WO2012059936A1 - Pharmaceutical compositions for colloidal drug delivery - Google Patents

Pharmaceutical compositions for colloidal drug delivery Download PDF

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Publication number
WO2012059936A1
WO2012059936A1 PCT/IN2011/000730 IN2011000730W WO2012059936A1 WO 2012059936 A1 WO2012059936 A1 WO 2012059936A1 IN 2011000730 W IN2011000730 W IN 2011000730W WO 2012059936 A1 WO2012059936 A1 WO 2012059936A1
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pharmaceutical compositions
compositions according
aqueous
non
aqueous phase
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PCT/IN2011/000730
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French (fr)
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WO2012059936A4 (en
Inventor
Padma Venkitachalam Devarajan
Sonali Vithal Kapse
Anil Brij Bhushan Jindal
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Padma Venkitachalam Devarajan
Sonali Vithal Kapse
Anil Brij Bhushan Jindal
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Priority to IN3055MU2010 priority
Application filed by Padma Venkitachalam Devarajan, Sonali Vithal Kapse, Anil Brij Bhushan Jindal filed Critical Padma Venkitachalam Devarajan
Publication of WO2012059936A1 publication Critical patent/WO2012059936A1/en
Publication of WO2012059936A4 publication Critical patent/WO2012059936A4/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5146Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

The present invention relates to preparation of drug loaded heterogeneous nanosystems resulting from mixing of two monophasic phases, the non-aqueous phase comprising of active agent/s, polymers, lipids, surfactants, solubilizer/s and other excipients and the aqueous phase comprising of buffers, isotonic solutions, sweetners, flavors and other excipients.The novel technique enables formation of stable colloidal particles with high drug loading and predictable size at the time of use. The invention represents a major step in circumventing the technological challenges in the design of colloidal particles which can remain suspended for at least 4h maintaining an effective average particle size of <1μm. The unique delivery system makes part of the active agent/s readily bioavailable and part of the agent is present within the polymeric matrix. The invention is applicable to agent/s that contains electrical group, as the particles are formed due to electrostatic interaction. The novel technique avoids use of organic solvent and can reduce energy requirements compared to the conventional preparation methods. The invention is aimed at the overall improvement of therapeutic efficacy, enhance solubility, enhance oral bioavailability and rapid dissolution for in vivo delivery of the BCS class agent/s. The heterogeneous nanosystems /compositions produced according to the invention can be useful in drug delivery, imaging and diagnosis and can be administered by oral and parenteral route.

Description

FIELD OF INVENTION

The present invention discloses pharmaceutical compositions comprising two monophasic liquids which on mixing form drug loaded heterogeneous nanosystems of average size <1μιη. The heterogeneous nanosystems comprises of nanoparticles, micelles, nano-drug particles crystalline or amorphous. The said monophasic liquid compositions comprise of at least one active agent and pharmaceutically acceptable excipients. The particulate compositions produced according to the invention can be useful in drug delivery, imaging and diagnosis and can be administered by oral and parenteral routes.

SUMMARY OF THE INVENTION

The present invention discloses pharmaceutical compositions an aqueous liquid composition and a non aqueous liquid composition which on mixing form drug loaded heterogeneous nanosystems of average size <1μπι. The aqueous liquid composition comprises polymer/s biodegradable and non-biodegradable, surfactants include cationic, anionic and nonionic, surface modifying agents including hydrophilic polymers, carbohydrate, proteins and receptor specific ligands, pH modulators includes buffers, acid and bases, stabilizers include antioxidants, absorption enhancers, targeting ligands. The non-aqueous liquid composition comprises surfactant/s cationic, anionic and nonionic, polymer/s biodegradable and non-biodegradable, lipid s fatty acids and glycerol esters of fatty acids and at least one non-aqueous solvent. Active agent is dissolved in either aqueous composition or non-aqueous composition. The drug loaded heterogeneous nanosystems of said inventions are generated by mixing the aqueous and non-aqueous compositions in a predetermined ratio.

OBJECTIVE OF THE INVENTION

The objective of the invention is to provide pharmaceutical compositions comprising two monophasic liquids which on mixing form drug loaded heterogeneous nanosystems of average size <1μπι that have improved bioavailability.

The another objective of the invention is to provide pharmaceutical compositions comprising two monophasic Mquids which on mixing form drug loaded heterogeneous nanosystems of average size <1μιη that have SBfHOved efficacy.

ΊΡβ* the another objective of the invention is to provide pharmaceutical composition comprising two aaenophasic liquids comprising of active agent s and pharmaceutically acceptable excipients which on mixing form drug loaded heterogeneous nanosystems of size <1μπι that is simple to prepare and scale up.

Yet the another objective of the invention is to provide pharmaceutical composition comprising two monophasic liquids comprising of drug s and pharmaceutically acceptable excipients which on mixing form drug loaded heterogeneous nanosystems of size <1μπι that may be targeting to specific body site.

BACKGROUND AND PRIOR ART

Drug loaded heterogeneous nanosystems including polymeric micro/nanoparticles, solid lipid nanoparticles, polymer-lipid hybrid particles, micelles etc. have been extensively investigated as potential carriers for drug delivery in recent years for a wide range of applications particularly for chemotherapeutic agents in oral and parenteral delivery. For improved efficacy and enhanced effectiveness of such carriers for in vivo delivery in therapy the size, shape, surface morphology along with high drug loading are important, since the latter decreases the manufacturing cost thereby increasing patient compliance and reducing the administration dose with reduced undesirable side effects.

Conventional methods for the preparation of nanoparticles include nanoprecipitation, emulsion solvent evaporation and emulsion solvent diffusion. Nanoparticles generated by these methods are isolated by centrifugation, filtered and dried preferentially by freeze drying to obtain dried particulate carriers which are reconstituted with aqueous medium. Problems encountered by these methods are undesirable particle heterogeneity as the matrix material and the drug molecules tend to self-aggregate during nanoprecipitation. Also problems associated with maintaining the integrity of the liquid suspension for a prolonged time period, despite addition of surface active agents to stabilize the suspension little aggregation is often observed upon storage. Improvement in stability represents an important issue in the development of these drug carriers. Freeze-drying4 is one of the most suitable methods to stabilize and facilitate the handling of colloidal systems. Increase in particle size after freeze drying is another significant problem. Inherent technological problems associated with production scale-up and commercialization of such carriers/systems by conventional methods limits their production in large quantities.

In an attempt to bypass the scale up challenges in the design of drug loaded particulate carriers, a simple yet unique approach for the preparation of heterogeneous nanosystems by in-situ nanoprecipitation method has been developed. The developed methodology provides drug loaded heterogeneous nanosystems with good batch-to-batch reproducibility. The invention provides a simple, one-step strategy for preparation of heterogeneous nanosystems with >50% entrapment efficiency. Among the methods reported for preparation of particulate carriers, nanoprecipitation is a single step, instantaneous method based on interfacial turbulence without application of external energy for reproducible formation of nanoparticles below 1 micron with low polydispersity index and high yields of hydrophobic drugs. The present invention discloses pharmaceutical compositions an aqueous liquid composition and a non aqueous liquid composition which on mixing forms drug loaded heterogeneous nanosystems of average size <1μπι. The present invention technique is a promising method for the preparation of heterogeneous nanosystems which are cost effective, ease to formulate, prepared under mild conditions without using harmful solvents and involves green technology.

Patents WO/2010/046681 Al, WO/2007/020416A1, EP2048116A1, WO/2008/032327A2, 5766635, EP0806894B1, EP1752142A2, WO/2006/045713A1, 6677386, EP2085080A1, WO/2009/095448 Al, 5118528, 5133908, WO/2008/030473A2, WO/2001/002087A1, WO/2010/005721A2, 5766635, EP2048116A1 discloses preparation of nanoparticles using organic solvents. Patents EP1448604B1, EP1774971A1, 7740883m, 5874111, 7820583, WO/2007/042572A1, WO/2009/048958A2 disclose preparation of nanoparticles by ionic gelation and nanoprecipitation. The patents 7147841, 7404969, 7691405, 5904932, 7611733, 5989583, 6685960, 7704525, 5885486, 5820879, 6770299, WO/1994/020072A1 discloses preparation of nanoparticles by homogenization, nanoprecipitation, solvent evaporation and melt method. Nevertheless all the above inventions necessitate isolation and freeze drying of nanosuspension to form dry yewder for reconstitution. Patent applications US20050196343, US20060013882, US20060073210, H82O06 O78624, US20080248126, US20080248126, US20060193787, US20070009441, US20070190160, 1»¾θ®β0241257, US20080241257, US20080253961, US20040247683, US20060153923, US20080102127, ®§£©β9ΘΟ61010, US20100233275, US20060083781, US20080193511 and US20070154907 also discloses Ae preparation of nanoparticles by standard methods followed by isolation and freeze drying.

A number of issues in the above methods are increase in particle size during isolation and/or freeze drying. Complicated method of isolation and the difficulty in scale up and reproducible production of such nanocarriers on large scale. All the above methods necessitate the application of external energy to obtain nanoparticles.

Dabur Pharma Ltd. (India) has developed a novel nanopolymer based tumor targeted delivery system NANOXEL Injection, wherein hydrophobic paclitaxel is delivered in nanomicelles (80-lOOnm) using polymeric carrier. The polymer is an amphophilic molecule (pH sensitive co-polymer of N-isopropyl acrylamide (NIPAM) and vinylpyrrolidone (VP) monomers) which forms nano-size micelles when exposed to an aqueous environment where the micelle core serves as reservoir for paclitaxel. NANOXEL (Paclitaxel nanoparticle injection) comprise of two components, one vial containing paclitaxel solution for nanoparticle in dehydrated alcohol while the other vial contains concentrate of excipients comprising of polymer, other excipients in water for injection. Reconstitution is done by adding concentrate of excipients to 10%w/v dextrose injection bottle followed by rapid injection of paclitaxel solution into the same bottle. Nevertheless the resultant nanosystem is a homogenous system comprising micelles.

Abraxis Bioscience, LLC marketed ABRAXANE® is a paclitaxel protein (albumin) bound particles for injectable suspension with a mean particle size of approximately 130nm. ABRAXANE is a lyophilized powder for reconstitution with 0.9% sodium chloride prior to intravenous infusion wherein paclitaxel exists in the particles in a non-crystalline, amorphous state. ABRAXANE is preservative and solvent free.

The present invention on the other hand, discloses pharmaceutical liquid compositions comprising of simple solution of active agent/s and excipients in aqueous and non-aqueous compositions which on simple mixing in different proportions without the application of external energy would generate heterogeneous nanosystems of average size <1μπι and entrapment efficiency >50% which are ready for administration. The heterogeneous nanosystems comprises of nanoparticles, micelles, nano-drug particles crystalline or amorphous.

DETAILED DESCRIPTION AQUEOUS PHASE

The aqueous liquid composition comprises polymer/s include biodegradable and non-biodegradable, surfactants include cationic, anionic and nonionic, surface modifying agents including hydrophilic polymers, carbohydrate, proteins and receptor specific ligands, pH modulators includes buffers, acid and bases, stabilizers include antioxidants, absorption enhancers, targeting ligands. The aqueous phase may be selected from water, water comprising of one or more buffering agents, sodium salts such as sodium chloride, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium salts such as potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate sugars and sugar alcohols such as mannitol, sorbitol, dextrose. Optionally the aqueous phase may be adjusted to isotonic or hypertonic.

SURFACTANTS

The surfactant suitable for use in the methods and compositions of the invention include nonionic, cationic,' anionic and amphoteric surfactants. Nonionic surfactant may be selected from fatty alcohols, that is, alcohols having the structural formula CH.sub.3(CH.sub.2).sub.nC(H)OH (e.g, where n is at least 6), such as lauryl, cetyl and stearyl alcohols; fatty sugars, such as octyl glucoside and digitonin; Lubrols, such as Lubrol.RTM. PX; Tritons, such as TRITON.RTM. X-100; sorbitan fatty acid esters (such as those sold under the tradename SPAN.RTM), polyoxyethylene sorbitan fatty acid esters (such as those sold under the tradename TWEEN.RTM.), polyoxyethylene fatty acid esters (such as those sold under the tradename MYRJ.RTM.), polyoxyethylene steroidal esters, polyoxypropylene sorbitan fatty acid esters, polyoxypropylene fatty acid esters, polyoxypropylene steroidal esters, polyoxyethylene ethers (such as those sold under the tradename BRIJ.RTM.), polyglycol ethers (such as those sold under the tradename TERGITOL.RTM.), and the like. Anionic surfactants may also be selected from long-chain alkyl sulfonates, carboxylates, and sulfates, as well as alkyl aryl sulfonates, and the like. Preferred anionic surfactants are sodium dodecyl sulfate, dialkyl sodium sulfosuccinate (e.g., sodium bis-(2-ethylhexyl)-sulfosuccinate), sodium 7-ethyl-2-methyl-4-dodecyl sulfate and sodium dodecylbenzene sulfonate, sodium lauryl sulfate. Cationic surfactants may also be selected from long-chain amine salts or quaternary ammonium salts, e.g., decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tefradecyltrimethylammonium bromide, tefradecyltrimethylammonium chloride, Cetyl Trimethyl Ammonium Bromide and the like. Amphoteric surfactants may be selected from carboxylate or phosphate group as the anion and an amino or quaternary ammonium moiety as the cation. These include, for example, various polypeptides, proteins, alkyl betaines, and natural phospholipids such as lysolecithins and lysocephalins. Ionic surfactants include, without limitation, anionic surfactants, such as fatty acids and salts of fatty acids (e.g., sodium lauryl sulfate); sterol acids and salts thereof (e.g., cholate and deoxycholate); cationic surfactants, such as alkyl tri-methyl and ethyl ammonium bromides (e.g., cetyl triethyl ammonium bromide (CTAB) and C.sub.l6TAB); amphoteric surfactants, such as lysolipids (e.g., lysophosphatidylcholine or phosphatidylethanolamine), and CHAPS; and Zwittergents, such as ZwittergentRTM. 3-14. PEGylated lipids suitable for use in the methods and compositions of the invention include, for example, PEG-DSPE (polyethyleneglycol conjugated to distearoylphosphatidylemanolamine), mPEG-DS (methylether-polyethyleneglycol conjugated to distearoyl), and PEG-ceramides. The lipids and phospholipids can be serve as surfactants. Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monopalmitate(Tween 40), polyoxyethylene sorbitan monolaurate (Tween 20), vitamin E-TPGS (D-.alpha.-tocopheryl PEG 1000 succinate), PEG-40 hydrogenated castor oil (cremophor RH40), Cremophor EL, phospholipids, PEGylated phospholipids, PEGylated lipids, polyoxyethylene- polyoxypropylene copolymers, ethoxylated ethers, sphingolipids, glycolipids, lysophospholipids, fatty acids, bile salts, ethoxylated glycerides, ethoxylated fatty alcohols, cetyltrimethyl ammonium bromide and mixtures thereof.

SOLUBILIZERS

The solubilizers may be selected from a partial ether or ester of a polyhydroxyl alcohol and a (C.sub.6-22) fatty alcohol or acid, ethyl diglycol, (Methylene glycol monoethyl ether (Transcutol), proylenene glycol, glycerol, 2-pyrrolidone derivatives thereof, oleic esters of polyglycerol, "plurol oleique", when it is not already used as a surfactant, triacetin, propylene glycol, polyethylene glycol and combinations thereof; the polyethylene glycol is selected from the group consisting PEG 300, PEG 400 PEG 600 and combinations thereof; and the alcohol is selected from a group consisting of ethanol, isopropanol and combinations thereof. Propylene carbonate ,ethyl lactate, N-alkylamines, such as primary, secondary or tertiary N-alkylamines, for example having in each case 5 to 22 carbon atoms, unsubstituted or substituted cycloalkylamines having preferably 5 to 12 C- Atoms, oxalkylated products of the N-alkylamines, fatty amines (for example C.sub.8 - C.sub.22 -fatty amines) with ethylene oxide and/or propylene oxide, in particular fatty amine ethoxylates having 8 to 18 carbon atoms in the fatty alkyl moiety and 1 to 6 ethyleneoxy units (EO), alkylaminepolypropyleneamines , coconut alkylpropylenediamines, -triamines or -polyamines (for example .RTMDinoram C, .RTM.Trinoram C or .RTM.Polyram C; all from Elf Atochem),oxalkylated products of amides or N-substituted amides, ethanolamine or diethanolamine, for example Comperlan LS.RTM. (Henkel), or such as oxalkylated N-(aminoalkyl)-amides or N,N-bis-(aminoalkyl)-amides, alkylamidopropylamines. N', N' Dimethylacetamide, alcohols such as ethanol, methanol.

POLYMERS

Polymers include, without limitation, PLGA, polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, poly(alkylene glycol), poly(methylmethacrylate), poly(methylacrylic acid), poly(methylmethacrylate-co-methacrylic acid), polyallylamine and polyhydroxybutyric acid. poly(vinyl methyl ether-maleic anhydride, polyethylene sebacate. Non-limiting examples of particle-forming Wodegradable polymers are polyesters such as, without being limited thereto, polyhydroxybutyric acids,

Figure imgf000005_0001

polyureas, polystyrenes, or polyamines, polyglutamate, dextran, or combinations thereof. In yet another embodiment, the polymeric matrix comprises PLGA and a copolymer of PLGA and PEG. In another embodiment of the controUed-release system of the invention, the nanoparticle comprises a polymeric matrix, wherein the polymeric matrix comprises a lipid-terminated polyalkylene glycol and polyester. In one embodiment, the polymeric matrix comprises lipid-terminated PEG and PLGA. In yet another embodiment, said system is suitable for target-specific treatment of a disease or disorder and delivery of a therapeutic agent.

LIPIDS

Typically, lipids include fats and fat-derived materials that are relatively insoluble in water but soluble in organic solvents, are related either actually or potentially to fatty acid esters, fatty alcohols, sterols, waxes, or the like, and are utilizable by the animal organism. Lipids are one of the chief structural components of living cells. The solid lipid nanoparticles of the invention comprise fatty acid glyceryl esters such as glycerylmonostearate, polyglyceryl-6distearate, glycerylpalmitostearate. By "solid," it is meant that at least a portion of the solid lipid nanoparticles of the invention are solid at room temperature and atmospheric pressure. However, it is understood that the solid lipid nanoparticles of the invention can include portions of liquid lipid and/or entrapped solventln one aspect, the lipid can comprise a monoglyceride, diglyceride, or triglyceride of at least one C 4 to C 24 carboxylic acid. The carboxylic acid can be saturated or unsaturated and can be branched or unbranched. For example, the lipid can be a monoglyceride of a C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 carboxylic acid. The carboxylic acid can be saturated or unsaturated and branched or unbranched. The carboxylic acid can be covalently linked to any one of the three glycerol hydroxyl groups. In another example, the lipid can be a diglyceride of C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 carboxylic acids. The two carboxylic acids can be the same or different, and the carboxylic acids can be covalently linked to any two of the three glycerol hydroxyl groups. In a further example, the lipid can be a triglyceride ofC 4 , C 5 , C 6 , C 7 , C 8 , C 9 , CIO, CI , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 carboxylic acids. The three carboxylic acids can be the same, two of the carboxylic acid can be the same, or all three can be different. That is, in one aspect, the triglyceride can comprise two fatty acids having the same chain length or can comprise three fatty acids having the same chain length. In a further aspect, the lipid can comprise a triglyceride of at least one saturated, even-numbered, unbranched natural fatty acid with a chain length of C 8 to C 18 . For example, the lipid can be a triglyceride of C 8, C 10, C 12, C 14, C 16, or C 18 carboxylic acids. The three carboxylic acids can be the same, two of the carboxylic acid can be the same, or all three can be different. In a further aspect, the lipid can comprise a blend of triglycerides of saturated even-numbered, unbranched natural fatty acids with a chain length of C 8 to C 18. For example* the lipid can be a blend of triglycerides, each triglyceride ofC 8 , C 10 , C 12 , C 14 , C 16 , or C 18 carboxylic acids. For each triglyceride in the blend, the three carboxylic acids can be the same, two of the carboxylic acid can be the same, or all three can be different. In a further aspect, the lipid can comprise a blend of monoglycerides, diglycerides, and triglycerides. The carboxylic acids of each monoglyceride, diglyceride, or triglyceride can be saturated or unsaturated, can be branched or unbranched, and can be a C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 carboxylic acid. In a further aspect, the lipid can comprise a blend of monoglycerides, diglycerides, and triglycerides of saturated even-numbered, unbranched natural fatty acids with a chain length of C 8 to C 18. For example, the lipid can be a blend of triglycerides, each triglyceride of C 8, C 10, C 12, C 14, C 16, or C 18 carboxylic acids. In a further aspect, the lipid can comprise a triglyceride of palmitic acid, oleic acid, and/or stearic acid. That is, each carboxylic acid of the triglyceride can be palmitic acid, oleic acid, or stearic acid. For each triglyceride in the blend, the three carboxylic acids can be the same, two of the carboxylic acid can be the same, or all three can be different. In a further aspect, the lipid can comprise a triglyceride of palmitic acid, oleic acid, and stearic acid. In an even further aspect, the lipid can comprise a blend of triglycerides as commercially available under the brand name SOFTISAN®. For example, the lipid can comprise the commercially available SOFTISAN® 100, SOFTISAN®133, SOFTISAN®134, SOFTISAN®138, SOFTISAN® 142, SOFTISAN® 154, or a blend thereof. In a still further aspect, the lipid can comprise a blend of triglycerides as commercially available under the brand name WITEPSOL H35®, and SOFTISAN 133®, SOFTISAN 134®, SOFTISAN 138®, SOFTISAN 378®, SOFTISAN 601®, and/or SOFTISAN 767®. In one aspect, the lipid can comprise at least one C 4 to C 24 carboxylic acid. In one aspect, the carboxylic acid can be saturated or unsaturated, can be branched or unbranched, and can be substituted or unsubstituted. For example, the carboxylic acid can be a C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , or C 24 carboxylic acid. In a further aspect, the carboxylic acid can comprise at least one saturated, even-numbered, unbranched carboxylic acid with a chain length of C 8 to C 18 . For example, the carboxylic acid can be a C 8, C 10, C 12, C 14, C 16, or C 18 alcohol. Prefered fatty acid include palmitic, stearic, arachidic, behenic, or lignoceric acid. Preferred fatty acid includes palmitic, stearic, arachidic, behenic.

ACTIVE AGENTS

Active agent for use in the methods and compositions of the invention include any physiologically or pharmacologically active substance or substances, optionally in combination with pharmaceutically acceptable carriers and additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc. that do not substantially adversely affect the advantageous results that can be attained with the compositions and methods of the present invention. In an embodiment of the invention, the active agent can be either hydrophilic or hydrophobic. The active agent may include drug agents, medicaments, vitamins, nutrients, or the like. Included among the types of agents that meet this description are lower molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food supplements, sex sterilants, imaging agents, fertility inhibitors and fertility promoters. Preferred pharmaceutical active agent include, for example, proteins, peptides, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, small molecules including, but not limited to, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, anti-migraine agents, anti- Alzheimer's agents, antimicrobial agents, pharmaceutical active agent that can be used in the methods and compositions of the present invention include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, oeuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Active agents useful in this invention include but are not limited to analgesics, ■eti-mflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti- eMtgHlaiits, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, antihypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolyptics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opiod analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti- osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, opioid analgesics, protease inhibitors, sex hormones and mixtures thereof, antibiotics, antibodies and bronchodilators, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiinfectives, anti-migraine agents, antiparkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides, and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents. Active agent may be selected from Abarelix, Aldesleukin, Aldesleukin, Alemtuzumab, Alitretinoin, Allopurinol, Altretamine, Amifostine, Anastrozole, Arsenic trioxide, Asparaginase, Azacitidine, BCG Live, Bevacuzimab, Avastin, Fluorouracil, Bexarotene, Bleomycin, Bortezomib, Busulfan, Calusterone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dactinomycin, Darbepoetin alfa, Daunorubicin, Denileukin, Dexrazoxane, Docetaxel, Doxorubicin, Doxorubicin hydrochloride, Dromostanolone Propionate, Epirubicin, Epoetin alfa, Erlotinib, Estramustine, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, floxuridine fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histrelin acetate, Hydroxyurea, Ibritumomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon alfa-2a, Interferon alfa-2b, Irinotecan, Lenalidomide, Letrozole, Leucovorin, Leuprolide Acetate, Levamisole, Lomustine, Megestrol Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxsalen, Mitomycin C, Mitotane, Mitoxantrone, Nandrolone, Nelarabine, Nofetumomab, Oprelvekin, Oxaliplatin, Paclitaxel, Palifermin, Pamidronate, Pegademase, Pegaspargase, Pegfilgrastim, Pemetrexed Disodium, Pentostatin, Pipobroman, Plicamycin, Porfimer Sodium, Procarbazine, Quinacrine, Rasburicase, Rituximab, Sargramostim, Sorafenib, Streptozocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testolactone, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, Uracil Mustard, Vairubicin, Vinblastine, Vincristine, Vinorelbine, Zoledronate, or Zoledronic acid, acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenaftne, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chloφheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, danazol, dantrolene, dexchloφheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donezepil, efavirenz, eprosartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, furazolidoneu, gabapentin, femfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, Uao ecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, iMMprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, Medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratriptan, nelfinayir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremitfene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, Zolpidem, zopiclone, pharmaceutically acceptable salts, isomers, and derivatives thereof, and mixtures thereof. Antiproliferative or chemotherapeutic agent is selected from any one or more of a taxane (e.g., paclitaxel), vincristine, adriamycin, vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxoribicin), epipodophyllotoxins (e.g., etoposide), cisplatin, methotrexate, actinomycin D, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin, and metronidazole. Active agents may include antiulcerants such as cimetidine, famotidine, ranitidine, roxatidine acetate, pantoprazole, omeprazole, lansoprazole or sucralfate; gut relaxants or prokinetics such as propantheline bromide, camylofin (acamylophenine), dicyclomine, hyoscine butyl bromide, mebeverine, cisapride, oxybutynin, pipenzolate methyl bromide, drotaverine, metoclopramide, clidinium bromide, isopropamide or oxyphenonium bromide; enzymes or carminatives, such as pancreatin, papain, pepsin, or amylase; hepatobiliary preparations such as chenodeoxycholic acid, ursodeoxycholic acid, L-ornithine or silymarin; antihypertensives such as clonidine, methyidopa, sodium nitroprusside, terazosin, doxazosin, (DI) hydralazine or prazosin; beta blockers such as esmolol, celiprolol, atenolol, labetolol, propranolol, metoprolol, carvedilol, sotalol, oxyprenolol or bisoprolol; calcium channel blockers such as felodipine, nitrendipine, nifedipine, benidipine, verapamil, amlodipine or lacidipine; ace inhibitors such as enalapril, lisinopril, ramipril, perindopril, benazepril or captopril; angiotensin II inhibitors such as losartan potassium; potassium channel activators, such as nicorandil; diuretics and antidiuretics such as hydrochlorothiazide, xipamide, bumetanide, amiloride, spironolactone, indapamide, triamterene, clopamide, furosemide or chlorthalidone; antianginals such as isoscorbide dinitrate, oxyfedrine, isosorbide 5-mononitrate, diltiazem, erythrityl tetramtrate, trimetazidine, lidoflazine, pentaerythritol tetramtrate, glyceryl trinitrate or dilazep; coagulants such as conjugated oestrogens, diosmin, menaphthone, menadione, haemocoagulase, ethamsylate (cydanamine), rutinflavonoids or adrenochrome monosemicarbazone; anticoagulants antithrombotics or antiplatelets such as ticlopidine, warfarin, streptokinase, phenindione, rtpa, urokinase, vasopressin, nicoumalone, heparin, low molecular weight heparins, mucopolysaccharide polysulphate or dipyridamole; antiarrhythmics such as quinidine, disopyramide, procainamide, lignocaine (lidocaine), mexiletine, amiodarone, adenosine, propafenone; drugs in cardiac failure and shock such as mephentermine, digoxin, dopamine, dobutamine or noradrenaline, vasodilators such as isoxsuprine, xanthinol nicotinate, nylidrin HC1, pentoxifylline (oxpentifylline) or cyclandelate; cardiac glycosides such as deslaneside, digitoxin, digoxin or digitalin; penicillins such as benzyl penicillin, procaine penicillin (G), benzathine penicillin (G), phenoxymethyl penicillin, penicillin G/V, bacampicillin, carbenicillin, piperadllin, ampicillin (optionally in combination with sulbactam or probenecid), cloxacillin, or amoxycillin (optionally in combination with bromhexine, cloxacillin, carbocysteine or clavulanic acid); quinolones or fluoroquinolones such as nalidixic acid, pefloxacin, ofloxacin, sparfloxacin, norfloxacin, ciprofloxacin, lomefloxacin, cephalosporins such as ceftizoxime, cefumxime, cefixime, cefotaxime, cefaclor, ceftriaxone sodium, cefadroxil, cephalexin, (optionally in combination with bromhexine HC1 or probenecid) cefazolin, cephaloridine, ceftazidime or ceforperazone; sulphonamides such as sulphonamides, sulphamoxole, sulphadimehtoxine, cotrifamole, cotrimoxazole, trimethoprim, aminoglycosides such as gentamicin, tobramycin, neomycin, amikacin, sisomicin, kanamycin, netilmicin, polymyxins such as polymyxin-b, colistin sulphate; chloramphenicol; tetracyclines such as tetracycline, doxycydine, minocycline, demeclocycline, oxytetracycline; macrolides such as erythromycin, (optionally in combination with bromhexine), clarithromycin, vancomycin, lincomycin, azithromycin, spiramycin, roxithromycin, clindamycin, cefpirome, teicoplanin (teichomycin a2), antivirals such as abacavir, lamivudine, acyclovir, amantadine, interferon, ribavirin, stavurdine, lamivudine or zidovudine (azt); antimalarials, such as quinine, proguanil, chloroquine, primaquine, amodiaquine, artemether, artesunate, mefloquine, pyrimemamine, arteether, mepacrine; antituberculars such as cycloserine, capreomycin, ethionamide, prothionamide, isoniazid (inh), rifampicin, rifampicin optionally in combination with inh, isoniazide, pyrazinamide and/or ethambutol; ethambutol (optionally in combination with isoniazid), streptomycin or pyrazinamide; anthelmintics & antiinfestives such as piperazine, niclosamide, pyrantel pamoate, levamisole, diethyl carbamazine, tetramisole, albendazole, praziquantel, sodium antimony gluconate or membendazole; antileprotics such as dapsone or clofazimine; antianaerobics, antiprotozoals or antiamoebics such as tinidazole, metronidazole (optionally in combination with furazolidone or norfloxacin), diloxanide furoate, secnidazole, hydroxyquinolones, dehydroemetine, ornidazole or furazolidone; antifungals such as fluconazole, ketoconazole, hamycin, terbinafine, econazole, amphotericin-b, nystatin, clotrimazole, griseofulvin, miconazole or itraconazole; vitamins; respiratory stimulants such as doxapram hydrochloride; antiasthmatics such as isoprenaline, salbutamol(albuterol), orciprenaline, ephedrine, terbutaline sulphate, salmeterol, aminophylline, therophylline, beclomethasone dipropionate or fluticasone propionate; antiallergics such as terfenadine, astemizole, loratadine, clemastine, dimethindene maletate, fexofenadine hydrochloride, kydroxyzine, clilorpheniramine, azatadine maleate, methdilazine, pheniramine maleate, diphenhydramine or cetrizine; skeletal muscle relaxants such as tizanidine methocarbamol, carisoprodol, valethamate, baclofen, cMorrnezanone or chlorzoxazone; smooth muscle relaxants such as oxyphenonium bromide, propantheline bromide, diclomine, hyoscine buytyl bromide, mebeverine, drotaverine, clidinium bromide, isopropamide or camylofin dihydrochloride; non steroidal anti-inflammatory drugs such as naproxen, mefenamic acid, nimesulide, diclofenac, tenoxicam, ibuprofen (optionally in combination with paracetamol), meloxicam, aspirin, flurbiprofen, ketoprofen, ketoprolac, phenylbutazone, oxyphenbutazone, indomethacin or piroxicam; antineoplastic agents, such as nitrogen mustard compounds (e.g. cyclophosphamide, trofosfamide, iofosfamide, melphalan or chlorambucil), aziridines (e.g. thioepa), N-nitrosurea derivatives (e.g. carmustine, lomustine or nimustine), platinum compounds (e.g. spiroplatin, cisplatin, and carboplatin), procarbazine, dacarbazine methotrexate, adriamycin, mitomycin, ansamitocin, cytosine arabinoside, arabinosyl adenine, mercaptopolylysine, vincristine, busulfan, chlorambucil, melphalan (e.g. PAM, L-PAM or phenylalanine mustard), mercaptopurine, mitotane, procarbazine hydrochloride dactinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, epirubicin, plicamycin (mithramycin), mitoxantrone, bleomycin, bleomycin sulfate, aminoglutethimide, estramustine phosphate sodium, flutamide, leuprolide acetate, megestrol acetate, tamoxifen citrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase (L- asparaginase) Erwina asparaginase, etoposide (VP-16), interferon .alpha.-2a, interferon .alpha.-2b, teniposide (V -26), vinblastine sulfate (VLB), vincristine sulfate, vindesine, paclitaxel (Taxol), methotrexate, adriamycin, arabinosyl, hydroxyurea; folic add antagonists (e.g. aminopterin, methotraxate), antagonists of purine and pyrimidine bases (e.g. mercaptopurine, tioguanine, fiuorouracil or cytarabine); narcotics, opiates or sedatives such as paregoric, codeine, morphine, opium, amobarbital, amobarbital sodium, aprobarbital, butobarbital sodium, chloral hydrate, ethchlorvynol, ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazine hydrochloride, methyprylon, midazolam hydrochloride, paraldehyde, pentobarbital, secobarbital sodium, talbutal, temazepam or triazolam; local or general anaesthetics such as bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, procaine or tetracaine, droperidol, etomidate, fentanyl citrate with droperidol, ketamine hydrochloride, methohexital sodium or thiopental; neuromuscular blockers such as atracurium mesylate, gallamine triethiodide, hexafluorenium bromide, metocurine iodide, pancuronium bromide, succinylcholine chloride, tubocurarine chloride or vecuronium bromide; or therapeutics for the hormonal system, such as growth hormone, melanocyte stimulating hormone, estradiol, beclomethasone dipropionate, betamethasone, cortisone acetate, dexamethasone, flunisolide, hydrocortisone, raethylprednisolone, paramethasone acetate, prednisolone, prednisone, triamcinolone or fludrocortisone acetate. Active agents useful in this invention include but are not limited to analgesics/antirheumatics such as morphine, codeine, fentanyl, indomethacin, naproxen, and piroxicam; antiallergics such as pheniramine, dimethindene, terfenadine, loratidine, and doxylamine; antibiotics such as azithromycin, clarithromycin, rifampicin, ethambutol, and thiacetazone; antiepileptics such as carbamazepine, clonazepam, alprazolam, medazolam, mesuximide, phenyloin, and valproic acid; antimycotics such as natamycin, amphotericin B, voriconazole, and miconazole; corticoids such as aldosterone, dexamethasone, triamcinolone, budesonide, fluticasone, and beclomethoasone; migraine agents such as lisuride, methysergide, dihydroergotamine, ergotamine; psychotropics such as benzodiazepines and clormethiazole; anticancer agents such as mephalan, carmustine, lomustine, cyclophosphamide, ifosamide, trofosamide, chlorambucil, fiuorouracil, methotrexate, vinblastine, vincristine, dactinomycin, and camptothecins; cytostatic drugs such as Ara-C, FudR, and 5FU; virostatic drugs such as AZT, ddC, and ddl; and asthma agents such as non-steroidal inflammatory agents such as VLA-4 inhibitors and phosphodiesterase inhibitors (eg, PD-4 inhibitors). Additional active agents include, but are not limited to cyclosporine, ciprofloxacin, amikacin, tobramycin, pentamidine isethionate, beclomethasone dipropionate, triamcinolone acetamide, flunisolide, fluticasone, fluticasone propionate, salmeterol xinofoate, formeterol fumarate, ergotamine tartrate, doxorubicin, mitoxantrone, progesterone, micronazole, piroxicam, tacrolimus, sirolimus, indomethacin, econazole, itraconazole, amiodarone, fexofenadine, gabapentin, sprionolactone, clarithromycin, saquinavir, didanosine paramethoxy cinnamate, THC, nicotine, halofantrine, statins, taxol, taxotere, alfaxlone, erythromycin, albendazole, nitroscanate, dantrolene, caphalone, tilmicosine, nitazoxanide, fluoroquinolone (eg, ciprofloxacin), tilmicosin, all-trans retinoic acid and the analogues, agonists and antagonists of the above. Drugs for which an immediate release into the bloodstream (ie, rapid onset of pharmaceutical effect) might be particularly desirable include those for use in the treatment of migraine, nausea, insomnia, allergic (including anaphylactic) reactions, neurological or psychiatric disorders (in particular panic attacks and other psychoses or neuroses), erectile dysfunction, diabetes and related disorders and cardiac disorders, anti-convulsants, bronchodilators and drugs for the alleviation of pain or mflammation.Anti-malarial drugs quinine sulphate and chloroquine; many oral corticosteroids such as are used for asthma treatment; many antibiotics; dicyclomine HC1 (anti-spasmodic); dipyridamole (platelet inhibitor); toprimate (anti-epileptic); oxycodone (analgesic); carispodol (used in the treatment of hyperactivity of skeletal muscles); bupropion (anti-depressant); sumatripan (used in migraine treatment); verapamil HC1 (calcium ion flux inhibitor); tinidazole (anti-parasitic); acetyl salicylic acid (aspirin, anti-pyretic); cimetidine HC1 (used in the treatment of acid/peptic disorders); diltiazem HC1 (anti-anginal); theophylline; paracetamol; anti-HIV agents such as lamivudine, stavudine, zidovudine, didanosine, saquinavir, amprenavir, ritonavir, indinavir and efavirenz; and orphenadrine citrate (anti-muscarinic). Further, the pharmaceutically active agent can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid and the like.Useful nutraceuticals include but are not limited to vitamins such as carotenoids, vitamin E, vitamin D, vitamin C, thiamine, riboflavin, niacin, folic acid, pyridoxine, biotin, pantothenic acid, cyanocobalamin and the like; minerals such as magnesium, manganese, zinc, selenium, chromium, copper and the like; nutritional elements such as alpha lipoic acid, lutein beta carotenoids and the like.

ANTIOXIDANT

The invention also can include antioxidant. Antioxidant which are usable in accordance with the invention include Ascorbic acid (vitamin C), Glutathione, Lipoic acid, Uric acid Carotenes, a-Tocopherol (vitamin E), Ubiquinol (coenzyme Q) and combination thereof.

SURFACE MODIFIERS

The invention also can include surface modifiers. Surface modifiers which are usable in accordance with the invention include stealth agents like hydrophilic polymers such as PEG, pluronic and derivative thereof and receptor specific ligands like folic acid and derivative thereof, nonionic surfactants such as tween 80, carbohydratessuch as pollulan, mannose, cell penetrating peptides such as TAT peptide, penetratin, transportan, poly-arginine, rabies virus glycoprotein (RVG) and other suitable ligands Transferin, insulin, leptin, monoclonal antibody.

pH MODULATORS

The invention also can include pH modulators. pH modulators which are usable in accordance with the invention include citrate , acetate, borate, phosphate, glutamate, tris HC1, saline sodium citrate, phosphate saline buffer, and tris buffer.

SWEETENER FLAVORING AGENTS

The invention also can include sweetener/flavoring agents. Sweetener/flavoring agents which are usable in accordance with the invention include, but are not limited to, saccharin, lactose, sucrose, fructose, sucralose, sorbitol, aspartame and raspberry blend and combinations thereof.

COLORING AGENTS/DYES

The composition can also include coloring agents/dyes. Examples of suitable coloring agent/dyes include, but are not limited to, FD&C Blue 2 and FD&C Red 33. Other conventional coloring agents/dyes can be employed, if desired.

Other exdipients reported in the art. Examples:

Example 1: Effect of aqueous phase composition on particle size and entrapment efficiency

la) Non-aqueous phase: Doxorubicin hydrochloride -lOmg, PLGA -5mg, dioctyl sodium sulfosuccinate -

20mg and block copolymer of polyoxyethylene polyoxypropylene -5mg were dissolved in Ν', Ν* dimethylacetamide -l ml by simple mixing

Aqueous phase: Water -30mL

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Doxorubicin hydrochloride with

Entrapment Efficiency of Doxorubicin hydrochloride 93.19 ± 1.2% and

Average particles size 197.1 ± 1.76 nm. lb) Non-aqueous phase: Doxorubicin hydrochloride -lOmg, PLGA -5mg, dioctylsulfosuccinate sodium - 20mg and block copolymer of polyoxyethylene polyoxypropylene -5mg were dissolved in N\ N' dimethylacetamide -lml by simple mixing

Aqueous phase: Dextrose anhydrous 1.5g dissolved in water - 30ml

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Doxorubicin hydrochloride with

Entrapment Efficiency of Doxorubicin hydrochloride 91.45 ± 0.85% and

Average particles size 191.0 ± 4.43 nm. lc) Non-aqueous phase: Doxorubicin hydrochloride -lOmg, PLGA -5mg, dioctyl sodium sulfosuccinate - 20mg and block copolymer of polyoxyethylene polyoxypropylene -5mg were dissolved in ', N' Dimethylacetamide - lml by simple mixing

Aqueous phase: Sodium chloride - 0.27g dissolved in water - 30ml

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Doxorubicin hydrochloride with

Entrapment Efficiency of Doxorubicin hydrochloride 92.74 ± 0.43% and

Average particles size 717.6 ± 2.9 nm.

The data in examples 1A, IB and 1C reveal that the particle size was influenced by change in the aqueous phase composition, while no significant change was seen in the entrapment efficiency. Example 2: Effect of surfactant concentration on particle size and entrapment efficiency

2a) Non-aqueous phase: Nevirapine -30mg, polyglyceryl-6distearate -30 mg, polyoxyethylene sorbitan fatty acid esters - lOmg were dissolved in N\ N' Dimethylacetamide -1ml by simple mixing

Aqueous phase: Water - 30ml

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Nevirapine with

Entrapment Efficiency of Nevirapine 74.67342 ± 0.35% and

Average particles size 233.85±7.56 nm.

2b) Non-aqueous phase: Nevirapine -30mg, polyglyceryl-6distearate -30 mg, polyoxyethylene- polyoxypropylene block co-polymers - lOmg were dissolved in N\ N' Dimethylacetamide -1ml by simple mixing

Aqueous phase: Water - 30ml

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Nevirapine with

Entrapment Efficiency of Nevirapine 63.35 ±0.17 % and

Average particles size 117.5±3.53 nm.

2c) Non-aqueous phase: Nevirapine -30mg, polyglyceryl-6distearate -30 mg, polyoxyl 15 hydroxystearate - lOmg were dissolved in N', N' Dimethylacetamide -1ml by simple mixing

Aqueous phase: Water - 30ml

Mixing of the non-aqueous phase with the aqueous phase resulted in the generation of drug loaded heterogeneous nanosystem of Nevirapine with

Entrapment Efficiency of Nevirapine 73.04 ±0.53 % and

Average particles size 175.15±4.17 nm.

The data in examples 2A, 2B and 2C reveal that both the particle size and entrapment efficiency were influenced by change in the surfactant.

Claims

We Claims
1. Pharmaceutical compositions comprising of two liquid compositions
a) A non-aqueous liquid composition comprising of at least one polymer or lipid, at least one surfactant dissolved in a non aqueous phase comprising at least one non aqueous solubilizer b) An aqueous liquid composition comprising water containing at least one electrolyte or one sugar
c) An active agent dissolved in either the aqueous composition or non aqueous composition wherein, mixing of the aqueous and non-aqueous compositions results in the formation of drug loaded heterogeneous nanosystems of average size less than 1 μπι, with not less than 60% of the active agent entrapped in the nanosystem.
2. Pharmaceutical compositions according to claim 1 wherein the non aqueous solubilizer comprises partial ether or ester of a polyhydroxyl alcohol and a fatty alcohol or acid, 2-pyrrolidone derivatives thereof, oleic esters of polyglycerol, polyethylene glycols, alcohols, N-substituted amides.
3. Pharmaceutical compositions according to claim 1 wherein the aqueous phase optionally comprises surface modifiers, polymers and surfactants.
4. Pharmaceutical compositions according to claim 2 wherein the non aqueous solubilizer is chosen from among diethylene glycol monoethyl ether, triacetin, propylene glycol, polyethylene glycol, Ν,Ν' dimethylacetamide, ethanol, diethylene glycol monoethyl ether, polyoxyl 15 hydroxystearate or combinations thereof.
5. Pharmaceutical compositions according to claim 1 wherein the polymer is chosen from among polylactides, polyglycolides, poly lactide-glycolides, poly anhydrides, poly acrylates, polyesters and vinyl polymers.
6. Pharmaceutical compositions according to claim 5 wherein the polymer selected is preferably PLGA, polyvinyl acetate/polyvinylpyrrolidone, acrylates/ dimethyl aminoethyl methacrylate copolymer, polyethylene sebacate, copolymer of methyl vinyl ether and maleic anhydride or combinations thereof.
7. Pharmaceutical compositions according to claim 1 wherein the lipid is chosen from among fatty acids, fatty acid esters, fatty alcohols and derivatives thereof.
8. Pharmaceutical compositions according to claim 7 wherein the lipid is preferably stearic acid, glycerylmonostearate, polyglyceryl-6distearate, glycerylpalmitostearate, Glyceryl Behenate, glyceryl palmitostearate or combinations thereof.
9. Pharmaceutical compositions according to claim 1 wherein the surfactant is chosen from among anionic, non-ionic, cationic and amphoteric surfactants.
10. Pharmaceutical compositions according to claim 9 wherein the preferred surfactants are dioctylsulfosuccinate sodium, sodium lauryl sulphate, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, cetrimide or combinations thereof.
11. Pharmaceutical compositions according to claim 1 wherein the electrolyte in the aqueous phase is sodium chloride or potassium chloride.
12. Pharmaceutical compositions according to claim 1 wherein the sugar in the aqueous phase is dextrose.
13. Pharmaceutical compositions according to claim 3 wherein the surface modifiers in the aqueous phase are selected from among polyethylene glycol, carbohydrate polymers, polyoxyethylene sorbitan fatty acid esters or combinations thereof.
14. Pharmaceutical compositions according to claim 1 wherein the active agent is chosen from among anticancer, anti HIV, anti malarial, antileishmaniasis agents.
15. Pharmaceutical compositions according to claim 14 wherein the active agent is preferably doxorubicin hydrochloride, tamoxifen citrate, paclitaxel, docetaxel, primaquine phosphate, chloroquine phosphate, amodiaquine, mefloquine, atovaquone, artemisinin, artemether, artesunate, dihydroartemisinin, arteether, halofantrine, clindamycin, nevirapine, stavudine, lamivudine, zidovuine, abacavir, ritonavir, abacavir, emtricitabine, tenofovir, efavirenz or combinations thereof.
16. Pharmaceutical compositions according to claim 1 wherein the concentration of active agent ranges from 0.1% to 10% w/v of the liquid composition.
17. Pharmaceutical compositions according to claim 1 wherein the concentration of surfactant ranges from 0.01% to 40% w/v of the liquid composition.
18. Pharmaceutical compositions according to claim 1 wherein the concentration of polymer ranges from 0.01% to 30% w/v of the liquid composition.
19. Pharmaceutical compositions according to claim 1 wherein the concentration of lipid ranges from 0.01 % to 30% w/v of the liquid composition.
20. Pharmaceutical compositions according to claim 1 wherein the ratio of non-aqueous to aqueous phase range from 1 :2 to 1 :250.
21. Pharmaceutical compositions according to claim 1 wherein the volume of the non-aqueous ranges from 0.5mL to 20mL.
22. Pharmaceutical compositions according to claim 1 wherein said compositions on mixing form drug loaded heterogeneous nanosystems may be administered via oral or intravenous route.
PCT/IN2011/000730 2010-11-03 2011-10-24 Pharmaceutical compositions for colloidal drug delivery WO2012059936A1 (en)

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