CA2325257A1 - Emulsified delivery system for hydrophobic and hydrophilic pharmaceutical agents - Google Patents
Emulsified delivery system for hydrophobic and hydrophilic pharmaceutical agents Download PDFInfo
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- CA2325257A1 CA2325257A1 CA 2325257 CA2325257A CA2325257A1 CA 2325257 A1 CA2325257 A1 CA 2325257A1 CA 2325257 CA2325257 CA 2325257 CA 2325257 A CA2325257 A CA 2325257A CA 2325257 A1 CA2325257 A1 CA 2325257A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
An emulsified pharmaceutical composition comprising a hydrophilic material, a hydrophobic material, and at least one surfactant for dispersing the hydrophilic and hydrophobic material. Where a hydrophilic pharmaceutical agent is incorporated in the hydrophilic material and a hydrophobic pharmaceutical agent is incorporated in the hydrophobic material.
Description
EMULSIFIED DELIVERY SYSTEM FOR HYDROPHOBIC AND
HYDROPHILIC PHARMACEUTICAL AGENTS
Field of the Invention The present invention relates to an emulsified pharmaceutical delivery system. More particularly the invention relates to a self emulsified pharmaceutical delivery system for delivery of hydrophobic and hydrophilic pharmaceuticals.
Background of the Invention Many of the developments in pharmaceutical self emulsifying compositions have been directed towards self emulsifying compositions containing the highly lipophilic drug Cyclosporine (Keown et al. (1996); Ritschel (1996); Frei et al.
(1998); and Gershanik et al. (1998)). Self emulsifying technologies have successfully enhanced the safety and efficacy of cyclosporine A. Cyclosporine is used to reduce the incidence of organ rejection after transplant surgeries.
This drug is extremely insoluble in hydrophilic environments, like that of the gastrointestinal tract. Consequently, its effective bioavailability was quite limited and large doses were necessary. Such large doses were very irritating to the gut and often precipitated side effects, especially in the long-term. The successful application of self emulsifying excipient systems with Cyclosporin has been documented in several of independent, academic investigations, demonstrating up to a 60% increase in bioavailability and a dramatic reduction in the incidence of side effects. The above-cited references all show that self emulsifying Cyclosporine compositions have a much faster rate and extent of absorption than conventional Cyclosporine formulations. Fischl et al. (1997) is directed towards self emulsifying compositions containing a hydrophobic urea-based peptidomimetic HIV-1 protease inhibitor.
Charman et al. (1992) is directed towards the use of self emulsifying compositions to increase the rate and efficiency of delivery of a lipophilic compound designated as WIN 54954 (no other description of the compound is given). Kimura et al.
(1989) is directed towards the use of self emulsifying compositions to increase the delivery of hydrophobic meclizine dihydrochloride. Lastly, Gershanik et al. (1996) demonstrated that self emulsifying formulations containing progesterone, also water insoluble, had a greater oral bioavailability than progesterone given in conventional oral doses.
U.S. Patent No. 5,993,858 ('858) is directed towards a self micro-emulsifying excipient formulation for increasing the bioavailability of a drug. The self emulsion composition includes an oil or other lipid material, a surfactant, and a hydrophilic co-surfactant. The '858 patent teaches that solid drugs having low water solubility exhibit a much higher degree of bioavailability when formulated into self emulsifying compositions. In addition, the '858 patent teaches that the extent of drug absorption is very dependent on the solubility of the drug in the gastrointestinal luminal contents. In particular, the '858 patent teaches that the more hydrophilic the co-surfactant is (i.e., high HLB number), the greater the dissolution of poorly hydrophilic drugs or pharmaceuticals.
The Rudnic et al. patents (U.S. Patent Nos. 5,952,004 and 5,897,876) are directed towards pharmaceutical compositions comprising a pharmaceutical agent incorporated into a pharmaceutical Garner emulsion comprised of a hydrophobic material selected from the group consisting of a long chain carboxylic acid, long chain carboxylic acid ester, long chain carboxylic acid alcohol and mixtures thereof emulsified with a hydrophilic material. More specifically, the Rudnic et al.
patents teach that a wide range of active agents can be administered in the pharmaceutical emulsion composition, including antibiotics, antimicrobials, antineoplastics, antivirals, cardiovascular and renal agents, immunosuppressive and immunostimulatory agents, and central nervous system active agents. The Rudnic et al patents focus in particular on emulsion compositions that can be used to deliver therapeutic polypeptides. The Rudnic et al. patents teach that the emulsion compositions increase drug solubility and protect peptide drugs against enzyme hydrolysis thereby increasing oral bioavailability.
The general concept of using self emulsifying compositions to enhance the uptake of hydrophobic pharmaceutical compositions is well-known in the art.
HYDROPHILIC PHARMACEUTICAL AGENTS
Field of the Invention The present invention relates to an emulsified pharmaceutical delivery system. More particularly the invention relates to a self emulsified pharmaceutical delivery system for delivery of hydrophobic and hydrophilic pharmaceuticals.
Background of the Invention Many of the developments in pharmaceutical self emulsifying compositions have been directed towards self emulsifying compositions containing the highly lipophilic drug Cyclosporine (Keown et al. (1996); Ritschel (1996); Frei et al.
(1998); and Gershanik et al. (1998)). Self emulsifying technologies have successfully enhanced the safety and efficacy of cyclosporine A. Cyclosporine is used to reduce the incidence of organ rejection after transplant surgeries.
This drug is extremely insoluble in hydrophilic environments, like that of the gastrointestinal tract. Consequently, its effective bioavailability was quite limited and large doses were necessary. Such large doses were very irritating to the gut and often precipitated side effects, especially in the long-term. The successful application of self emulsifying excipient systems with Cyclosporin has been documented in several of independent, academic investigations, demonstrating up to a 60% increase in bioavailability and a dramatic reduction in the incidence of side effects. The above-cited references all show that self emulsifying Cyclosporine compositions have a much faster rate and extent of absorption than conventional Cyclosporine formulations. Fischl et al. (1997) is directed towards self emulsifying compositions containing a hydrophobic urea-based peptidomimetic HIV-1 protease inhibitor.
Charman et al. (1992) is directed towards the use of self emulsifying compositions to increase the rate and efficiency of delivery of a lipophilic compound designated as WIN 54954 (no other description of the compound is given). Kimura et al.
(1989) is directed towards the use of self emulsifying compositions to increase the delivery of hydrophobic meclizine dihydrochloride. Lastly, Gershanik et al. (1996) demonstrated that self emulsifying formulations containing progesterone, also water insoluble, had a greater oral bioavailability than progesterone given in conventional oral doses.
U.S. Patent No. 5,993,858 ('858) is directed towards a self micro-emulsifying excipient formulation for increasing the bioavailability of a drug. The self emulsion composition includes an oil or other lipid material, a surfactant, and a hydrophilic co-surfactant. The '858 patent teaches that solid drugs having low water solubility exhibit a much higher degree of bioavailability when formulated into self emulsifying compositions. In addition, the '858 patent teaches that the extent of drug absorption is very dependent on the solubility of the drug in the gastrointestinal luminal contents. In particular, the '858 patent teaches that the more hydrophilic the co-surfactant is (i.e., high HLB number), the greater the dissolution of poorly hydrophilic drugs or pharmaceuticals.
The Rudnic et al. patents (U.S. Patent Nos. 5,952,004 and 5,897,876) are directed towards pharmaceutical compositions comprising a pharmaceutical agent incorporated into a pharmaceutical Garner emulsion comprised of a hydrophobic material selected from the group consisting of a long chain carboxylic acid, long chain carboxylic acid ester, long chain carboxylic acid alcohol and mixtures thereof emulsified with a hydrophilic material. More specifically, the Rudnic et al.
patents teach that a wide range of active agents can be administered in the pharmaceutical emulsion composition, including antibiotics, antimicrobials, antineoplastics, antivirals, cardiovascular and renal agents, immunosuppressive and immunostimulatory agents, and central nervous system active agents. The Rudnic et al patents focus in particular on emulsion compositions that can be used to deliver therapeutic polypeptides. The Rudnic et al. patents teach that the emulsion compositions increase drug solubility and protect peptide drugs against enzyme hydrolysis thereby increasing oral bioavailability.
The general concept of using self emulsifying compositions to enhance the uptake of hydrophobic pharmaceutical compositions is well-known in the art.
However, the use of self emulsifying compositions to obtain superior uptake of hydrophobic and hydrophilic pharmaceutical agents is not described in the art.
None of the patents or research publications, discussed above, either individually or in combination, teach self emulsifying compositions containing both hydrophilic and hydrophobic pharmaceutical agents. In addition, none of the prior art references discuss the advantages of using self emulsifying compositions to increase absorption of nutrient components of any kind in persons who have had a portion or all of their large intestine removed. In contrast, the prior art references, discussed above, are directed towards compositions that contain highly lipophilic compounds whose water insolubility properties prevent efficient absorption by a normal intestine.
The present invention seeks to improve self emulsifying compositions by providing a self emulsifying compositions for both highly soluble and insoluble materials to be packaged within a self emulsifying pharmaceutical delivery system and also allows for multiple pharmaceuticals to be packaged within a single dose for the purpose of enhancing solubility, dispersion, dissolution or bioavailability of one or more ingredients. The present invention employs emulsifying materials and techniques to create a unique, multi-layered delivery system that allows the administration of multiple pharmaceutical agents which may be soluble, insoluble or a combination thereof, and whose purpose for inclusion may be symbiotic or unrelated in nature.
Thus it is an object of the present invention to improve the solubility, dispersion, dissolution or bioavailability of pharmaceutical agents.
It is a further object of the present invention to improve the solubility, dispersion, dissolution or bioavailability of both hydrophilic and hydrophobic pharmaceutical agents.
It is a further object of the present invention to enhance the intestinal absorption of both hydrophobic and hydrophilic pharmaceutical agents into bowel resected patients.
Summary of the Invention The present invention provides a composition containing both hydrophilic and hydrophobic pharmaceutical agents which are mixed with other components that upon ingestion spontaneously form an multiple pharmaceutical agent containing emulsion in the aqueous environment of the stomach. More specifically, the self emulsifying pharmaceutical delivery system of the present invention comprises hydrophilic and hydrophobic material combined with surfactant in which multiple pharmaceutical agents are mixed. In an aqueous environment, the self emulsifying pharmaceutical delivery system of the present invention spontaneously forms conglomerates called micelles. Once in the intestinal tract, the micelles facilitate transport across the mucous lining where the micelles are absorbed, intact, into the intestinal lymph system.
In a preferred embodiment of the present invention, a water-in-oil emulsion is formed with a hydrophilic pharmaceutical agent incorporated into the hydrophilic material and a hydrophobic pharmaceutical agent incorporated into the hydrophobic material.
In another embodiment the present invention, an oil-in-water emulsion is formed with a hydrophilic pharmaceutical agent incorporated into the hydrophilic material and a hydrophobic pharmaceutical agent incorporated into the hydrophobic material.
In another embodiment the self emulsifying multiple pharmaceutical agent compositions of the present invention are used for delivery of multiple pharmaceutical agents to persons with resected bowels or truncated gastrointestinal tracts.
Detailed Description of the Preferred Embodiment The present invention is modeled upon the process by which the body naturally digests fats. During digestion, dietary fats form large micelles (chylomicrons), which consist of several thousand amphiphilic molecules in a large sphere, each of which may include an array of molecules in their interiors.
Chylomicrons are incorporated into the intestinal lymph and transported through the lymphatic vessels. The present invention provides a self emulsifying system, which spontaneously forms conglomerates of several dozen to a few thousand molecules upon contact with an aqueous environment. These groups of molecules, called micelles, are generally spherical. The formation of micelles is spontaneous, and while a myriad of both soluble and insoluble active ingredients can occupy their respective interior layers, the excipient molecules are designed so that they alternate between a micelle conformation and a free state. Without being limited by theory, it is believed that, the micelles of the present invention are absorbed, intact, into the intestinal lymph delivering the pharmaceutical agents contained therein to the desired sites) of action throughout the body.
None of the patents or research publications, discussed above, either individually or in combination, teach self emulsifying compositions containing both hydrophilic and hydrophobic pharmaceutical agents. In addition, none of the prior art references discuss the advantages of using self emulsifying compositions to increase absorption of nutrient components of any kind in persons who have had a portion or all of their large intestine removed. In contrast, the prior art references, discussed above, are directed towards compositions that contain highly lipophilic compounds whose water insolubility properties prevent efficient absorption by a normal intestine.
The present invention seeks to improve self emulsifying compositions by providing a self emulsifying compositions for both highly soluble and insoluble materials to be packaged within a self emulsifying pharmaceutical delivery system and also allows for multiple pharmaceuticals to be packaged within a single dose for the purpose of enhancing solubility, dispersion, dissolution or bioavailability of one or more ingredients. The present invention employs emulsifying materials and techniques to create a unique, multi-layered delivery system that allows the administration of multiple pharmaceutical agents which may be soluble, insoluble or a combination thereof, and whose purpose for inclusion may be symbiotic or unrelated in nature.
Thus it is an object of the present invention to improve the solubility, dispersion, dissolution or bioavailability of pharmaceutical agents.
It is a further object of the present invention to improve the solubility, dispersion, dissolution or bioavailability of both hydrophilic and hydrophobic pharmaceutical agents.
It is a further object of the present invention to enhance the intestinal absorption of both hydrophobic and hydrophilic pharmaceutical agents into bowel resected patients.
Summary of the Invention The present invention provides a composition containing both hydrophilic and hydrophobic pharmaceutical agents which are mixed with other components that upon ingestion spontaneously form an multiple pharmaceutical agent containing emulsion in the aqueous environment of the stomach. More specifically, the self emulsifying pharmaceutical delivery system of the present invention comprises hydrophilic and hydrophobic material combined with surfactant in which multiple pharmaceutical agents are mixed. In an aqueous environment, the self emulsifying pharmaceutical delivery system of the present invention spontaneously forms conglomerates called micelles. Once in the intestinal tract, the micelles facilitate transport across the mucous lining where the micelles are absorbed, intact, into the intestinal lymph system.
In a preferred embodiment of the present invention, a water-in-oil emulsion is formed with a hydrophilic pharmaceutical agent incorporated into the hydrophilic material and a hydrophobic pharmaceutical agent incorporated into the hydrophobic material.
In another embodiment the present invention, an oil-in-water emulsion is formed with a hydrophilic pharmaceutical agent incorporated into the hydrophilic material and a hydrophobic pharmaceutical agent incorporated into the hydrophobic material.
In another embodiment the self emulsifying multiple pharmaceutical agent compositions of the present invention are used for delivery of multiple pharmaceutical agents to persons with resected bowels or truncated gastrointestinal tracts.
Detailed Description of the Preferred Embodiment The present invention is modeled upon the process by which the body naturally digests fats. During digestion, dietary fats form large micelles (chylomicrons), which consist of several thousand amphiphilic molecules in a large sphere, each of which may include an array of molecules in their interiors.
Chylomicrons are incorporated into the intestinal lymph and transported through the lymphatic vessels. The present invention provides a self emulsifying system, which spontaneously forms conglomerates of several dozen to a few thousand molecules upon contact with an aqueous environment. These groups of molecules, called micelles, are generally spherical. The formation of micelles is spontaneous, and while a myriad of both soluble and insoluble active ingredients can occupy their respective interior layers, the excipient molecules are designed so that they alternate between a micelle conformation and a free state. Without being limited by theory, it is believed that, the micelles of the present invention are absorbed, intact, into the intestinal lymph delivering the pharmaceutical agents contained therein to the desired sites) of action throughout the body.
In one embodiment of the present invention, the self emulsifying multiple pharmaceutical agent compositions of the present invention, enhances the intestinal absorption of both hydrophilic and hydrophobic pharmaceutical agents. More specifically, the present invention enhances bio-availability of multiple pharmaceuticals for persons with resected bowels who have difficulty absorbing sufficient quantities of both hydrophilic and hydrophobic pharmaceutical agents. In the case of hydrophilic pharmaceutical agents the problem appears to be that the highly soluble pharmaceutical agents pass through the truncated gastrointestinal tract so fast that they are inefficiently absorbed. Inclusion of the hydrophilic pharmaceutical agents in the micelles of the present invention slows down the transit time of the pharmaceutical agents thereby allowing sufficient uptake of the hydrophilic pharmaceutical agents.
The present invention provides a self emulsifying system, where an emulsion is a dispersed system containing at least two immiscible liquid material, a hydrophobic material and a hydrophilic material. The emulsion comprises the dispersed material, the dispersion material and an emulsifying agent or surfactant.
The surfactant may simultaneously be a hydrophobic material known as a "self emulsifying agent," preferably an ester, whereby it is possible to produce an emulsion without a separate emulsifying agent. One of the two immiscible liquid materials may be hydrophobic while the other is hydrophilic. Which material becomes the dispersed material depends on the relative amounts of the two liquid materials and which surfactant is selected. Therefore, an emulsion in which the hydrophobic material is dispersed as droplets throughout the hydrophilic material is called an oil-in-water emulsion. Similarly, an emulsion in which hydrophilic material is dispersed as droplets throughout the hydrophobic material is called a water-in-oil emulsion. The hydrophobic and hydrophilic materials can each independently be solid, semisolid or liquid. The pharmaceutical agent may be dispersed or incorporated into the hydrophobic material, the hydrophilic material or in both the hydrophobic and hydrophilic materials.
In a preferred embodiment the present invention comprises a water-in-oil emulsion. In an alternative embodiment the present invention comprises a oil-in-water emulsion. In addition to the two basic emulsified forms of water-in-oil or oil-in-water, another embodiment of the present invention may also possess multiple hydrophobic and hydrophilic layers in alternating emulsified stratums, such as water-in-water-in-oil, oil-in-water-in-oil, or similar combinations thereof. The present invention may include one or more surfactants present in or among the hydrophilic and hydrophobic materials, as well as one or more pharmaceutical agents present in one or more of the hydrophilic or hydrophobic materials. The advantage of a multiplicity of materials is that it allows multiple pharmaceutical agents to be S delivered at varying time intervals or in varying environments.
Depending on which specific surfactant is used, in the present invention, the dispersion of material will either be in the form of a monolayer, micelles, or bilayer vesicles. In a preferred embodiment of the present invention, micelles are formed.
In another embodiment of the present invention bilayer vesicles are formed as an alternative to miscelles.
In the bi-layer embodiment of the present invention, for example, a lipid bi-layer - consisting of surfactant arranged such that the hydrocarbon chains are associated with one another, and whose the polar groups are associated with either the aqueous exterior environment or an interior hydrophilic compartment respectively - may contain an insoluble pharmaceutical agent, while the "interior,"
hydrophilic compartment may contain a water soluble pharmaceutical agent.
Alternatively, the described bi-layer may be inverted - polar groups associating with one another, hydrocarbon chains forming hydrophobic barners to the external environment and an internal, "hydrophobic" compartment - to contain a water soluble pharmaceutical agent within the bi-layer and an insoluble pharmaceutical agent in the interior compartment.
The present invention utilizes multiple pharmaceutical agents, which may be soluble or insoluble in nature. These pharmaceutical agents may include prescription or OTC pharmaceuticals, health supplements-vitamins, minerals, prohormones, homeopathic formulas, antioxidants, cofactorsandlor other nutritional and natural products or combination of these.
Certain materials, when combined in accordance with the present invention to form a water-in-oil microemulsion, give enhanced absorption capabilities. In a preferred embodiment, these materials may constitute a hydrophobic material, composed of long chain fatty acids or esters or alcohols thereof, a hydrophilic material composed primarily of water, and a surfactant, primarily of the non-ionic block copolymer type.
In a preferred embodiment the hydrophobic material comprises long chain carboxylic acids, generally containing from 4-36 carbon atoms and preferably contains at least 12 carbon atoms, most preferably 12 to 22. In some cases this carbon _'J-chain is fully saturated and unbranched, while others contain one or more double bonds. The hydrophobic material can have saturated, unsaturated, branched or straight chain hydrocarbon chains. A few contain 3-carbon rings or hydroxyl groups.
The hydrophobic materials are not surface active. They are poorly soluble in water and the longer the acid chain and the fewer the double bonds, the lower the solubility in water. The carboxylic acid group is polar and ionized at neutral pH. This accounts for the slight solubility of short-chain acids in water. Examples of such acids are those ranging from Cl6 to C22 with up to three unsaturated bonds (also branching). Examples of saturated straight chain acids are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefinic straight chain monocarboxylic acids. Examples of these are oleic acid, gadoleic acid and enicic acid. Also useful are unsaturated (polyolefinic) straight chain monocaboxyic acids. Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Examples of long chain carboxylic acid esters include, but are not limited to, those from the group of: glyceryl monostearates; glyceryl monopalmitates;
mixtures of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate;
glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleat a and glyceryl monolinoleate; glyceryl monolinolenate;
glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglycerides;
mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide; mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide;d-alpha tocopherol polyethylene glycol 1000 succinate; mixtures of mono- and di-glyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides;
lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactylic esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of _8_ waxes; stearyl octanoate; Cl0 -C30 cholesterol/lavosterol esters;
and sucrose long chain carboxylic acid esters.
The present invention can further include a surfactant, or a mixture of two or more surfactants. A surfactant is an amphiphilic molecule consisting of a hydrophobic tail and a hydrophilic head. These molecules possess distinct regions of both hydrophilic and hydrophobic character. The hydrophobic tail can be a hydrocarbon or fluorocarbon chain of 8 to 18 carbon atoms. Surface active agents or surfactants are long chain molecules, such as soaps and detergents, which accumulate at the hydrophilic/hydrophobic(water/oil) interface and lower the surface tension at the interface. One effect of a reduced surface tension is the stabilization of the emulsions. This is because molecules with both polar and non-polar groups become oriented such that the hydrocarbon tail embeds itself into the hydrophobic material and the hydrophilic head protrudes into the hydrophilic material. In a preferred embodiment the surfactant is form the following group: polyoxyethylene sorbates, 1 S sorbitan long chain carboxylic acid esters, ethylene or propylene oxide block copolymers, polyglycolyzed glycerides, sorbitan esters of oleate, stearate, laurate or other long chain carboxylic acids, polyethylene-polypropylene glycol block copolymers, other sorbitan or sucrose long chain carboxylic acid esters, mono and diglycerides, PEG derivatives of caprylic/capric triglycerides and mixtures thereof.
In an alternative embodiment of the present invention, the surfactant may simultaneously be a hydrophobic material known as a self emulsifying agent.
Examples of the self emulsifying agent of long chain carboxylic acid esters include those from the groups of stearates, palmitates, ricinoleates, oleates, behenates, ricinolenates, myristates, laurates, caprylates, and caproates. The alcohols useful in the invention are exemplified by the hydroxyl forms of the carboxylic acids exemplified above and also stearyl alcohol. Additives to the carboxylic acid/alcohol material can be used to create a solid at room temperature. This addition affords the opportunity to make better use of enteric coatings. Examples of such additives are glycerol behenate, cetyl alcohol, stearic acid, sorbitan ester derivatives such as sorbitan stearate, sobitan is stearatea, polyethylene glycol 1000 to 6000.
Microemulsions are generally formed by adding the hydrophilic material, hydrophobic material, and surfactant to a suitable vessel and mixing. If any ingredient is a solid, it should be added to a liquid material in which it is soluble and heated to dissolve. For example, if the surfactant is a solid, and it is soluble in the hydrophobic material, then it should be dissolved completely in the liquid hydrophobic material, then followed with hydrophilic material, etc. On the other hand, if the surfactant is soluble in the hydrophilic material, then it should first be added to the hydrophilic material, dissolved completely, followed by the hydrophobic material. Suitable pharmaceuticals-usually those that are organic molecules and poorly soluble in hydrophilic media-are added with the hydrophobic material. Similarly, pharmaceuticals that are poorly soluble in hydrophobic media are added with the hydrophilic material. The micelles that result from this emulsifying process generally are non-opaque, (e.g. transparent or opalescent), have a particle size of from 200-40 nanometers. It is preferred to reduce the size of the sphere as much as possible, most preferably below 20 nanometers.
In accordance with the invention, drugs are incorporated into the microemulsions by admixture using conventional mixing devices and homogenizers used for semi-solid ointments and lotions, with agitation at speeds common to emulsified products such as creams and emulsions. Examples of common equipment employed are propeller or turbine mixers, homogenizers, colloid mills, ultrasonic mixers, microfluidizers; conventional mixers can also be employed so long as suitable vacuum is provided to prevent formation of bubbles. Monitoring and evaluation of pH, viscosity, specific gravity and aggregate sizes are necessary. In most cases the pharmaceutical agents are introduced into their respective soluble environments, (e.g. hydrophilic drug added to hydrophilic solution, hydrophobic drug added to hydrophobic solution), prior to the mixing of the soluble and insoluble solutions.
In the oil-in-water embodiment, the hydrophobic material forms the discontinuous material and the hydrophilic material forms the continuous material in which the hydrophobic material is emulsified. The oil-in-water emulsions of the invention are generally made by adding hot (70-80° C.) hydrophobic material (smaller by weight) to hot (70-80° C.) hydrophilic material (larger by weight) forcing inversion of the surface active agent to form a disperse emulsion of unaggregated, dispersed material particles. This produces an emulsion when processed under suitable shear.
In the water-in-oil embodiment, the hydrophilic material forms the discontinuous material and the hydrophobic material forms the continuous material in which the hydrophilic material is emulsified. The pharmaceutical preparation comprises a water-in-oil emulsion containing an hydrophobic material (such as a long chain carboxylic acid or ester or alcohol thereof), a surface active agent (such as poloxamer) and an hydrophilic material. The advantage of using a water-in-oil microemulsion is that it has the ability to dissolve relatively large amounts of polar solutes in an overall hydrophobic enviromnent, creating an oral delivery system for drug molecules.
One method of design is to incorporate the mixture of solutions-including all pharmaceuticals, carrier solutions, and surfactant(s)-into particles, e.g.
beads or spheres, by spray-congealing or "prilling". This process uses a spray nozzle which atomizes the material in a cooling tower or chamber. As the material is sprayed, surface tension causes a uniform spherical bead to be formed. As the bead falls through the cooling chamber, it hardens into a stable, intact sphere. The particles generally have a particle size of from 0.5 microns to 100 microns. It is preferred to reduce the size of the sphere as much as possible, most preferably below 10 microns, still allowing for multiple micelles to be packaged within a single spherical particle.
Optionally, the particles are coated with a sustained-release coating, an enteric coating, and/or other controlled-release coating to modify the rate of drug release from the particles.
Another, less preferred method of design is to microencapsulate via extrusion-sphereonization. The solution-including all pharmaceuticals, carrier solutions, and surfactant(s~is introduced into a solid-material dispersion medium which substantially equivalent solubility as the continuous material (i.e. if the hydrophobic solution forms the continuous material then it should be dissolved into a hydrophobic solid-phase dispersion medium). The solid-phase dispersion medium should be heated until a liquid-phase is achieved, at which time the solution is introduced. The medium is allowed to cool, and then is subsequently granulated, extruded, and sphereonized into particles.
Particles can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. Because of their hydrophobic nature, the particles should not need a lubricant, but one can be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.
The particles may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a tablet that can accept the particles, but will not allow their S destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (Avicel), soy polysaccharide (Emcosoy), pre-gelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-SO% (w/w).
In addition, disintegrants are added in order to disperse the particles once the tablet is ingested. Suitable disintegrants include, but are not limited to:
cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasdone-XL). These materials should be present in the range of 3-1 S% (w/w), with a preferred range of 5 10% (w/w).
Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil.
These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
Tablets are formed, for example, as follows. The particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
Capsules may be formed through standard techniques, and may or may not employ additional proprietary delivery technologies.
In an alternative embodiment, the self emulsifying compositions of the present invention can be administered in liquid form, (e.g. non-congealed), as a parenteral preparation for intra-muscular structures or intravenous pathway use. In another embodiment, bioadhesive polymers may also be added to the emulsion to promote absorption of the emulsion through mucosal surfaces by achieving mucoadhesion of the emulsion particles. Delivery to the mucosal surfaces would allow the formulation to be administered by oral, rectal, vaginal, nasal, corneal, buccal, sub-lingual, or other mucosal surface route. The bioadhesive polymer, while increasing the size of the emulsion particles to 70-300 nanometers, allows for a prolonged residence time in-situ and may be localized to a specific region to improve targeted bioavailability of delivered drugs.
In an alternative embodiment of the present invention, the present invention can be incorporated in a sustained delivery form which may include, but are not limited to, an uncoated hydrophobic particle in an enteric coated capsule; a sustained release coated particle within an enteric coated capsule or tablet; an enteric coated particle enclosed within a regular soft gelatin capsule or uncoated tablet.
This allows pH sensitive pharmaceuticals to be protected and not released in the stomach.
The types of protective or sustained release coatings that can be used include, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and esters of methacrylic and ethacrylic acid. The enteric protective materials or coatings can be, for example, cellulose acetate pthalate, hydroxypropylmethylcellulose pthalate, ethylvinylacetate pthalate, polyvinylacetate pthalate and esters of methacrylic and ethacrylic acid.
Analytical Methods An indication of the bioavailability of the pharmaceutical may be determined measuring a pharmaceutical agent's solubility in the laboratory. The dispersion of the present invention's micelles throughout the solution may be visually examined using a circular, polarized filter. Once the micelles have been determined to be sufficiently solubilized, the present invention's micelles may be treated with excess surfactant such as to suitably decrease the surface tension to allow for complete release of the pharmaceutical. UV-Vis Spectraphotomic analysis yields a measurement of the amount of pharmaceutical agent in solution.
Micelle size in the initial emulsions, (e.g. pre-spray congealing), may also be determined via photon correlation spectroscopy using a super nanosizer apparatus to analyze a diluted preparation of filtered and sonicated glycerin solution.
Particle-size analysis via light-diffraction and/or visual examination may also be conducted.
The charge on the emulsion may be determined via eletrophoretic mobility.
The expected result of which (in the water-in-oil embodiment) is the migration of micelles toward the negatively charged electrode, reflecting the positive charge of the micelles' lipid outer layer. The zeta potential may also be measured using moving boundary electrophoresis in a dilute glycerin solution.
High Performance Liquid Chromatography (HPLC) analysis plasma levels may also be performed using standard methods.
While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
The present invention provides a self emulsifying system, where an emulsion is a dispersed system containing at least two immiscible liquid material, a hydrophobic material and a hydrophilic material. The emulsion comprises the dispersed material, the dispersion material and an emulsifying agent or surfactant.
The surfactant may simultaneously be a hydrophobic material known as a "self emulsifying agent," preferably an ester, whereby it is possible to produce an emulsion without a separate emulsifying agent. One of the two immiscible liquid materials may be hydrophobic while the other is hydrophilic. Which material becomes the dispersed material depends on the relative amounts of the two liquid materials and which surfactant is selected. Therefore, an emulsion in which the hydrophobic material is dispersed as droplets throughout the hydrophilic material is called an oil-in-water emulsion. Similarly, an emulsion in which hydrophilic material is dispersed as droplets throughout the hydrophobic material is called a water-in-oil emulsion. The hydrophobic and hydrophilic materials can each independently be solid, semisolid or liquid. The pharmaceutical agent may be dispersed or incorporated into the hydrophobic material, the hydrophilic material or in both the hydrophobic and hydrophilic materials.
In a preferred embodiment the present invention comprises a water-in-oil emulsion. In an alternative embodiment the present invention comprises a oil-in-water emulsion. In addition to the two basic emulsified forms of water-in-oil or oil-in-water, another embodiment of the present invention may also possess multiple hydrophobic and hydrophilic layers in alternating emulsified stratums, such as water-in-water-in-oil, oil-in-water-in-oil, or similar combinations thereof. The present invention may include one or more surfactants present in or among the hydrophilic and hydrophobic materials, as well as one or more pharmaceutical agents present in one or more of the hydrophilic or hydrophobic materials. The advantage of a multiplicity of materials is that it allows multiple pharmaceutical agents to be S delivered at varying time intervals or in varying environments.
Depending on which specific surfactant is used, in the present invention, the dispersion of material will either be in the form of a monolayer, micelles, or bilayer vesicles. In a preferred embodiment of the present invention, micelles are formed.
In another embodiment of the present invention bilayer vesicles are formed as an alternative to miscelles.
In the bi-layer embodiment of the present invention, for example, a lipid bi-layer - consisting of surfactant arranged such that the hydrocarbon chains are associated with one another, and whose the polar groups are associated with either the aqueous exterior environment or an interior hydrophilic compartment respectively - may contain an insoluble pharmaceutical agent, while the "interior,"
hydrophilic compartment may contain a water soluble pharmaceutical agent.
Alternatively, the described bi-layer may be inverted - polar groups associating with one another, hydrocarbon chains forming hydrophobic barners to the external environment and an internal, "hydrophobic" compartment - to contain a water soluble pharmaceutical agent within the bi-layer and an insoluble pharmaceutical agent in the interior compartment.
The present invention utilizes multiple pharmaceutical agents, which may be soluble or insoluble in nature. These pharmaceutical agents may include prescription or OTC pharmaceuticals, health supplements-vitamins, minerals, prohormones, homeopathic formulas, antioxidants, cofactorsandlor other nutritional and natural products or combination of these.
Certain materials, when combined in accordance with the present invention to form a water-in-oil microemulsion, give enhanced absorption capabilities. In a preferred embodiment, these materials may constitute a hydrophobic material, composed of long chain fatty acids or esters or alcohols thereof, a hydrophilic material composed primarily of water, and a surfactant, primarily of the non-ionic block copolymer type.
In a preferred embodiment the hydrophobic material comprises long chain carboxylic acids, generally containing from 4-36 carbon atoms and preferably contains at least 12 carbon atoms, most preferably 12 to 22. In some cases this carbon _'J-chain is fully saturated and unbranched, while others contain one or more double bonds. The hydrophobic material can have saturated, unsaturated, branched or straight chain hydrocarbon chains. A few contain 3-carbon rings or hydroxyl groups.
The hydrophobic materials are not surface active. They are poorly soluble in water and the longer the acid chain and the fewer the double bonds, the lower the solubility in water. The carboxylic acid group is polar and ionized at neutral pH. This accounts for the slight solubility of short-chain acids in water. Examples of such acids are those ranging from Cl6 to C22 with up to three unsaturated bonds (also branching). Examples of saturated straight chain acids are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefinic straight chain monocarboxylic acids. Examples of these are oleic acid, gadoleic acid and enicic acid. Also useful are unsaturated (polyolefinic) straight chain monocaboxyic acids. Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Examples of long chain carboxylic acid esters include, but are not limited to, those from the group of: glyceryl monostearates; glyceryl monopalmitates;
mixtures of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate;
glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleat a and glyceryl monolinoleate; glyceryl monolinolenate;
glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglycerides;
mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide; mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide;d-alpha tocopherol polyethylene glycol 1000 succinate; mixtures of mono- and di-glyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides;
lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactylic esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of _8_ waxes; stearyl octanoate; Cl0 -C30 cholesterol/lavosterol esters;
and sucrose long chain carboxylic acid esters.
The present invention can further include a surfactant, or a mixture of two or more surfactants. A surfactant is an amphiphilic molecule consisting of a hydrophobic tail and a hydrophilic head. These molecules possess distinct regions of both hydrophilic and hydrophobic character. The hydrophobic tail can be a hydrocarbon or fluorocarbon chain of 8 to 18 carbon atoms. Surface active agents or surfactants are long chain molecules, such as soaps and detergents, which accumulate at the hydrophilic/hydrophobic(water/oil) interface and lower the surface tension at the interface. One effect of a reduced surface tension is the stabilization of the emulsions. This is because molecules with both polar and non-polar groups become oriented such that the hydrocarbon tail embeds itself into the hydrophobic material and the hydrophilic head protrudes into the hydrophilic material. In a preferred embodiment the surfactant is form the following group: polyoxyethylene sorbates, 1 S sorbitan long chain carboxylic acid esters, ethylene or propylene oxide block copolymers, polyglycolyzed glycerides, sorbitan esters of oleate, stearate, laurate or other long chain carboxylic acids, polyethylene-polypropylene glycol block copolymers, other sorbitan or sucrose long chain carboxylic acid esters, mono and diglycerides, PEG derivatives of caprylic/capric triglycerides and mixtures thereof.
In an alternative embodiment of the present invention, the surfactant may simultaneously be a hydrophobic material known as a self emulsifying agent.
Examples of the self emulsifying agent of long chain carboxylic acid esters include those from the groups of stearates, palmitates, ricinoleates, oleates, behenates, ricinolenates, myristates, laurates, caprylates, and caproates. The alcohols useful in the invention are exemplified by the hydroxyl forms of the carboxylic acids exemplified above and also stearyl alcohol. Additives to the carboxylic acid/alcohol material can be used to create a solid at room temperature. This addition affords the opportunity to make better use of enteric coatings. Examples of such additives are glycerol behenate, cetyl alcohol, stearic acid, sorbitan ester derivatives such as sorbitan stearate, sobitan is stearatea, polyethylene glycol 1000 to 6000.
Microemulsions are generally formed by adding the hydrophilic material, hydrophobic material, and surfactant to a suitable vessel and mixing. If any ingredient is a solid, it should be added to a liquid material in which it is soluble and heated to dissolve. For example, if the surfactant is a solid, and it is soluble in the hydrophobic material, then it should be dissolved completely in the liquid hydrophobic material, then followed with hydrophilic material, etc. On the other hand, if the surfactant is soluble in the hydrophilic material, then it should first be added to the hydrophilic material, dissolved completely, followed by the hydrophobic material. Suitable pharmaceuticals-usually those that are organic molecules and poorly soluble in hydrophilic media-are added with the hydrophobic material. Similarly, pharmaceuticals that are poorly soluble in hydrophobic media are added with the hydrophilic material. The micelles that result from this emulsifying process generally are non-opaque, (e.g. transparent or opalescent), have a particle size of from 200-40 nanometers. It is preferred to reduce the size of the sphere as much as possible, most preferably below 20 nanometers.
In accordance with the invention, drugs are incorporated into the microemulsions by admixture using conventional mixing devices and homogenizers used for semi-solid ointments and lotions, with agitation at speeds common to emulsified products such as creams and emulsions. Examples of common equipment employed are propeller or turbine mixers, homogenizers, colloid mills, ultrasonic mixers, microfluidizers; conventional mixers can also be employed so long as suitable vacuum is provided to prevent formation of bubbles. Monitoring and evaluation of pH, viscosity, specific gravity and aggregate sizes are necessary. In most cases the pharmaceutical agents are introduced into their respective soluble environments, (e.g. hydrophilic drug added to hydrophilic solution, hydrophobic drug added to hydrophobic solution), prior to the mixing of the soluble and insoluble solutions.
In the oil-in-water embodiment, the hydrophobic material forms the discontinuous material and the hydrophilic material forms the continuous material in which the hydrophobic material is emulsified. The oil-in-water emulsions of the invention are generally made by adding hot (70-80° C.) hydrophobic material (smaller by weight) to hot (70-80° C.) hydrophilic material (larger by weight) forcing inversion of the surface active agent to form a disperse emulsion of unaggregated, dispersed material particles. This produces an emulsion when processed under suitable shear.
In the water-in-oil embodiment, the hydrophilic material forms the discontinuous material and the hydrophobic material forms the continuous material in which the hydrophilic material is emulsified. The pharmaceutical preparation comprises a water-in-oil emulsion containing an hydrophobic material (such as a long chain carboxylic acid or ester or alcohol thereof), a surface active agent (such as poloxamer) and an hydrophilic material. The advantage of using a water-in-oil microemulsion is that it has the ability to dissolve relatively large amounts of polar solutes in an overall hydrophobic enviromnent, creating an oral delivery system for drug molecules.
One method of design is to incorporate the mixture of solutions-including all pharmaceuticals, carrier solutions, and surfactant(s)-into particles, e.g.
beads or spheres, by spray-congealing or "prilling". This process uses a spray nozzle which atomizes the material in a cooling tower or chamber. As the material is sprayed, surface tension causes a uniform spherical bead to be formed. As the bead falls through the cooling chamber, it hardens into a stable, intact sphere. The particles generally have a particle size of from 0.5 microns to 100 microns. It is preferred to reduce the size of the sphere as much as possible, most preferably below 10 microns, still allowing for multiple micelles to be packaged within a single spherical particle.
Optionally, the particles are coated with a sustained-release coating, an enteric coating, and/or other controlled-release coating to modify the rate of drug release from the particles.
Another, less preferred method of design is to microencapsulate via extrusion-sphereonization. The solution-including all pharmaceuticals, carrier solutions, and surfactant(s~is introduced into a solid-material dispersion medium which substantially equivalent solubility as the continuous material (i.e. if the hydrophobic solution forms the continuous material then it should be dissolved into a hydrophobic solid-phase dispersion medium). The solid-phase dispersion medium should be heated until a liquid-phase is achieved, at which time the solution is introduced. The medium is allowed to cool, and then is subsequently granulated, extruded, and sphereonized into particles.
Particles can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. Because of their hydrophobic nature, the particles should not need a lubricant, but one can be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.
The particles may also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a tablet that can accept the particles, but will not allow their S destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (Avicel), soy polysaccharide (Emcosoy), pre-gelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-SO% (w/w).
In addition, disintegrants are added in order to disperse the particles once the tablet is ingested. Suitable disintegrants include, but are not limited to:
cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasdone-XL). These materials should be present in the range of 3-1 S% (w/w), with a preferred range of 5 10% (w/w).
Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil.
These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).
Tablets are formed, for example, as follows. The particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.
Capsules may be formed through standard techniques, and may or may not employ additional proprietary delivery technologies.
In an alternative embodiment, the self emulsifying compositions of the present invention can be administered in liquid form, (e.g. non-congealed), as a parenteral preparation for intra-muscular structures or intravenous pathway use. In another embodiment, bioadhesive polymers may also be added to the emulsion to promote absorption of the emulsion through mucosal surfaces by achieving mucoadhesion of the emulsion particles. Delivery to the mucosal surfaces would allow the formulation to be administered by oral, rectal, vaginal, nasal, corneal, buccal, sub-lingual, or other mucosal surface route. The bioadhesive polymer, while increasing the size of the emulsion particles to 70-300 nanometers, allows for a prolonged residence time in-situ and may be localized to a specific region to improve targeted bioavailability of delivered drugs.
In an alternative embodiment of the present invention, the present invention can be incorporated in a sustained delivery form which may include, but are not limited to, an uncoated hydrophobic particle in an enteric coated capsule; a sustained release coated particle within an enteric coated capsule or tablet; an enteric coated particle enclosed within a regular soft gelatin capsule or uncoated tablet.
This allows pH sensitive pharmaceuticals to be protected and not released in the stomach.
The types of protective or sustained release coatings that can be used include, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and esters of methacrylic and ethacrylic acid. The enteric protective materials or coatings can be, for example, cellulose acetate pthalate, hydroxypropylmethylcellulose pthalate, ethylvinylacetate pthalate, polyvinylacetate pthalate and esters of methacrylic and ethacrylic acid.
Analytical Methods An indication of the bioavailability of the pharmaceutical may be determined measuring a pharmaceutical agent's solubility in the laboratory. The dispersion of the present invention's micelles throughout the solution may be visually examined using a circular, polarized filter. Once the micelles have been determined to be sufficiently solubilized, the present invention's micelles may be treated with excess surfactant such as to suitably decrease the surface tension to allow for complete release of the pharmaceutical. UV-Vis Spectraphotomic analysis yields a measurement of the amount of pharmaceutical agent in solution.
Micelle size in the initial emulsions, (e.g. pre-spray congealing), may also be determined via photon correlation spectroscopy using a super nanosizer apparatus to analyze a diluted preparation of filtered and sonicated glycerin solution.
Particle-size analysis via light-diffraction and/or visual examination may also be conducted.
The charge on the emulsion may be determined via eletrophoretic mobility.
The expected result of which (in the water-in-oil embodiment) is the migration of micelles toward the negatively charged electrode, reflecting the positive charge of the micelles' lipid outer layer. The zeta potential may also be measured using moving boundary electrophoresis in a dilute glycerin solution.
High Performance Liquid Chromatography (HPLC) analysis plasma levels may also be performed using standard methods.
While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
Claims (2)
1. An emulsified pharmaceutical composition comprising:
a hydrophilic material;
a hydrophobic material;
at least one surfactant for dispersing the hydrophilic and hydrophobic material;
a hydrophilic pharmaceutical agent incorporated in the hydrophilic material;
and a hydrophobic pharmaceutical agent incorporated in the hydrophobic material.
a hydrophilic material;
a hydrophobic material;
at least one surfactant for dispersing the hydrophilic and hydrophobic material;
a hydrophilic pharmaceutical agent incorporated in the hydrophilic material;
and a hydrophobic pharmaceutical agent incorporated in the hydrophobic material.
2. A method of delivering pharmaceutical agents to a human comprising:
(a) providing a composition comprising:
(i) a hydrophilic material;
(ii) a hydrophobic material;
(iii) at least one surfactant for dispersing the hydrophilic and hydrophobic material;
(iv) a hydrophilic pharmaceutical agent incorporated in the hydrophilic material;
(v) a hydrophobic pharmaceutical agent incorporated in the hydrophobic material; and (b) delivering the composition to a predetermined one of a digestive tract, a mucosal surface, an intra-muscular structure, and an intravenous pathway of the human.
(a) providing a composition comprising:
(i) a hydrophilic material;
(ii) a hydrophobic material;
(iii) at least one surfactant for dispersing the hydrophilic and hydrophobic material;
(iv) a hydrophilic pharmaceutical agent incorporated in the hydrophilic material;
(v) a hydrophobic pharmaceutical agent incorporated in the hydrophobic material; and (b) delivering the composition to a predetermined one of a digestive tract, a mucosal surface, an intra-muscular structure, and an intravenous pathway of the human.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2325257 CA2325257A1 (en) | 2000-11-07 | 2000-11-07 | Emulsified delivery system for hydrophobic and hydrophilic pharmaceutical agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2325257 CA2325257A1 (en) | 2000-11-07 | 2000-11-07 | Emulsified delivery system for hydrophobic and hydrophilic pharmaceutical agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2325257A1 true CA2325257A1 (en) | 2002-05-07 |
Family
ID=4167570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2325257 Abandoned CA2325257A1 (en) | 2000-11-07 | 2000-11-07 | Emulsified delivery system for hydrophobic and hydrophilic pharmaceutical agents |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2325257A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021072535A1 (en) * | 2019-10-16 | 2021-04-22 | Immunovaccine Technologies Inc. | Oil-in-water emulsion formulations for delivery of active or therapeutic agents |
-
2000
- 2000-11-07 CA CA 2325257 patent/CA2325257A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021072535A1 (en) * | 2019-10-16 | 2021-04-22 | Immunovaccine Technologies Inc. | Oil-in-water emulsion formulations for delivery of active or therapeutic agents |
| CN114727957A (en) * | 2019-10-16 | 2022-07-08 | 免疫疫苗技术公司 | Oil-in-water emulsion formulations for delivery of active or therapeutic agents |
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