807, 584005, 3649807, 4004005, 366 , 5883087, 5880115, 5869475, 5866558, 5861390, 5861388, 5854235, 5837698, 5834452, 5830886, 5792758, 5792757, 5763361, 5744462, 57417875 5741786, 5733899, 5731345, 57264, 575, 576, 576, 576, 576, 576, 526, 576 5700793, 5698720,5698545, 5696106, 5677293, 5674861, 5661141, 5656621, 5646136, 5637691, 5616574, 5614514, 5604215, 5604213, 5599807, 5585482, 5565588, 5563259, 55637, 556, 556, 556, 556, 556, 556 5506221, 5494907, 5491136, 5478956, 5426179, 5422262, 539I776, 5382661, 5380841, 5380840, 5380839, 5373095, 5371078, 5352809, 5344827, 5344826, 5338837, 5336686, 528, 535, 528, 535, 528, 535 5219879, 5218109, 5215972, 5212166, 5206415, 5194602, 5166201, 5166055, 5126488, 5116829, 5108996, 5099037, 5096892, 5093502, 5086047, 5084450, 5082835, 5081114, 5053404, 5041433, 5041432, 5034548, 5032586, 5026882, 4996335, 4975537, 4970205, 4954446, 4950728, 4950, 4950, 4950, 4949 4892867, 4888336, 4885280, 4882322, 4882319, 4882315, 4874855, 4868167, 4865767, 4861875, 4861765, 4861763, 4847014, 4774236, 4753932, 4711856, 4710495, 4701450, 46106, 466, 466, 466, 466, 466, 466 and 466 4634695, 4634693, 4588530, 4567000, 4560557, 4558041, 4552871, 4552868, 4541956, 4519946, 4515787, 4512986, 4502989, 4495102; whose disclosures are hereby incorporated by reference.
[0055] [0055] Also of interest are those active agents listed in Appendix A to application US 61 / 276,057 filed on May 6, 2009; whose disclosure is hereby incorporated by reference.
[0056] [0056] In certain embodiments, the agent is an active Resveratrol agent. By active agent Resveratrol is meant Resveratrol, (i.e., trans-3,5,4'-trihydroxystylbene; 3,4 ', 5-stylbenetriol; trans-Resveratrol; (E) -5- (p-hydroxystyryl) resorcinol) described by the formula:
[0057] [0057] or an analogue or derivative thereof, for example as disclosed in US patents 7,026,518; 6,790,869 and 6,572,882; whose disclosures are hereby incorporated by reference.
[0058] [0058] In certain embodiments, the active agent is an active agent of retinol, for example, a retinol ester (vitamin A), such as retinyl palmitate, that is [(2E, 4E, 6E, 8E) -3, 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) nona-2,4,6,8-tetraenyl] hexadecanoate.
[0059] [0059] In certain embodiments, the active agent is salicylic acid, that is, 2-hydroxybenzoic acid.
[0060] [0060] Active agents of interest also include those listed in Appendix I of that application.
[0061] [0061] Analogs of the above compounds are also of interest.
[0062] [0062] For all the active agents above, the active agents can be present in any convenient way. In some cases, the active agents are present in a form that is only slightly soluble in water. By no more than little soluble, it is meant that the active agent is present in a form that is poorly soluble in water or insoluble in water. By sparingly soluble in water, it is meant that the agent is sparingly soluble in water. In such embodiments, the solubility of the agent in water, if any, is 0.5 g / liter or less, such as 0.25 g / liter or less, including 0.1 g / liter or less. Water-insoluble agents are agents that have substantially no solubility, if any solubility in water. Examples of forms of active agents of interest include, but are not limited to: small uncharged molecules, high molecular weight peptides and proteins, polysaccharides and nucleic acids, etc.
[0063] [0063] In some cases, the particles are coated, such that they include a coating layer on their outer surface. Coating layers of interest include, but are not limited to, layers of material that provide controlled release of the active agent from the particles into the particle environment. Coatings of interest include physiologically acceptable polymeric coatings. Materials that find use in controlled release coatings include, but are not limited to: Acrocomia Aculeata seed butter, almond butter, Aloe butter, apricot seed butter, Argan butter, Attalea Maripa seed butter, butter avocado, Babaçu butter, bacuri butter, Bagura Soft butter, Baobab Soft butter, Bassia Butyracea seed butter, Bassia Latifolia seed butter, black currant seed butter, Pará nut butter, butter Camelina, Camellia butter, Candelilla butter, Carnauba butter, Carpotroche Brasiliensis seed butter, Chamomile butter, cocoa butter, Coco butter, coffee butter, soft cotton butter, cranberry butter, Cupuaçu butter, grape seed butter, hazelnut butter, hemp seed butter, Horsetail butter, 'Illipe butter, Irvingia Gabonensis seed butter, butter Jojoba, Karite butter, Kokum butter, Kukui butter, Lavender butter, Lemon butter, Lime butter, Macadamia butter, Mango butter, Marula butter, Monoi butter, Mowrah butter, Mucaja butter , Murumuru butter, Olea butter, olive butter, orange butter, palm oil, Passion butter, Phulwara butter, Pistachio butter, Pomegranate butter, Pumpkin butter, Raspberry butter, Rice butter, Butter Salt, Sapucainha butter, Sesame butter, Shea butter, Soy butter, Tamanu butter, Sunflower seed butter, Sweet almond butter, Tangerine butter, Tucuma seed butter, Ucuuba butter, Butter wheat germ, resin, beeswax, glicowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic resins, di-polylactic acid, bu cellulose acetate tyate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidine, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl methyl methacrylate acrylate, polyvinyl chloride , polyethylene and / or halogenated fluorocarbon. TOPICAL COMPOSITIONS
[0064] [0064] Aspects additionally include topical compositions that are configured for application to an individual's topical location. Topical compositions of the invention include: (a) uniform, rigid, spherical, nanoporous calcium phosphate particles comprising a porous structure that defines an internal space and an amount of active agent present in the internal space; and (b) a topical delivery vehicle.
[0065] [0065] Topical compositions of the invention are compositions that are formulated to deliver an active agent to a topical site, such as a mucosal surface or keratinized skin surface of a mammalian individual, such as a human individual. By mucosal surface is meant a place of an individual that includes a mucous membrane, such as the inside of the mouth, inside of the nose, etc. By keratinized skin surface is meant an individual's skin location, that is, a location on the outer covering or integument of an animal's body. Since the topical compositions of the invention are formulated for delivery to a topical site, they are formulated to be physiologically compatible with the topical site for which they are formulated. Therefore, when contacted with the target keratinized skin surface for which they are formulated, the topical compositions do not cause a substantial physiological response, if any (such as inflammation or irritation) that would make the use of the topical compositions unsuitable for topical application.
[0066] [0066] As indicated above, the topical compositions include a population of uniform, rigid, spherical nanoporous particles loaded with active agent. In some cases, the compositions are ones in which at least a little, for example, 10% or more, 25% or more, 50% or more, 75% or more, 80% or more, 90% or more by weight, including substantially all of, for example, 95% or more, 97% or more, 99% or more, by weight of the particles of the composition include an internal amount of active agent. The amount of active agent component (which is composed of one or more distinct active agents) that is bound to the particles can vary depending on the specific active agent (s) composing the particles bound by the active agent, and in certain embodiments range from 0.01 to 2000 mg / g, such as 0.1 to 1000 mg / g including 1 to 300 mg / g of active agent (s) / gram of particle.
[0067] [0067] In a given topical composition of the invention, a diameter distribution for the particles of the same may be present in some cases the majority (such as 60% or more, 75% or more, 90% or more, 95% or more) of the particles have diameters ranging from 0.01 to 20 µm, such as from 0.1 to 10 µm, and including from 0.1 to 2 µm. In some cases, the proportion of particles that have an average particle diameter of 2 µm or less is 50% or more by number, such as 70% or more by number, including 90% or more by number.
[0068] [0068] As indicated above, the topical compositions of the invention further include a topical delivery vehicle. The delivery vehicle (i.e., topical delivery component) refers to that portion of the topical composition that is not the particles loaded with the active agent. The amount of particles loaded with active agent that is present in the delivery composition and therefore combined with a delivery vehicle can vary. In some embodiments, the amount of particles loaded with active agent present in the delivery vehicle ranges from 0.01 to 200 mg / g, such as 0.1 to 100 mg / g including 1 to 50 mg / g of particles loaded with active agent per gram of distribution vehicle. In certain embodiments, the particles are present in compositions in an amount ranging from approximately 0.001 to approximately 80% by weight, as from approximately 0.01 to approximately 70% by weight, and including from approximately 0.05 to approximately 60% by weight .
[0069] [0069] Distribution vehicles of interest include, but are not limited to, compositions that are suitable for distribution via one or more oral, topical, injection, implant, ocular, aural, rectal, vagina, etc. in certain embodiments, the vehicle is formulated for application to a topical region or surface of an individual, such as a keratinized skin surface. The present compositions can be formulated as stable solutions or suspensions of the components, for example, in an aqueous solvent. Where desired, the components can be combined with one or more carrier materials to form a solution, suspension, gel, lotion, cream, ointment, aerosol spray or the like, as desired. Of interest, in certain modalities are aqueous distribution vehicles, that is, aqueous vehicles that include a certain amount of water. Examples of aqueous vehicles include hydrogel, spray, serum, etc. vehicles.
[0070] The topical composition may also contain other physiologically acceptable excipients or other secondary additives, particularly associated with organoleptic properties, such as fragrances, dyes, buffers, cooling agents (eg menthol), stabilizers or the like. Secondary excipients and additives will be present in conventional amounts, for example, ranging from approximately 0.001% to 5%, such as 0.001 to 2% by weight, and in some cases not exceeding a total of 10% by weight.
[0071] [0071] As indicated above of interest in certain modalities are semi-solid distribution compositions such as gels, creams and ointments. Such compositions can be mixtures of (in addition to the active agent) water, water-soluble polymers, preservatives, alcohols, polyvalent alcohols, emulsifying agents, wax, solvents, thickeners, plasticizers, pH regulators, water retention agents and the like. In addition, such compositions may also contain other physiologically acceptable excipients or other minor additives, such as fragrances, dyes, buffers, stabilizers or the like.
[0072] [0072] Also of interest are solid formulations, such as topical adhesive formulations. Topical adhesive formulations can vary significantly. Topical adhesive formulations can include an active agent layer, a support and a release liner. The active agent layer can include physiologically acceptable excipients or other secondary additives, such as fragrances, dyes, buffers, stabilizers or the like. The support can be made of a flexible material that is capable of adapting to the movement of the human body and includes, for example, plastic films, various non-woven fabrics, woven fabrics, spandex and the like. Various inert coatings can be employed, which include the various materials that can be used in plasters described below. Alternatively, non-woven or woven covers can be employed, particularly elastomeric covers, which allow for the transport of steam and heat. These covers allow cooling of the pain site, which provides greater comfort, while protecting the gel against mechanical removal. The release liner can be made of any convenient material, where representative release films include polyesters, such as PET or PP and the like.
[0073] [0073] The modalities of the compositions show greater stability with respect to UV light, including both UVA and UVB light, in comparison with other formulations of the active agent, for example, formulations in which a calcium phosphate particle is not present in the composition. As such, the compositions of the invention exhibit reduced sensitivity to UV light compared to an appropriate control, as determined using any convenient UV light sensitivity assay.
[0074] [0074] The modalities of the compositions show greater pH stability compared to other formulations of the active agent, for example, formulations in which a particle of calcium phosphate is not present in the composition. As such, the compositions of the invention exhibit reduced sensitivity to pH compared to an appropriate control, as determined using any convenient pH sensitivity assay. In certain embodiments, the compositions are stable in pH ranging from 3 to 11, for example 4 to 11, such as 4.25 to 10.75.
[0075] [0075] The modalities of the compositions present greater stability with respect to oxidation, in comparison with other formulations of the active agent, for example, formulations in which a particle of calcium phosphate is not present in the composition. As such, compositions of the invention exhibit reduced sensitivity to oxidation compared to an appropriate control, as determined using any convenient oxidation sensitivity assay.
[0076] [0076] The modalities of the compositions present greater stability with respect to thermal degradation, in comparison with other formulations of the active agent, for example, formulations in which a particle of calcium phosphate is not present in the composition. As such, compositions of the invention exhibit reduced sensitivity to thermal degradation compared to an appropriate control, as determined using any convenient thermal degradation sensitivity assay.
[0077] [0077] The modalities of the compositions show greater stability with respect to mechanical degradation, in comparison with other formulations of the active agent, for example, formulations in which a particle of calcium phosphate is not present in the composition. As such, compositions of the invention exhibit reduced sensitivity to mechanical degradation compared to an appropriate control, as determined using any convenient mechanical degradation sensitivity assay. MANUFACTURING METHODS
[0078] [0078] Aspects of the invention further include methods of making uniform, rigid, spherical nanoporous particles loaded with active agent and topical compositions that include them. With respect to methods of making uniform, rigid, spherical nanoporous calcium phosphate particles loaded with active agent, aspects of these methods include combining a quantity of uniform, rigid, spherical nanoporous calcium particles comprising a porous structure that defines a space internal; and an active agent. The particles and active agent are combined in the presence of a non-aqueous solvent under conditions sufficient for the active agent to enter the internal space of uniform, rigid, spherical nanoporous calcium phosphate particles to produce uniform, rigid, spherical nanoporous calcium phosphate particles loaded with active agent. This step results in the production of a liquid composition that includes an amount of uniform, rigid, spherical nanoporous particles loaded with active agent present in a non-aqueous solvent, which may include one or more co-solvents. After this combining step, methods include separating the non-aqueous solvent from uniform, rigid, spherical nanoporous calcium particles loaded with active agent to produce a dry product composition, that is, a powder that is composed of phosphate particles uniform, rigid, spherical nanoporous calcium agents loaded with active agent.
[0079] [0079] In some cases, the methods include pre-wetting an initial amount of uniform, rigid, spherical nanoporous calcium phosphate particles with a non-aqueous solvent to remove gas present within the uniform, rigid, spherical nanoporous calcium phosphate particles . For example, a quantity of particles can be combined with a non-aqueous organic solvent under conditions sufficient to produce moist particles. The protocol used to combine the particles with the non-aqueous solvent may vary, where examples of protocols of interest include, immersion, with or without agitation, etc. solvents of interest include, but are not limited to: cosmetic or dermopharmaceutical solvents such as, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol, ethoxy diglycol, polyethylene glycol, methyl or ethyl diglylic ethers, polyols cyclic, ethoxylated or propoxylated glycols and solvent listed at USP 467 Residual Solvents - Class 3 residual solvents such as heptane acetic acid, acetone, isobutyl acetate, anisol, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3 -methyl-1-butanol, butyl acetate, methyl ethyl ketone, methyl tert-butyl ether, methyl isobutyl ketone, cumene, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethanol, 1-pentanol, ethyl acetate, 1 -propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate, formic acid and solvent listed at USP 467 - Class 2 residual solvents such as acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2- dichloroethene, 1,2 -Ethian dimethoxy , N, N-dimethyl acetamide, N, N-dimethyl formamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxy ethanol, methyl butyl ketone, methyl cyclohexane, methylene chloride, N-methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, teetralin, toluene, trichlorethylene and xylene. After the combination, excess solvent can be separated from the particles as desired to produce the moistened particles.
[0080] [0080] The particles (dry or pre-moistened as described above) can be combined with a solution of an active agent present in a non-aqueous (for example, organic) solvent to produce a liquid composition that includes particles and one (ones) active agent (s) in a non-aqueous, e.g. organic, solvent. The non-aqueous, for example, organic solvent of the active agent solution may vary. The solvents of interest include, but are not limited to: cosmetic or dermopharmaceutical solvents such as, but not limited to: ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol, ethoxy diglycol, polyethylene glycol, methyl ethers or diglylic ethyl , cyclic polyols, ethoxylated or propoxylated glycols and solvent listed at USP 467 Residual Solvents - Class 3 residual solvents such as heptane acetic acid, acetone, isobutyl acetate, anisol, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol , 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, methyl isobutyl ketone, cumene, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethanol, 1-pentanol, acetate ethyl, 1-propanol, ethyl ether, 2-propanol, ethyl format, propyl acetate, formic acid and solvent listed at USP 467 - Class 2 residual solvents such as acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene , 1,2- dimethoxy ethyl, N, N-dimethyl acetamide, N, N-dimethyl formamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxy ethanol, methyl butyl ketone, methyl cyclohexane, methylene chloride , N-methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, teetralin, toluene, trichlorethylene and xylene. The solvent can be the same or different from the solvent used to moisten the particles. If different, in certain embodiments, the solvent in the active agent solution is at least miscible with the solvent used to moisten the particles. The active agent solution can include one or more cosolvents, where co-solvents of interest include, but are not limited to: polyethylene glycols, for example, PEG 400, PEG 200, etc., glycerides, etc.
[0081] [0081] The active agent solution and particles (dry or pre-moistened, as desired) can be combined using any convenient protocol, for example, with stirring, to produce a liquid composition that includes both the particles and the active agent. In certain cases, the uniform, rigid, spherical, nanoporous calcium phosphate particles and active agent are combined in the presence of the non-aqueous solvent under controlled pressure. When combined under controlled pressure, the pressures of interest can vary and in some cases range from 0.001 torr to 1 torr, such as 0.01 torr to 0.1 torr and including 0.05 torr to 0.5 torr.
[0082] [0082] Next, the non-aqueous solvent is separated from the particles of the liquid composition to produce the desired product from uniform, rigid, spherical, nanoporous calcium phosphate particles comprising a porous structure that defines an internal space and an amount of active agent present in the internal space. The separation can be carried out using any convenient protocol, where in certain modalities the separation includes drying under negative pressure, for example, in a vacuum, through a vacuum dissector, vacuum dryer, spray dryer, rotary evaporator, etc. where desired, elevated temperatures can be employed in this separation step.
[0083] [0083] The manufacturing protocol above results in the production of a dry powder composition that includes uniform, rigid, spherical, nanoporous particles loaded with active agent, that is, uniform, rigid, spherical calcium phosphate particles, nanoporous which include a porous structure that defines an internal space and an amount of active agent present in the internal space.
[0084] [0084] To produce topical compositions as described above, an amount of the resulting uniform, rigid, spherical, nanoporous active agent loaded calcium phosphate particles can be combined with a delivery vehicle of interest as desired. Conventional manufacturing protocols can be employed. UTILITY
[0085] [0085] Topical compositions of the invention find use in methods of delivering active agents to an individual's topical site, where the topical site may be a site on the skin surface or a site of mucosa. By delivering active agents to an individual's topical site, formulations of the invention can deliver active agent-loaded particles at least to an epidermal site that is below the surface of an individual's skin. As such, the embodiments of the invention include methods of delivering particles loaded with active agent into an individual's stratum corneum, where the methods can result in distribution of the complexes in an individual's deep stratum corneum and / or dermis. By "deep stratum corneum" is meant a region that is 2 or more layers of cells below the skin surface, such as 5 or more layers of cells below the skin surface, including 10 or more layers of cells below the skin surface . In some cases, the complexes are distributed to the stratum corneum region that is 2 µm or more like 5 µm or more and including 15 µm or more below the skin surface.
[0086] [0086] After reaching their target dermal site, the active agent charged particles begin to release their active agent "payload" and divide (for example, via dissolution caused by the skin's pH gradient), as the uniform particles rigid, spherical, nanoporous dissolve under acidic conditions, for example, conditions of pH 6 or less, such as 5.5 or less, including 5.0 or less, such as the physiological acidic conditions of the stratum corneum. The time required to dissolve particles in the stratum corneum can vary, and in certain embodiments it ranges from 1 minute to 24 hours, such as 10 minutes to 12 hours and including 30 minutes to 3 hours, during which time the active agent is released from the particles linked by active agent. The proportion of active agent that is released from particles bound by active agent can vary and in certain cases is 1% or more, such as 10% or more, including 50% or more (weight / weight).
[0087] [0087] The methods of the invention may therefore result in delivery of an active agent at least in an individual's stratum corneum. In some modalities, the active agent remains in the stratum corneum to exercise its desired activity. In still other modalities, the active agent can perform its desired activity in one or more other target locations on the body. Additional target sites of the body of interest include additional epidermal regions such as, but not limited to, stratum lucidum, stratum granulosum, stratum spinusom, stratum basale and dermis. In certain embodiments, the active agent is distributed to a region of the dermis. In certain embodiments, the active agent is distributed to a region below the dermis, for example, in subcutaneous tissues. Depending on the location that is contacted by the active agent after delivery with the inventive dermal delivery formulations, in some cases the active agent can be systemically delivered to the individual. When the active agent is systemically distributed to the individual, therapeutic plasma levels of the active agent are obtained. Therapeutic levels of active agent plasma may vary depending on the specific active agent and condition being treated. In certain embodiments, active therapeutic levels that are obtained vary from 1 pg to 20 µg, such as 1 ng to 1 µg and including 10 ng to 100 ng.
[0088] [0088] In practicing the methods of the invention, a topical composition is applied to a topical region of an individual and maintained in the topical region for a period of time sufficient to result in the desired distribution of active agent to the individual, as described above. The topical region is, in certain modalities, a region of keratinized skin. The region of keratinized skin, including hair follicles, sweat glands and sebaceous glands, can be present in a variety of locations, for example, limbs, arms, legs; back, for example, chest, back, stomach; head, for example, neck, face; etc. in certain embodiments, the region will be a region of the head, such as a facial region, for example, forehead, occipital region, around the mouth, etc. the topical region to which the composition is applied may vary with respect to the area, varying in certain modalities from 1 mm2 to 300 cm2 or more, such as from 1 to 50 cm2, and including from 3 to 10 cm2.
[0089] [0089] After application, the topical is kept at the application site for a period of time sufficient for a desired therapeutic result to occur, for example, improvement of a symptom of interest, reducing dryness. The time period can vary and in certain modalities it varies from 1 min. to 24 hours or more, such as 30 min. 12 hours and including 1 hour to 12 hours or more.
[0090] [0090] When practicing the methods of the invention, an individual can be administered a single dose or two or more doses over a given period of time. For example, during a given treatment period of one month, 1 or more doses, such as 2 or more doses, 3 or more doses, 4 or more doses, 5 or more doses, etc., can be administered to the individual, where the doses can be administered weekly or daily or even multiple times a day.
[0091] [0091] In some cases, the methods of the invention result in increased penetration of the active agent compared to an appropriate control, such as a composition composed of the same active agent and delivery vehicle, with the exception that the active agent is not loaded into the uniform, rigid, spherical, nanoporous calcium phosphate particles. Penetration is intensified in such modalities compared to a control by a factor of 2 or more times, such as 5 or more times including 10 or more times.
[0092] [0092] The present methods and compositions can be used in a variety of different types of animals, where animals are typically "mammals" or "class of mammals", where these terms are used widely to describe organisms that are comprised in the class mammals, including the carnivorous orders (eg, dogs and cats), rodents (eg, mice, guinea pigs, and rats), lagomorphs (eg, rabbits) and primates (eg, humans, chimpanzees and monkeys) ). In certain embodiments, individuals or patients are human beings.
[0093] [0093] The present topical formulations find use in applications where it is desired to deliver an active agent to an individual. In certain embodiments, the present topical formulations are employed in the treatment of a disease condition, for example, a disease condition responsive to the administration of the active agent. By "treatment" is meant that at least an improvement in the symptoms associated with the condition that afflicts the individual is obtained, where the improvement is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, for example, symptom associated with the condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated with it, are totally inhibited, for example, prevented from occurring, or stopped, for example, ended, in such a way that the individual no longer suffers from the condition. , or at least the symptoms that characterize the condition. In certain embodiments, an individual can be diagnosed in relation to the presence of the disease condition, such that topical formulations are provided to an individual known to be suffering from the disease condition.
[0094] [0094] The following examples are offered by way of illustration and not by way of limitation. EXPERIMENTAL I. Manufacture and characterization of uniform, rigid, spherical, nanoporous calcium phosphate particles A. Manufacturing
[0095] [0095] Calcium phosphate nano crystal paste was prepared by adding drops of aqueous phosphate complex solution to aqueous calcium complex solution or suspension under controlled conditions of temperature, pH, stirring speed, reagent concentration, rate of addition and aging time. The paste was lyophilized to form spherical porous powder using a pressure nozzle type spray dryer with a liquid-air fluid nozzle. The dry powder was sintered at a temperature ranging from 300 to 900 ° C for a period of time ranging from 1 to 24 hours with a gas oven or an electric oven. B. Characterization
[0096] [0096] Figures 1A and 1B show the porous structure of the resulting uniform, rigid, spherical, 2 micron nanoporous calcium phosphate particles (produced as described above) using SEM (A) 10,000 X, (B) 50,000 X. as Figures 2A and 2B show the external and internal structure of uniform, rigid, spherical, 2 micron nanoporous calcium phosphate particles (produced as described above), using both SEM (A) and TEM (B) (15000 X). the large internal and external surface areas (250-50 m2 / g) are substantial, allowing high capacity bonding with active agents. Figure 3 shows the particle size distribution of the particles, as determined by the Coulter Multisizer 3 particle counter and confirmed by scanning electron microscopy. The average particle size was 2 µm. II. Loading of active agent of uniform, rigid, spherical, nanoporous calcium phosphate particles A. Salicylic acid
[0097] [0097] Salicylic acid, a small hydrophobic molecule useful for anti-acne agent, is insoluble in water and shows low hydroxyapatite-binding capacity (having a hydroxyapatite-binding capacity of approximately 1mg or less). Salicylic acid is soluble in ethanol and PEG (polyethylene glycol) up to 30%. Hydroxyapatite is soluble and degrades in acidic solution.
[0098] [0098] As illustrated below, when the ratio of uniform, rigid, spherical, nanoporous calcium phosphate particles HIDROXISOMES® (Laboratory Skin Care, Olympic Valley CA) to solid salicylic acid is small enough to prevent dissolution of phosphate particles from calcium, a dry powder composite of highly charged calcium phosphate particle and salicylic acid can be obtained by removing the solvent after a soak and penetration process under vacuum pressure, as described in more detail below.
[0099] 1. Preparar a suspensão de partículas por embeber partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas de HIDROXISOMES® com 89g de etanol por 30 minutos com ou sem vácuo. 2. Preparar solução saturada com ácido salicílico por misturar ácido salicílico, PEG-8 e 81 g de etanol no béquer até que a mistura se torne homogênea. 3. Misturar suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® e solução de ácido salicílico por 30 minutos. 4. Remover etanol utilizando o evaporador giratório a vácuo a 600 mmHg por 2 h 30 minutos. 5. O complexo de pó seco foi obtido. [0099] The following raw materials were used to make the complex of uniform, rigid, spherical, nanoporous calcium phosphate particles HIDROXISOMES® loaded with 25% salicylic acid.
[0100] 1. Preparar solução saturada de ácido salicílico por misturar ácido salicílico e 10 g de etanol no béquer até se tornar homogênea. 2. Adicionar a suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® em solução de ácido salicílico. 3. Remover etanol utilizando o evaporador giratório a vácuo a 600 mm Hg por 1 h 30 minutos. a pressão de partida era 173 mbar e a pressão final era 30 mbar. 4. O complexo de pó seco foi obtido. [00100] The following raw materials were used to make complex suspension of uniform, rigid, spherical, nanoporous calcium phosphate particles HIDROXISOMES® loaded with 20% salicylic acid.
[0101] 1. Preparar suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® por embeber as partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® com 18g de Etanol por 30 minutos sob condições de vácuo com uma bomba de vácuo de diafragma. 2. Preparar solução de Resveratrol misturando Resveratrol e 20 g de etanol no béquer até se tornar homogênea. 3. Misturar a suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® e solução de Reseveratrol por 30 minutos. 4. Remover etanol utilizando o evaporador giratório (Buchi Rotavapor R-215) sob vácuo. 85 mbar a 40°C por 8 h. 5. O complexo de Resveratrol de pó seco foi obtido. [00101] Uniform, rigid, spherical, nanoporous HIDROXISOMES® calcium phosphate particles loaded with Resveratrol were prepared as described above in example 1. The following raw materials were used to make the complex of uniform, rigid, spherical calcium phosphate particles , HIDROXISOMES® nanoporous loaded with 20% Resveratrol.
[0102] [00102] The maximum amount of the Resveratrol complex produced above that can be dissolved in an aqueous formulation has been compared with free Resveratrol. It has been found that the seven times higher amount of Resveratrol can be uniformly dispersed and formulated in the aqueous formulation compared to free Resveratrol. D. Retinyl palmitate
[0103] 1. Preparar suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® por embeber as partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES com 80 g de etanol por 30 minutos sob condição a vácuo com uma bomba a vácuo de diafragma. 2. Preparar solução de palmitato de retinila por misturar palmitato de retinila e 200 g de etanol no béquer até se tornar homogênea. 3. Misturar a suspensão de partículas de fosfato de cálcio uniformes, rígidas, esféricas, nanoporosas HIDROXISOMES® e solução de palmitato de retinila por 30 minutos. 4. Remover etanol utilizando o evaporador giratório (Buchi Rotavapor R-215) sob vácuo 75 mbar a 40°C por 8 h. 5. O complexo de Palmitato de retinila de pó seco foi obtido [00103] Uniform, rigid, spherical, nanoporous HDYROXYSOMES® calcium phosphate particles loaded with retinyl palmitate were prepared as described above in example 1. The following raw materials were used to make complex, uniform, rigid, calcium phosphate particles spherical, nanoporous HIDROXISOMES® loaded with 16.7% retinyl palmitate.
[0104] [00104] The resulting uniform, rigid, spherical, nanoporous calcium retinyl HYDROXISOMES (R) particles of retinyl palmitate have been successfully formulated as a complex in an aqueous formulation. E. Example of the other water-insoluble assets
[0105] [00105] Lipophilic assets such as Polyphenol, carotenoid, flavonoid, anthocyanin, vitamin A, vitamin E, astaxanthin, argyrelin, (hydroxyproline dipalmitoíla), Ubiquinol, lipophilic drugs such as Adapalene, Duclofenac, Lidocina can be loaded into uniform phosphorus particles, calcium phosphate particles rigid, spherical, nanoporous HIDROXISOMES® according to the methods described above. I. Characterization of uniform, rigid, spherical, nanoporous calcium phosphate particles loaded with active agent A. Particle size distribution
[0106] [00106] The particle size distribution of the Hidroxisomes® Complex loaded with Resveratrol as produced above was evaluated using a Horiba LA-300 laser particle size analyzer. Both Hidroxisomes® and the Resveratrol complex showed a weight-based average particle size of approximately 6 µm with uniform particle size distribution, as shown in Figure 4. B. Mechanical stability
[0107] [00107] The mechanical stability of Hidroxisomes® and the Hidroxisomes® Resveratrol complex was measured using the Shimadzu MCT microcompression tester. There was no change in the breakpoint strength between Hidroxisomes® and the Hidroxisomes® Resveratrol complex. The mechanical stability of the Hidroxisomes® Resveratrol complex during the homogenization process and the mixing process were evaluated using a Horiba LA-300 laser particle analyzer. There was no change in particle size after processing. C. Microscopy
[0108] [00108] Microscopic observation showed the uniform spherical structure of the Hidroxisomes® Resveratrol complex as shown in figure 5. D. Confirmation of loading
[0109] [00109] Reverse phase HPLC analysis of the extraction of methanol from the Hidroxisomes® Resveratrol complex showed the effective loaded amount of Resveratrol in the complex as follows.
[0110] [00110] Although the above invention has been described in some detail as an illustration and example for the sake of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of the present invention that certain changes and modifications may be made in the without departing from the spirit or scope of the attached claims.
[0111] [00111] Therefore, the foregoing merely illustrates the principles of the invention. It will be recognized that those skilled in the art will be able to devise various arrangements that, although not explicitly described or shown here, incorporate the principles of the invention and are included in its spirit and scope. In addition, all examples and conditional language mentioned here are intended primarily to assist the reader in understanding the principles of the invention and the concepts contributed by the inventors to promote the technique, and should be interpreted as being without limitation to such examples and conditions specifically mentioned. . In addition, all statements here mentioning principles, aspects and modalities of the invention as well as specific examples thereof, are intended to cover both structural and functional equivalents thereof. In addition, it is intended that such equivalents include both equivalents currently known as equivalents developed in the future, that is, any developed elements that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described here. Instead, the scope and spirit of the present invention are incorporated by the appended claims. Appendix I

权利要求:
Claims (11)
[0001]
Composition, characterized by the fact that it comprises: particles of micro-size of uniform, rigid, spherical, nanoporous calcium phosphate, which comprises a porous structure that defines an internal space and an amount of active agent present in the internal space, the particles have an average particle size of 2 microns; wherein the amount of active agent present in the internal space is 10% by weight or more of the calcium phosphate particle; wherein the uniform, rigid, spherical, nanoporous calcium phosphate particle comprises pores ranging in size from 2 nm to 100 nm.
[0002]
Composition according to claim 1, characterized by the fact that the uniform, rigid, spherical, nanoporous calcium phosphate particle is ceramic.
[0003]
Composition according to claim 1 or 2, characterized by the fact that the uniform, rigid, spherical, nanoporous calcium phosphate particle is coated.
[0004]
Composition according to any one of claims 1 to 3, characterized in that the composition is a liquid and comprises the uniform, rigid, spherical, nanoporous calcium phosphate particles present in a non-aqueous solvent.
[0005]
Composition according to any one of claims 1 to 4, characterized in that the composition is a dry powder.
[0006]
Topical composition, characterized by the fact that it comprises the composition, as defined in any one of claims 1 to 5; and a topical delivery vehicle.
[0007]
Topical composition according to claim 6, characterized in that the topical delivery vehicle is an aqueous topical delivery vehicle.
[0008]
Method, characterized by the fact that it comprises: (a) combine: uniform, rigid, spherical, nanoporous calcium phosphate particles comprising a porous structure that defines an internal space; and an active agent; in the presence of a non-aqueous solvent and under pressure for the active agent to enter the internal space of the uniform, rigid, spherical, nanoporous calcium phosphate particles to produce uniform, rigid, spherical, nanoporous calcium phosphate particles loaded with active agent; and (b) separating the non-aqueous solvent from the uniform, rigid, spherical, nanoporous calcium phosphate particles loaded with active agent; the non-aqueous solvent being separated from the uniform, rigid, spherical nanoporous calcium phosphate particles and loaded with active agent by evaporation of the non-aqueous solvent; where evaporation occurs under negative pressure.
[0009]
Method according to claim 8, characterized in that it comprises pre-wetting the uniform, rigid, spherical, nanoporous calcium phosphate particles with a non-aqueous solvent to remove gas present within the uniform, rigid calcium phosphate particles , spherical, nanoporous.
[0010]
Method according to claim 8, characterized in that the non-aqueous solvent is an organic solvent.
[0011]
Method according to claim 10, characterized in that the organic solvent comprises an organic cosolvent.

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同族专利:

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-17| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-01-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-03-26| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-10-01| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-01-21| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-05-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-01| B09X| Republication of the decision to grant [chapter 9.1.3 patent gazette]|

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2021-04-06| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 06/04/2021, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-05-25| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/09/2009 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

优先权:

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申请号 | 申请日 | 专利标题

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US9950008P| true| 2008-09-23|2008-09-23|

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PCT/US2009/058108|WO2010039560A2|2008-09-23|2009-09-23|Active agent loaded uniform, rigid, spherical, nanoporous calcium phosphate particles and methods of making and using the same|

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