US20060068021A1

US20060068021A1 - Sustained-release microencapsulated delivery system

Info

Publication number: US20060068021A1
Application number: US11/249,022
Authority: US
Inventors: Eric Kuhrts
Original assignee: Individual
Current assignee: Lipoprotein Technologies Inc
Priority date: 2000-02-01
Filing date: 2005-10-11
Publication date: 2006-03-30
Also published as: WO2001056545A2; WO2001056545A3; US6953593B2; US20020098239A1; AU2001234746A1; US6689388B2; US20020086062A1

Abstract

Disclosed is a process for producing sustained-release powders that is fast, efficient, and economical. The process involves melting a naturally derived oil with a melting point above 110° F. in specially designed mixer through either the work energy input of the mixer shaft itself, or a specially fitted plow type mixer equipped with a heating tank, cooling unit, jacket for hot water circulation, and heated lines with nozzles for atomizing the hot oil to be sprayed on. The entire manufacturing process can be completed in about 5-30 minutes, and results in small, sustained-release particles that are free flowing and solid at room temperature. The preferred oil is a hydrogenated soy oil with a melting point range of 145° F. to 160° F. which is applied at about a 1% level by weight in a high shear mixer. Also included are sustained-release compositions for therapeutic agents such as drugs, botanicals, biological agents, fungicides, and fertilizers.

Description

The present application is a continuation-in-part of U.S. Pat. No. 6,953,593, issuing on Oct. 11, 2005 and filed on Feb. 1, 2000, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a sustained-release microencapsulated compositions that can be produced efficiently and result in a very high percentage of active substance at the composition core.

BACKGROUND OF THE INVENTION

The benefits of producing sustained-release formulations for drugs or other therapeutic agents is now widely recognized in the medical literature and is utilized in many commercial products. It is important to distinguish at the out-set between solid monolithic dosage forms such as tablets and powders, and particles that are loosely packed into capsules. A sustained-release powder is typically made up of microparticles that are microencapsulated using a manufacturing process that enables them to be ingested as, for example, a powdered drink-mix which can be added to a liquid and still retain its sustained-release and taste masking properties, or encapsulated in two piece hard shell gelatin capsules. Microencapsulated powders may behave differently when subjected to the high pressures required to form tablets, and may fracture in the process. In addition, sustained-release tablet formulations may employ other techniques that emanate from their large size, surface area, and/or the swelling properties of hydrocolloids. In this case, diffusion and solubility issues become significant for sustained-release profiles.
In general, sustained-release dosage forms are multi-particle formulations that, when ingested in capsule form, rapidly disintegrate into a large number of subunits. This is typically fine for drugs that are effective at relatively low doses or at dose levels that can fit into a capsule that is a reasonable size. The amount of drug that can fit into a two piece hard shell capsule that is easy for most people to swallow is about 800 mg or less, based on bulk density of the compound. However, when large doses are required, such as for example with nutraceuticals, amino acids, or botanical substances, it is often desirable to take them in a powder dosage form that can be mixed with a liquid and consumed.
There are many different ways to microencapsulate drugs producing sustained-release. Many of these methods can be found in “Microcapsules and Microencapsulation Techniques”, 1976, M. H. Goucho, and Microcapsules and other Capsules, 1979, also by M. H. Goucho. Another resource book is “Aqueous Polymeric Coatings For Pharmaceutical Dosage Forms”, 1989, Marcel Dekker, Inc. Most of the methods of producing sustained-release microparticles can be classified into either physical or chemical systems. Physical methods would include such techniques as pan coating, gravity-flow, centrifuge, and the Wurster Process. The Wurster Process employs a high velocity air stream that is directed through a cylindrical fluid bed in which the particles are suspended in the air. A coating is sprayed onto the suspended particles, and the particles flow out the top of the cylinder and descend back to the layer of fluid. The flow of air-dries the coating, so that successive layers can be applied repeatedly by further spraying. Variables that control the process include the number of cycles, temperature, pressure, and humidity, and can be used to provide the desired coating composition and thickness.
Chemical methods of microencapsulation are usually coacervation or phase separation. This technique involves dissolving the membrane forming polymer in a suitable solvent or vehicle and the drug to be dissolved is suspended in this solution and kept under agitation. The coating precipitates onto a droplet of the drug, similar to crystallization.
Fluid bed granulation or coating is one of the most common techniques used at the present time for small particle sustained-release. Fluidized bed equipment is available as “top spray,” bottom spray,” and “tangential-spray.” The core drug is first preheated in the vessel to about 30° C. with hot air, placing the particles in suspension. The floating particles are then sprayed with an aqueous suspension to provide a coating, while drying at the same time. Inlet temperature, spray rate, and air throughput must be adjusted to provide optimum end product. Furthermore, the finished particles must be subjected to a post-drying period at around 40° C., where any residual moisture can be driven off. In some case, this last drying period may be up to 24 hours.
Many of the polymers that are used to provide sustained-release properties to powders in the fluid bed process require solvents such as acetone, isopropyl alcohol, chlorinated solvents, alkanes, methyl ethyl ketone, cyclohexane, toluene, carbon tetrachloride, chloroform, and the like. Evaporation of the solvents becomes an environmental concern, and in many states, it is illegal to release these emissions into the atmosphere. Aqueous or water based polymers are limited mainly to ethyl cellulose and methacrylic acid esters such as poly methacrylate dispersions. In addition, 10-20% of a suitable plasticizer such as triethyl citrate must be added to the polymer. For example, U.S. Pat. No. 5,603,957 uses a solvent-based polymer system to deliver aspirin over a 24-hour period. Preferred solvents are acetone/alkanol mixtures, or cyclohexane, toluene, or carbon tetrachloride. Castor oil, a low melting point oil, is also included in the polymer solvent mix.
Typical aqueous ethyl cellulose polymers currently in wide use include Surelease®, (Colorcon, West Point, Pa.) and Aquacoat® (FMC Corporation, Philadelphia, Pa.). In the Aquacoat® brochure available on their web site, it is recommended that for sustained-release applications, at least a two hour curing time at 60° C. is conducted to insure reproducible release profiles. This should be done in a tray dryer. Subjecting drugs and other therapeutic agents to 60° C. temperatures for 2 hours or more is likely to result in a loss of potency or degradation of active principles, and is especially problematic for substances with low melting points. For example, botanical extracts have many volatile compounds that can be destroyed if kept at high temperatures for long periods.
Another polymer in common use for sustained-release applications is Eudragit® (Huls America, Somerset N.J.). This is a neutral methacrylic acid ester with a small proportion of trimethylammonioethyl methacrylate chloride. This polymer is also applied using the fluid bed process, or can be used in a standard wet granulation procedure. Wet granulation involves mixing the drug or therapeutic agent with water in a conventional high-speed mixer until a pasty mass is formed, and then drying the mass in an oven for over 24 hours at 60° C.
Wet granulations have the additional draw backs in that they can affect the potency of the therapeutic agent being encapsulated. For example, wet granulation can cause botanical extracts often lose potency or become less stable as a result of wet granulation techniques. In addition, when dried at 60° C., many sensitive active principles are lost.
Carnauba wax has also been used to produce sustained-release dosage forms. Usually, at least a 15% level of wax is applied to the drug to form an initial core, followed by a further coat of ethyl cellulose and polyvinylpyrrolidone (PVP) at about 10 to 15% by weight. This results in drug levels in the cores that range from 50 to 70%, with the other 50 to 30% being the wax and polymers.
Synthetic waxes are also available such as Syncrowax® (Croda Inc., Parsippany, N.J.). These triglyceride waxes have properties similar to carnauba wax, and have melting points of 60° C. to 75° C.
Another method of producing sustained-release particles is by starting with sugar spheres or nonpareils. The sugar spheres are also processed in a fluid bed granulator, but the drug must be dissolved in an aqueous solution and sprayed onto the sugar spheres. The sugar spheres are then spray coated with polymers that produce sustained-release particles. This system results in large particles that are not acceptable in most drink mix applications. Another drawback is that botanical extracts cannot be sufficiently dissolved to allow for this effective use of the system. The therapeutic agent needs to be absorbed into the sugar particle. The smallest starting particle size for non-pareils is about 60 mesh (US standard sieve number). After coating, the particles are often 30 mesh and larger. The large particle size also presents a problem when encapsulating or tableting.
Another technique is melt-spinning. Melt spinning techniques involve subjecting a therapeutic agent to sustained heat treatment with a melted polymer which is pumped at a constant rate under high pressure through a plate having a number of small holes, referred to as a spinneret. Filaments emerge from the spinnerets into air where they are cooled. These filaments are made into sustained-release formulations. In this process, a polymer is melted on a hot grid or by extrusion-type screw, and then passed to a metered pump. U.S. Pat. Nos. 5,445,769 and 5,458,823 describe the use of a melt-spinning technique called a liquiflash spheronization or liquiflash microspheres. Temperatures as high as 130° C. to 240° C. are often required in this process. In addition, the polymers for the final coats are dissolved in solvents such as acetone and sprayed onto the microspheres in a fluidized bed apparatus with a Wurster column.
U.S. Pat. No. 5,700,471 involves subjecting an aqueous dispersion of a drug or dye to turbulent mixing at a temperature that is above the melting point of the dye or drug, producing a melt emulsion which is then spray dried or converted into a suspension by cooling.
A hot melt technique is described in U.S. Pat. No. 5,718,921 in which a polymer is dissolved in a volatile organic solvent, and the drug is dispersed or dissolved in the polymer solution. The mixture is then suspended in an organic oil, and the organic solvent is extracted into the oil, creating microspheres. In this process, silicon oil, vegetable oil, paraffin, and mineral oil are used. These are all low melting point oils.
U.S. Pat. No. 4,855,326 discloses combining sugar with low melting point oils such as vegetable oil, baby oil, margarine, cocoa butter and the like to help over come hydrophobic properties and facilitate dispersion in water. None of the oils are solid at room temperatures or have high melting points. The oils themselves are not providing sustained-release properties.
In another process, ethyl cellulose, polyvidone and a small amount of castor oil are dissolved in acetone and isopropanol and sprayed onto aspirin particles in a fluid bed granulator such as is described in U.S. Pat. No. 5,603,957. In this case the oil is liquid at room temperatures, and is being used as a plasticizer. The polymers are providing the sustained-release properties, not the oil. Castor oil itself cannot be used as a solid coating material because of its low melting point.
Research has continued in an effort to develop a microencapsulation technique that is quick, inexpensive, yields high concentrations of active agent in the core, and does not require the use of solvents.

DETAILED DESCRIPTION OF THE INVENTION

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
The singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a naturally derived oil” includes one or more naturally derived oil and reference to “the therapeutic agent” includes reference to one or more therapeutic agents.
As used herein, the term “naturally derived oil” or “naturally occurring oil” refer to oils obtained from animal, plant, or vegetable sources as well as mixtures thereof.
As used herein, the term “core material” refers to the encapsulated portion of in the microencapsulated particles of the present invention.
As used herein, the term “processing solvent” refers to solvents that are often used to dissolve or disperse components of sustained release compositions during the preparation of the microencapsulated particles per se. Even if dried, these processing solvents can remain present in residual amounts in the final composition. In accordance with embodiments of the present invention, by mixing core materials with naturally derived oils without using processing solvents, microencapsulated particles can be formed that are free of processing solvents introduced during microencapsulation. For clarity, solvents that may be used to form core materials for use in the microencapsulation process described herein are not considered to be processing solvents in accordance with the present invention, as they are not used for microencapsulation per se.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc.
This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
In accordance with embodiments of the present invention, a microencapsulation process can comprise adding a core material and a naturally derived oil having a melting point above 110° F. into a high shear mixer; mixing the core material and the naturally derived oil until microencapsulated particles are formed in the high shear mixer, wherein the microencapsulated particles comprise the core material and the naturally derived oil and being formed without dissolving or dispersing the core material or naturally derived oil with solvent; and collecting the microencapsulated particles as a powder directly from the high shear mixer.
In another embodiment, a solid sustained-release pharmaceutical composition can comprise a microencapsulated core material that is microencapsulated by a naturally derived oil having a melting point above 110° F. The naturally derived oil can be present in an amount of 0.25% to 50% by weight of the microencapsulated particles. In this embodiment, the composition can be free of processing solvent, even in residual amounts.
In another embodiment, a solid sustained-release pharmaceutical composition can comprise a microencapsulated core material that is microencapsulated by a naturally derived oil having a melting point above 110° F., wherein the naturally derived oil is present in an amount of 0.25% to 3% by weight of the microencapsulated particles.
In accordance with these and other embodiments, the present invention provides a sustained-release microencapsulation process that can be produced inexpensively and quickly and result in a very high percentage of active substance in the core. One advantage of the instant invention is that it does not necessitate the use of solvents or synthetic polymers, although polymers can be used as an additional means of control if desired. A further advantage of the present invention is that the process does not require extremely high temperatures to produce the microspheres, and can shorten the length of time the materials are processed or exposed to elevated temperatures. In the present invention, the drug particles are processed in a way to yield a high percentage of active component powder that is still small enough to be virtually indistinguishable from the original drug particles themselves. Surprisingly, drug cores having 99.75% of the active agent are possible that release over a prolonged period.
As mentioned, the present invention relates to a process for manufacturing pharmaceutical formulations that result in sustained-release microencapsulated particles, as well as certain compositions per se. These microencapsulated particles release a therapeutic agent gradually in a consistent fashion over a prolonged period of time, and can be manufactured in a way to yield a high percentage of an active agent core at a very economical cost. The process consists of heating and mixing naturally derived oil having a very high melting point with a therapeutic agent or drug until the agent or drug is well coated, and then cooling to room temperature until hard. The resultant particles are small, free flowing, and exhibit release profiles that can be adjusted to extend from 6-24 hours, for example. Other fibers, sugars, or polymers can be added in layers as an outer coat after cooling to affect the release profile and the hydrophobic properties of the particles, or directly to the matrix to accelerate drug release by creating additional channels for diffusion during erosion while dissolving. Other substances such as minerals can be added to the cores to provide additional weight to the particles causing them to sink due to heaviness.
In accordance with the invention, there is provided a microsphere that is produced by mixing the therapeutic agent with a naturally derived oil with a melting point at least above 110° C., and preferably about 140° F., in a vertical or horizontal high intensity schear mixer until the particles of the core substance are thoroughly mixed with the oil, and then cooling the hot melt to produce fine particles that exhibit excellent sustained-release properties. Surprisingly, the entire process can be completed in about 20 minutes or less in a jacketed high intensity mixer to melt the oil and intimately mix it with the core agent. The ideal high temperature melting point oil for this process is a hydrogenated vegetable oil such as hydrogenated soy oil, cottonseed oil, or stearic acid. The melting point ranges are from 140° F. to 165° F. Such an oil with these specifications is Dritex S® in flake form or Sterotex HM® which is a spray chilled, powder. Both are available from AC Humko, Memphis Tenn. The melting point profile is more uniform if the spray chilled powder is used.
Alternatively, a non-hydrogenated vegetable oil such as fractionated palm oil can be used. Such oil is a refined vegetable oil of non lauric origin derived from palm fruit, and is not hydrogenated. The typical Iodine value of this type of oil is about 14, and another beneficial property of this oil is that it contains less than 1% trans fatty acids. The melting point of this oil is about 65° C.
The apparatus that is used to manufacture the powder can be a Littleford vertical or horizontal high intensity mixer (LittleforDay, Florence Ky.), or a standard Hobart type mixer or plow mixer that is jacketed with a hot water bath. If the Littleford high intensity shear mixer is used, the oil or fat is melted by circulating hot water or steam in the jacket while mixing. The unique mixing action of the auger shaft revolving at a high rate of speed causes the particles to fluidize in free space, providing a high volume rate of material transfer throughout the entire length of the vessel. This results in the mixing, blending and melting of the oil with the other core materials all in the same process and within minutes. The vessel is jacketed so it can be kept at the melting point temperature of the oil. In addition, the vessel can be fitted with high speed impact choppers to enhance mixing and or drying. After processing this way, the material is cooled and discharged as a free flowing powder.
If desired, the molten oil can be sprayed on from a heating tank fitted with heated insulated lines using a tower-mounted, hydraulic atomizing nozzle. If sprayed onto the core material, the work input is not needed to melt the oil because it is already melted, and less shear is needed. This results in less compaction of the particles because more shear results in harder particles. In some cases this may be desirable for shorter release profiles. Surprisingly, the high shear mixer with good compaction of the oil/core particles can result in sustained-release profiles that span over hours with only a 0.25% to 3% by weight oil level. In other words, 97% to 99.75% of the powder is the core material. This sustained-release powder is of fine particle size and exhibits excellent flow properties, and may be used as a food additive, incorporated into a powdered drink mix, or manufactured into solid dosage forms.
While oils have been used in various sustained-release formulations, they are not usually used as the coating material encapsulated substance nor are they usually the primary material that is providing the barrier to gastric erosion. Most of the oils used are liquid or soft at room temperature making their use for encapsulation ineffective and undesirable.
Oils such as low melting point vegetable oil, castor oil, baby oil, margarine, cocoa butter, paraffin, and the like have been used in the pharmaceutical industry for a variety of purposes, but not as sustained-release agents. For example, soft oils are often used for suppositories. These oils cannot be used to provide solid particles at room temperature. Various resins and shellac have also been used, but usually not for sustained-release. Carnauba wax is widely used in pharmaceutical dosage forms.
An oil, such as a stearic acid with a melting point above 120° F., is solid at room temperature. Oils or fats with a melting points above 140° F. allow melting to occur only at temperatures that are significantly above those temperatures normally encountered by food or pharmaceutical products, even during shipment on hot days. Another oil is Sterotex HM®, manufactured by AC Humko, Memphis Tenn. Sterotex is a spray chilled hydrogenated soy oil that completely melts at about 160° F. This oil is completely solid at lower temperatures, and is commercially available as a powder. Other oils of similar melting points are also available, but are usually sold as a solid mass, and can require that it be chiseled or chipped apart, and therefore are difficult to use and weigh out. Some oils are available in flake form such as Dritex S also from AC Humko. Both Dritex S and Sterotex HM are preferable to the solid mass hydrogenated soy oils. However, any oil with a melting point above about 110° F. can be used in the present invention. The most desirable oils are those with melting points from 120° F. to 200° F., and most preferably with melting points from about 120° F. to 180° F. These melting points are usually below the melting point of most drugs or therapeutic compounds, and are readily achievable using the equipment described herein.
Naturally derived oils such as palm oil, soy oil, other vegetable oils, or combinations thereof are the most preferred types of oils. These oils are physiologically acceptable and are appealing to health conscious consumers and in turn to producers of health related products. One example of a naturally derived oil is Stearic acid. Stearic acid is an oil that is derived from either animal or vegetable sources and has a melting point of about 158° F. USP stearic acid is primarily a mixture of stearic and palmitic acids and is commercially available.
The core material used in the present invention compositions may be selected from any suitable drug, therapeutic or prophylactic agent, food or botanical substance, fertilizer, or animal feed, which can be incorporated in the hot melt without losing substantial activity for the chosen therapy. A broad range of materials are therefore useful.
Examples of specific therapeutic agents which may be used as the core material in the present invention include but are not limited to the following: acetaminophen, acetic acid, acetylsalicylic acid and its buffered form, albuterol and its sulfate, alcohol, alkaline phosphatase, allantoin, aloe, aluminum acetate, carbonate, chlorohydrate, hydroxide-alprozolam, amino acids, aminobenzoic acid, arnoxicillin, ampicillin, ansacrine, amsalog, anethole, ascorbic acid, aspartame, aspirin, atenolol, bacitracin, balsam peru, BCNU (carmustine) beclomethasone dipropionate, benzocaine, benzoic acid, benzophenones, benzoyl peroxide, bethanechol, biotin, bisacodyl, bomyl acetate, bromopheniramine maleate, buspirone, caffeine, calamine, calcium, calcium carbonate, casinate and hydroxide, camphor, captopril, cascara sagrada, castor oil, cefaclor, cefadroxil, cephalexin, cetylalcohol, cetylpyridinium chloride, chelated minerals, chloramphenicol, chlorcyclizine hydrochloride, chlorhexidine gluconate, chloroxylenol, chloropentostatin, chlorpheniramine maleate, cholestyramine resin, choline bitartrate, chondrogenic stimulating protein, cimetidine hydrochloride, cinnamedrine hydrochloride, citalopram, citric acid, cocoa butter, cod liver oil, codeine and codeine phosphate, clonidine and its hydrochloride salt, clorfibrate, cortisone acetate, ciprofloxacin HC I, cyanocobalamin, cyclizine hydrochloride, danthron, dexbrompheniranime maleate, dextromethorphan hydrobromide, diazaparn, dibucaine, diclofenac sodium, digoxin, diltiazem, dimethicone, dioxybenzone, diphenhydramine citrate, diphenhydramine hydrochloride, docusate calicurn, potassium and sodium, doxycycline hyclate, doxylamine succinate, efaroxan, enalpril, enoxacin, erythromycin, estropipate, ethinyl estradiol, ephedrine, epinephrine bitartrate, erythropoictin, eucalyptol, ferrous fiamarate, gluconate and sulfate, folic acid, fosphenytoin, 5-fluorouracil (5-FU) fluoxetine HCI, furosemide, gabapentan, gentamicin-gemfibrozil, glipizide, glycerin, glyceryl stearate, griseofulvin, growth hormone, guaifenesin, hexylresorcinol, hydrochlorothiaxide, hydrocodone bitartrate, hydrocortisone and its acetate, 8- hydroxyquinoline sulfate, ibuprofen, indomethacin, inositol, insulin, iodine, ipecac-, iron, isoxicam, ketarnine, koalin, lactic acid, lanolin, lecithin, leuprolide acetate, lidocaine and its hydrochloride salt, lifinopril, liotrix, lovastatin, luteinizing hormone, LHRH (luteinizing hormone releasing hormone),-magnesium carbonate, hydroxide, salicylate, trisilocate, mefenamic acid, meclofenanic acid, meclofenamate sodium, medroxyprogesterone acetate, methenamine mandelate, menthol, meperidine hydrochloride, metaproterenol sulfate, methyl nicotinate, methyl salicylate, methylcellulose, methsuximide, metronidazole and its hydrochloride, metoprolol tartrate, miconazole nitrate, mineral oil, minoxidil, morphine, naproxen and its sodium salt, nifedipine, neomycin sulfate, niacin,_niacinamide, nicotine, nicotinamide, nitroglycerin, nonoxynol-9, norethindone and its acetate, nystatin, octoxynol, octoxynol 9, octyl dimethyl PABA, octyl. methoxycinnamate, omega-3 polyunsaturated fatty acids, orneprazole, oxolinic acid, oxybenzone, oxtriphylfine, para-aminobenzoic acid (PABA), padimate 0, paramethadione, pentastatin, peppermint oil, pentaerythriol tetranitrate, pentobarbital sodium, pheniramine maleate, phenobarbital, phenol, phenolphthalein, phenylephrine hydrochloride, phenylpropanolamine and its hydrochloride salt, phenytoin, phenelzine sulfate, pirmenol, piroxicam, polymycin B sulfate, potassium chloride and nitrate, prazepam, procainamide hydrochloride, procaterol, propoxyphene and its HC I salt, propoxyphene napsylate, pramiracetin, pramoxine and its hydrochloride salt, propronolol HC I, pseudoephedrine hydrochloride and sulfate, pyridoxine, quinapril, quinidine gluconate and sulfate, quinestrol, ralitoline, ranitadine, resorcinol, riboflavin, salicylic acid, sesame oil, shark liver oil, simethicone, sodium bicarbonate, citrate and fluoride, sodium monofluorophosphate, sucralfate, sulfanethoxazole, sulfasalazine, sulfur, tacrine and its FIC I salt, theophylline, terfenidine, thioperidone, trimethrexate, triazolam, timolol maleate, tretinoin, tetracycline hydrochloride, tolmetin, tolnaftate, triclosan, triprolidine hydrochloride, undecylenic acid, vancomycin, verapamil HC I, vidaribine phosphate, vitamins A, B, C, D, B I, B2, B 6, B12, E, K, witch hazel, xylometazoline hydrochloride, zinc, zinc sulfate, zinc undecylenate. Mixtures of these agents and their salts used for appropriate therapies are also contemplated
Useful dosage forms include without limitation oral forms such as tablets, capsules, drink mix powders, beads, granules, aggregates, powders, gels, solids, semi-solids, and suspensions. Injectable forms, lotions, transdermal delivery systems including dermal patches, implantable forms or devices, aerosols or nasal mists, suppositories, salves and ointments are also useful.
The inventive compositions have great versatility in their application. The compositions can be used for wound management such as by direct application to burns, abrasions, skin diseases or infections and the like. Other uses such as packing agents for nasal wounds or other open wounds are also contemplated.
In certain preferred embodiments, an amino acid like substance such as L-arginine, or L-camitine, sports supplements such as creatine monohydrate, or a vitamin such as niacin or vitamin C may be used as the core material. Examples of botanical substances which can be used as core materials in the present invention include but are not limited to garlic powder and grape polyphenols. Other botanical substances which can be used as core materials in the present invention include tocotrienols and co-enzyme Q-10. Anti-histamines such as loratadine can also be used as the core material particularly when it is desirable to have a 24 hour release profile. The core material can also be a stimulant such as caffeine or blood pressure medication. Additional examples of core materials which can be used in accordance with the present invention include fertilizers and fungicides. Slow release of fertilizers and fungicides in the soil is especially desirable for nitrogen containing formulas. In a sustained-release microcapsule, the nitrogen fertilizer tends not to leach out of the soil when wet.
Examples of classes of additives include but are not limited to excipients, lubricants, hydrocolloid suspending agents, buffering agents, disintegrating agents, stabilizers, foaming agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, etc.
A variety of additives can be incorporated into the inventive compositions depending on their intended functions. These additives are usually used in small amounts. One example of an additive are hydrocolloids which can be used as suspending agents, as for example in a powdered drink mix that is reconstituted in liquid. Other useful additives include but are not limited to gelatin, vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, rape seed proteins, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, gum arabic, and related gums (gum ghatti, gum karaya, gum tragacanth), pectin; water-soluble derivatives of cellulose, alkylcelluloses, hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxpropylmethylceflulose, hydroxbutylmethylceflulose, cellulose esters and hydroxyalkylceRulose esters such as: cellulose acetate phthalate (CAP), carboxyalky I celluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethyl cellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone (PVP), PVP/vinyl acetate copolymer, and polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates possessing, for example, a tertiary or quaternary amino group, such as the diethylan-finoethyl group, which may be quaternized if desired; and other similar polymers.
Processing aids such as sucrose, polydextrose, maltodextrin, lactose, maltose, and the like may also be used in the present invention. Where accelerated release is desired, a sugar may be incorporated into the hot melt. Since the oil coating is hydrophobic, incorporating a hydrophilic sugar in the hot melt helps counteract the tendency of the encapsulated microparticles to float. The sugar also helps to increase the rate of release of the core material by providing solubility to the matrix. Other substances such as calcium carbonate or other minerals can be added to provide weight to the particles and affect the release profile.

EXAMPLES

Example 1

About 200 KG of creatine monohydrate is added to a 600 liter Littleford high speed mixer, which is capable of operating at high temperatures because it is jacketed with a second layer to allow hot water to flow around the vessel. A high speed chopper operating at 10 hp is fitted at the discharge point. 0.5% weight % hydrogenated soy oil flakes (Dritex S®, AC Humko, Memphis, Tenn.) with a melting point of about 80′ C. or 140° F. to 160° F. are added to the vessel. Efficient coating or microencapsulation of the powder can be achieved in about 20 minutes when a temperature of about 155° F. is reached and the hot oil is thoroughly mixed with the powder. Cooling can be achieved by discharging the batch into a cooler mounted directly below the mixer. The resulting granules are small, free flowing, and exhibit sustained-release properties when a dissolution test is conducted. The weight percent of the creatine monohydrate in the finished product is 99.5%, and the weight percent of the hydrogenated soy oil is 0.5%.

Percent of

Time points Creatine

(hours) Released

1 60%

2 76.2%

4 82%

6 84%

Example 2

The amino acid L-arginine free base, is charged to a Littleford W- 10 high shear mixer with a hot water jacket to allow circulating hot water to keep the vessel hot. Stearic acid is added to equal 1% by weight. The work input is increased to 2000 RPM and is then adjusted down to about 600 RPM for 5 minutes. The high shear of the mixer melts the oil and mixes with the core ingredients. The powder is discharged into a cooler mounted below the unit. The resulting particles are small, powder like, free flowing, and exhibit excellent sustained-release properties with an 8 hour release profile at only a 1% by weight of oil.

Example 3

Creatine monohydrate is charged to a Littleford high shear mixer with calcium carbonate (5% by weight) and sucrose (10% by weight) and is mixed at 1000 RPM. Sterotex HM® hydrogenated soy oil is added at a 5% level and the speed of rotation is increased to 2000 RPM to melt the oil, and is then decreased to maintain the power draw to within the allowable motor amperage. Unexpectedly, after 3-5 minutes the oil is fully melted and mixed with the core materials, and upon inspection, the batch is fully granulated. The powder is discharged into the cooling unit and appears as a fine granular, free flowing sustained-release powder.

Dissolution Test



	Creatine monohydrate	80%
	Sucrose	10%
	Calcium Carbonate	5%
	Hydrogenated soy oil (Sterotex HM ®)	5%



	Time Points	Percent
	(Hours)	Released

	1	46%
	2	63%
	3	78%
	4	85%
	5	100%

Example 4

Creatine monohydrate is charged to a Littleford high shear mixer with calcium carbonate (5% by weight) and sucrose (10% by weight) and is mixed at 1000 RPM. A non-hydrogenated palm oil is added to make up 3% by weight and the speed of rotation is increased to 2000 RPM to melt the oil, and then decreased to maintain the power draw to within the allowable motor amperage. After 3-5 minutes the oil is fully melted and is mixed with the core materials. Upon inspection, the batch is fully granulated. The powder can be discharged into the cooling unit and appears as a fine granular, free flowing sustained-release powder.

Example 5

Vitamin C is charged to a Littleford high shear mixer with calcium carbonate (5% by weight) and sucrose (10% by weight) and is mixed at 1000 RPM. A non-hydrogenated palm oil is added to make up 40% by weight and the speed of rotation is increased to 2000 RPM to melt the oil, and then decreased to maintain the power draw to within the allowable motor amperage. After 3-5 minutes the oil is fully melted and is mixed with the core materials. Upon inspection, the batch is fully granulated. The powder is discharged into the cooling unit and appears as a fine granular, free flowing sustained-release powder.
While the present invention is described above in connection with the preferred or illustrative embodiments, those embodiments are not intended to be exhaustive or limiting of the invention, but rather, the invention is intended to cover any alternatives, modifications or equivalents that may be included within its scope as defined by the appended claims.

Claims

1. A microencapsulation process comprising:

a) adding a core material and a naturally derived oil having a melting point above 110° F. into a high shear mixer,

b) mixing the core material and the naturally derived oil until microencapsulated particles are formed in the high shear mixer, said microencapsulated particles comprising the core material and the naturally derived oil and being formed without dissolving or dispersing the core material or naturally derived oil with solvent; and

c) collecting the microencapsulated particles as a powder directly from the high shear mixer.

2. The process of claim 1, wherein no classification step is performed during the microencapsulation process.

3. The process of claim 1, wherein the naturally derived oil is an plant oil, vegetable oil, animal oil, combinations thereof.

4. The process of claim 1, wherein the naturally derived oil is a non-hydrogenated oil.

5. The process of claim 1, wherein the core material comprises ace-inhibitors, anti-anginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrhea preparations, anti-histamines, anti-hypertensive drugs, anti-infectives, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-tussives, anti-uricernic drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anabolic drugs, analgesics, anesthetics, angiogenesis inhibitors, antacids, antiarthritics, antibiotics, anticoagulants, antiemetics, antiobesity drugs, antiparasitics, antipsychotics, antipyretics, antispasmodics, antithrombotic drugs, anxiolytic agents, appetite stimulants, appetite suppressants, beta blocking agents, bronchodilators, cardiovascular agents, cerebral dilators, chelating agents, cholecystokinin antagonists, chemotherapeutic agents, cognition activators, contraceptives, coronary dilators, cough suppressants, decongestants, deodorants, dermatological agents, diabetes agents, diuretics, emollients, enzymes, erythropoietic drugs, expectorants, fertility agents, fungicides, gastro-intestinal agents, growth regulators, hormone replacement agents, hyperglycemic agents, hypnotics, hypoglycernic agents, laxatives, migrain treatments, mineral supplements, mucolytics, narcotics, neuroleptics, neuromuscular drugs, NSAIDS, nutritional additives, peripheral vaso-dilators, polypeptides, prostaglandins, psychotropics, renin inhibitors, respiratory stimulants, steroids, stimulants, sympatholytics, thyroid preparations, tranquilizers, uterine relaxants, vaginal preparations, vaso-constrictors, vago-dilators, vertigo agents, vitamins, wound healing agents, botanical substances, fungicides, or fertilizers.

6. The process of claim 1, wherein the animal or vegetable oil is a vegetable oil with a melting point from 110° F. and 200° F.

7. The process of claim 1, wherein the animal or vegetable oil is a vegetable oil with a melting point from 135° F. to 165° F.

8. The process of claim 1, wherein the oil is present in the microencapsulated particles at from 0.25% to 50% by weight.

9. The process of claim 1, wherein the oil is present in the microencapsulated particles at from 0.25% to 3% by weight.

10. The process of claim 1, wherein the oil is present in the microencapsulated particles at from 0.25% to 20% by weight.

11. The process of claim 1, wherein a high shear mixer includes a heated jacket, and wherein said heated jacket heats the mixer sufficiently to melt the naturally derived oil.

12. The process of claim 1, wherein a sugar or mineral is mixed with the core material and the naturally derived oil in the high shear mixer.

13. The process of claim 12, wherein the sugar is present in the microencapsulated particles at from 1% to 30% by weight.

14. The process of claim 12, wherein the sugar is present in the microencapsulated particles at from 5% to 20% by weight.

15. The process of claim 12, wherein the sugar is selected from the group consisting of sucrose, dextrose, lactose, polydextrose, maltodextrin, and maltose.

16. The process of claim 12, wherein the mineral is present in the microencapsulated particles at from 1% to 20% by weight.

17. The process of claim 12, wherein the mineral is present in the microencapsulated particles at from 5% to 10% by weight.

18. The process of claim 12, wherein the mineral is calcium carbonate.

19. A solid sustained-release pharmaceutical composition, comprising a microencapsulated core material that is microencapsulated by a naturally derived oil having a melting point above 110° F., and wherein the naturally derived oil is present in an amount of 0.25% to 50% by weight of the microencapsulated particles, said composition being free of processing solvent.

20. The composition of claim 19, wherein the composition is in an oral dosage form.

21. The composition of claim 19, wherein naturally derived oil in the microencapsulated particles present at from 0.25% to 3% by weight.

22. The composition of claim 19, wherein naturally derived oil in the microencapsulated particles present at from 0.25% to 20% by weight.

23. The composition of claim 19, wherein the naturally derived oil has a melting point between 110° F. to 200° F.

24. The composition of claim 19, wherein the naturally derived oil has a melting point from 120° F. to 180° F.

25. The composition of claim 19, wherein the naturally derived oil has a melting point of about 160° F.

26. The composition of claim 19, wherein the naturally derived oil is a vegetable oil.

27. The composition of claim 19, wherein the naturally derived oil is a non-hydrogenated palm oil with a melting point range from 140° F. to 160° F.

28. The composition of claim 19, wherein the core material is selected from the group consisting of a drug, a nutritional agent, a botanical substance, a biological substance, a fungicide, a fertilizer, and mixtures thereof.

29. The composition of claim 19, wherein the core material comprises ace-inhibitors, anti-anginal drugs anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrhea preparations, anti-histamines, anti-hypertensive drugs, anti-infectives, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-tussives, anti-uricernic drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anabolic drugs, analgesics, anesthetics, angiogenesis inhibitors, antacids, antiarthritics, antibiotics, anticoagulants, antiemetics, antiobesity drugs, antiparasitics, antipsychotics, antipyretics, antispasmodics, antithrombotic drugs, anxiolytic agents, appetite stimulants, appetite suppressants, beta blocking agents, bronchodilators, cardiovascular agents, cerebral dilators, chelating agents, cholecystokinin antagonists, chemotherapeutic agents, cognition activators, contraceptives, coronary dilators, cough suppressants, decongestants, deodorants, dermatological agents, diabetes agents, diuretics, emollients, enzymes, erythropoietic drugs, expectorants, fertility agents, fungicides, gastro-intestinal agents, growth regulators, hormone replacement agents, hyperglycemic agents, hypnotics, hypoglycernic agents, laxatives, migrain treatments, mineral supplements, mucolytics, narcotics, neuroleptics, neuromuscular drugs, NSAIDS, nutritional additives, peripheral vaso-dilators, polypeptides, prostaglandins, psychotropics, renin inhibitors, respiratory stimulants, steroids, stimulants, sympatholytics, thyroid preparations, tranquilizers, uterine relaxants, vaginal preparations, vaso-constrictors, vago-dilators, vertigo agents, vitamins, or wound healing agents.

30. The composition of claim 19, wherein the core material is selected from the group consisting of niacin, L-arginine, creatine monohydrate, L-camitine, aspirin, loratidine, lovastatin, vitamin C, garlic powder, grape polyphenols, tocotrienol, co-enzyme Q-10 and mixtures thereof.

31. A solid sustained-release pharmaceutical composition, comprising a microencapsulated core material that is microencapsulated by a naturally derived oil having a melting point above 110° F., and wherein the naturally derived oil is present in an amount of 0.25% to 3% by weight of the microencapsulated particles.

32. The composition of claim 31, wherein the composition is in an oral dosage form.

33. The composition of claim 31, wherein the naturally derived oil has a melting point between 110° F. to 200° F.

34. The composition of claim 31, wherein the naturally derived oil has a melting point from 120° F. to 180° F.

35. The composition of claim 31, wherein the naturally derived oil has a melting point of about 160° F.

36. The composition of claim 31, wherein the naturally derived oil is a vegetable oil.

37. The composition of claim 31, wherein the naturally derived oil is a non-hydrogenated palm oil with a melting point range from 140° F. to 160° F.

38. The composition of claim 31, wherein the core material is selected from the group consisting of a drug, a nutritional agent, a botanical substance, a biological substance, a fungicide, a fertilizer, and mixtures thereof.

39. The composition of claim 31, wherein the core material comprises ace-inhibitors, anti-anginal drugs anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrhea preparations, anti-histamines, anti-hypertensive drugs, anti-infectives, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-tussives, anti-uricernic drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anabolic drugs, analgesics, anesthetics, angiogenesis inhibitors, antacids, antiarthritics, antibiotics, anticoagulants, antiemetics, antiobesity drugs, antiparasitics, antipsychotics, antipyretics, antispasmodics, antithrombotic drugs, anxiolytic agents, appetite stimulants, appetite suppressants, beta blocking agents, bronchodilators, cardiovascular agents, cerebral dilators, chelating agents, cholecystokinin antagonists, chemotherapeutic agents, cognition activators, contraceptives, coronary dilators, cough suppressants, decongestants, deodorants, dermatological agents, diabetes agents, diuretics, emollients, enzymes, erythropoietic drugs, expectorants, fertility agents, fungicides, gastro-intestinal agents, growth regulators, hormone replacement agents, hyperglycemic agents, hypnotics, hypoglycernic agents, laxatives, migrain treatments, mineral supplements, mucolytics, narcotics, neuroleptics, neuromuscular drugs, NSAIDS, nutritional additives, peripheral vaso-dilators, polypeptides, prostaglandins, psychotropics, renin inhibitors, respiratory stimulants, steroids, stimulants, sympatholytics, thyroid preparations, tranquilizers, uterine relaxants, vaginal preparations, vaso-constrictors, vago-dilators, vertigo agents, vitamins, or wound healing agents.

40. The composition of claim 31, wherein the core material is selected from the group consisting of niacin, L-arginine, creatine monohydrate, L-carnitine, aspirin, loratidine, lovastatin, vitamin C, garlic powder, grape polyphenols, tocotrienol, co-enzyme Q-10 and mixtures thereof.