MXPA01004774A - Method and apparatus for liposome production - Google Patents

Abstract

A new method of producing liposomes is described using an in-line mixing system. The liposomes produced by this method find utility in numerous therapeutic applications.

Description

METHOD AND APPARATUS FOR THE PRODUCTION OF LIPOSOMES BACKGROUND OF THE INVENTION Technical Field The present invention relates to a formulation for the delivery of a variety of beneficial and / or therapeutic compounds by encapsulation within the liposomes and a machine of unique design for controlled production thereof. Specifically, the invention relates to a precisely controlled measuring system for mixing two or more components of the liposomal preparations so that the various factors affecting the consistency, reproducibility and efficacy of the product can be monitored and controlled. The present invention also relates to a method and apparatus for the production of liposomal suspensions, emulsions, ointments and creams. Background Liposomes are lipid vesicles made from membrane-like lipid bilayers separated by aqueous layers. Liposomes have been widely used to biologically encapsulate active agents for use as drug vehicles since lipid-soluble substances or water can be trapped within the aqueous layers or within the bilayers themselves. There are numerous variables that can be adjusted to optimize this drug delivery system. These include the number of lipid layers, size, surface charge, lipid composition and preparation methods. Liposomes have been used in numerous pharmaceutical applications, including injectable, inhalation, oral and topical formulations and provide advantages such as controlled or sustained release, improved drug delivery and reduced systemic side effects as a result of localization of the supply. The materials and methods for forming liposomes are well known to those skilled in the art and will only be briefly described herein. Once the dispersion is in an appropriate medium, a wide variety of phospholipids dilate, hydrate and form concentric bilayer multilamellar vesicles with layers of aqueous media separating the lipid bilayers. These systems are referred to as multilamellar liposomes or multilamellar lipid vesicles ("MLVs") and have diameters in the range of 10 nm to 100 μm. These MLVs were first described by Bangham et al., J. Mol. Bi ol. 13: 238-252 (1965). In general, lipid or lipophilic substances are dissolved in an organic solvent. When the solvent is removed, such as under vacuum by rotary evaporation, the lipid residue forms a film on the wall of the container. An aqueous solution which typically contains biologically active electrolyte or hydrophilic materials is then added to the film. Large MLVs are produced by agitation. When smaller MLVs are desired, large vesicles are subjected to sonication, sequential filtration through filters with decreasing pore size or reduced by other forms of mechanical cutting. There are also techniques by which MLVs can be reduced in both size and number of lamellae, for example, by pressurized extrusion (Barenholz et al., FEBS Le tt. 99: 210-214 (1979)). The liposomes can also take the form of unilamellar vesicles, which are prepared by more extensive sonication of the MLVs and consist of a single spherical lipid bilayer surrounding an aqueous solution. Unilamellar vesicles ("ULVs") can be small, having diameters in the range of 20 to 200 nm, while larger ULVs can have diameters in the range of 200 nm to 2 μm. There are numerous well-known techniques for making unilamellar vesicles. In Papahadj opoulos et al., Bi ochim e t Bi ophys Ac ta 135: 624-238 (1968), the sonication of an aqueous dispersion of phospholipids produces small ULVs having a lipid bilayer surrounding an aqueous solution. The US Patent of Schneider 4, 089,801, discloses the formation of liposome precursors by ultrasonication, followed by the addition of an aqueous medium containing amphipathic compounds and centrifugation to form a biomolecular bilayer lipid system. Small ULVs can also be prepared by the ethanol injection technique described by Batzri et al., Bi ochim et Bi ophys Ac ta 298: 1015-1019 (1973) and the ether injection technique of Deamer et al Bi ochim et Bi ophys Acta 443: 629-634 (1976). These methods comprise the rapid injection of an organic solution of lipids into a buffer solution, which results in the rapid formation of unilamellar liposomes. Another technique for making ULVs was taught by eder and collaborators in "Liposome Technology" ed. G. Gregoriadis, CRC Press Inc., Boca Raton, Florida, Vol. I, Chapter 7, pp. 79-107 (1984). This detergent removal method comprises solubilizing the lipids and additives with detergents by stirring or sonication to produce the desired vesicles. U.S. Patent of Papahadj opoulos et al 4,235,871, describes the preparation of large ULVs by a reverse phase evaporation technique comprising the formation of a water-in-oil emulsion of lipids in an organic solvent and the drug to be encapsulated in an aqueous buffer solution. The organic solvent is removed under pressure to produce a mixture that is converted to long ULVs by agitation or dispersion in an aqueous medium. US Patent Suzuki et al No. 4,016,100 discloses another method of encapsulating agents in unilamellar vesicles by freezing / thawing an aqueous phospholipid dispersion of the agent and the lipids. In addition to MLVs and ULVs, liposomes can also be multifilaments. Described in that of Kim and collaborators Bi ochim e t Bi ophys Ac ta 728: 339-348 (1983), these multifocal liposomes are spherical and contain internal granular structures. The outer membrane is a lipid bilayer and the internal region contains small compartments separated by a bilayer septum. Still another type of liposomes are oligolamellar vesicles ("OLVs"), which have a large central compartment surrounded by several peripheral lipid layers. These vesicles, which have a diameter of 2-15 μm, are described in Callo et al., Cryobiology 22 (3): 251-267 (1985). The US Patents of Mezei et al. Nos. 4,485,054 and 4,761,288 also describe methods for the preparation of lipid vesicles. More recently, US Patent No. 5,653,996 to Hsu describes a method for the preparation of liposomes using aerosolization and US Patent No. 5,013,497 to Yioumas et al. Describes a method for the preparation of liposomes using a high speed shear mixing chamber. . Methods that use specific starting materials to produce ULVs (US Patent of Wallach et al. No. 4,853,228) or OLVs (US Patents of Wallach Nos. 5,474,848 and 5,628,936) are also described. An extensive review of all mentioned lipid vesicles and methods for their preparation in "Liposome Technology", ed. G.

Gregoriadis, CRC Press Inc., Boca Raton, Florida, Vol. I, II & III (1984). This and the referenced references that describe various lipid vesicles suitable for use in the invention are incorporated herein by reference. Current methods of liposome preparation are typically discontinuous processes. Large-scale or continuous manufacturing attempts have been largely unsuccessful mainly due to the problems associated with the mixing of an aqueous liquid phase with a lipid phase and the need to maintain the lipid phase at a relatively constant temperature. Accordingly, there is a need for an improved method for the production of liposomes, preferably one that can produce liposomes in a continuous mode, rather than by discontinuous methods without the variations and uncontrolled differences which make the production of large liposomal preparations problematic. scale. In addition, there is a need for an improved method and apparatus for producing other liquid compositions, including but not limited to emulsions, ointments and creams. Those needs are satisfied by the present invention.

SUMMARY OF THE INVENTION The present invention relates to a method for the continuous production of a composition of matter, such as lipid vesicles by in-line mixing, the method comprising: (a) preparing a first phase, such as a lipid phase and storing the lipid phase in a first storage medium that is maintained at a set temperature; (b) preparing a second phase, such as an aqueous phase and storing the aqueous phase in a second storage medium which is maintained at a set temperature; (c) combining the lipid and aqueous phases by means of a mixing device having first and second measuring systems, a pre-mixing system and a mixer, such as a static mixer, by: transferring the lipid phase from the first storage means to the first measurement system by means of a first pressurized transfer medium and transferring the aqueous phase from the second storage means to the second measurement system by means of a second pressurized transfer medium; transferring the lipid phase from the first measurement system to a first inlet in the pre-mixing system by means of a third pressurized transfer medium and transferring the aqueous phase from the second measurement system to a second inlet in the system of pre-mixing by means of a fourth pressurized transfer medium; wherein the lipid phase and the aqueous phase are transferred to the premixing system with a high velocity producing turbulent flow; combining the lipid and aqueous phases in the pre-mixing system by shearing mixing under conditions to ensure that the lipid phase is fully hydrated by the aqueous phase to form a pre-mixed formulation; and transferring the pre-mixed formulation from an exit orifice of the pre-mixing system to the mixer, such as by means of a fifth pressurized transfer medium or other suitable connection or accessory; (d) forming a mixed formulation comprising lipid vesicles, in the mixer to cause the premixed formulation to pass through the mixer; (e) optionally measuring the optical properties of the lipid vesicles; and (f) distributing the mixed formulation from the mixer in a storage chamber, in means for further modification of the properties of the lipid vesicles or in packaging means of the mixed formulation. In a second aspect, the invention relates to lipid vesicles and other compositions of matter produced by the method of the invention. In yet another aspect, the invention pertains to a method of producing compositions such as lipid vesicles using an in-line mixing system, wherein an active agent is encapsulated in either the aqueous core of the lipid vesicles within the lipid bilayer. of the lipid vesicles or both. In still another aspect the invention relates to active agents encapsulated in lipid vesicles produced by the method of the invention. Another aspect of the invention pertains to an apparatus for the continuous production of a composition of matter such as lipid vesicles by in-line mixing, the apparatus comprising: (a) a first phase, such as a lipid phase, capable storage media maintaining a set temperature and a first pressurized transfer medium to transfer the lipid phase from the storage medium; (b) a second phase, such as an aqueous phase, storage media capable of being maintained at a set temperature and a second pressurized transfer medium for transferring the aqueous phase from the storage medium; (c) a mixing device comprising: a first measuring system for receiving the lipid phase from the first pressurized transfer medium; a second measuring system for receiving the aqueous phase from the second pressurized transfer medium; a pre-mixing system for preparing a premixed formulation, having a pre-mixing chamber; a third pressurized transfer medium for transferring the lipid phase from the first measurement system to a first entry port in the pre-mixing system and a fourth pressurized transfer medium for transferring the aqueous phase from the second measurement system to a second entry hole in the pre-mixing system; a mixer such as a static mixer, for preparing a mixed formulation comprising lipid vesicles, having a mixing chamber and an optional means for determining the optical properties of the mixed formulation; a fifth pressurized transfer medium or other suitable connection or accessory for transferring the pre-mixed formulation from the outlet orifice of the pre-mixing system to the mixing chamber; and an optional means for applying ultrasonic energy to the pre-mixing chamber, the mixing chamber or both of the chambers; and (d) a distribution medium for transferring the mixed formulation from the mixing chamber to a storage chamber or to a medium for further modification of the properties of the lipid vesicles or to a packing medium of the mixed formulation. In another aspect, the invention relates to liposomes produced by the apparatus of the invention. Still another aspect of the invention relates to the use of the method and apparatus described herein for the preparation of emulsions and the emulsions produced thereby. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic illustration of the invention. Figure 2 is a cut-away side view of one embodiment of the invention. Figure 3 is a plan view of the embodiment shown in Figure 2. Figure 4 illustrates one embodiment of the measurement system of the invention. Figure 5 is a cross-sectional view of a metering pump taken along line 5-5 of Figure 4. Figure 6 illustrates one embodiment of a manifold. Figure 7 is a cross-sectional view of a manifold, taken along line 7-7 of Figure 6. Figure 8 is a cross-sectional view of a manifold, taken along the line 8- 8 of Figure 7. Figure 9 is a side view in section separated from another embodiment of the invention. Figure 10 is a plan view of the embodiment shown in Figure 9. Figure 11 is a partial cross-section of one embodiment of the pre-mixing system. Figure 12 illustrates another embodiment of a manifold. Figure 13 illustrates a rear view of the manifold of Figure 12. Figure 14 illustrates a front view of a metering pump that engages the manifold of Figure 12. Figure 15 is a cross-sectional view of a manifold, taken at along line 15-15 of Figure 12. Figure 16 is a cross-sectional view of a manifold, taken along line 16-16 of Figure 12. Figure 17 is a cross-sectional view of a manifold, taken along line 17-17 of Figure 12. Figures 18 and 19 illustrate the control panels for the invention. Figure 20 illustrates the bottom view of an energy distribution module. DESCRIPTION OF THE INVENTION The apparatus and method of the present invention allows the flexible adaptation of various methods of producing lipid vesicles and other compositions of matter in a small space with a single device that can use a variety of methodologies and production techniques according to it is ordered by the particular requirements of the product formula, any active agent incorporated in the composition and the application for which the final product is intended. For purposes of illustration only, the method and apparatus of the invention will be described for the production of lipid vesicles. However, the product and other compositions such as emulsions, ointments and creams are also contemplated by the invention. Typically, an active agent is encapsulated in either the aqueous core or liposomes within the lipid bilayer of the liposomes or both, by dissolving or dispersing the agent in an organic solvent containing lipid. However, the invention also contemplates the preparation of lipid vesicles that do not contain any active agent. Such empty liposomes are commonly used in cosmetic preparations and may be required as a placebo material in clinical trials of therapeutic formulations. As used herein, the term "active agent" includes biologically active agents and is used to mean any molecule that acts as a beneficial or therapeutic compound, when administered to an animal, so as to avoid or alleviate a disease, prevent or relieves a disease state or treats a disease in an animal, particularly a mammal, more particularly a human, and includes: preventing the disease from occurring in a subject who may be predisposed to the disease but who has not yet been diagnosed as having has; inhibit the disease, i.e. prevent its development; or relieve the disease, i.e. cause the regression of the disease. Examples of the active agents that are included for illustration and not for limitation are anti-inflammatory agents; anti-cancer and anti-tumor agents; anti-microbial and anti-viral agents, including antibiotics; anti-parasitic agents; vasodilators; bronchodilators, antiallergic and anti-asthmatic agents; peptides, proteins, glycoproteins and lipoproteins; carbohydrates; receivers; growth factors; hormones and steroids; neurotransmitters; analgesics and anesthetics; narcotics catalysts and enzymes; vaccines; genetic material such as DNA. Although, the products of the invention are particularly well suited for pharmaceutical use, they are not limited to that application and can be designed for food use, use for agriculture, for imaging applications and so on. Accordingly, the term "active agent" is used more broadly to refer to any chemical or material that is desired to be applied, administered or used in a liposome formulation and may include by way of illustration and not limitation, pesticides, herbicides, cosmetics, agents and perfumes, food supplements, including vitamins and minerals, flavorings and other food additives, imaging agents, dyes, fluorescent labels, radio labels, plasmids, vectors, viral particles, toxins, catalysis and so on. The term "filler" is used herein to include active agents as defined above, along with any other ingredients that may be desirable to add to the product, such as, by way of illustration and not limitation, diagnostic markers that include radioetched tags. , dyes, quimiluminiscent markers and fluorescent; Contrast media; auxiliary image formation; and so on. The charge can be a solid, liquid or gas. Various phospholipids are useful in the preparation of lipid vesicles, particularly those selected from the group consisting of phosphatidyl clolines, 1 isofosfat idyl clolins, phosphatidyl serines, phosphatidyl ethanolamines and phosphatidyl inositols. Particularly suitable phospholipids are natural phospholipids such as phospholipids based on soybean oil, for example the phosphatidylcholines, Phospholipon®90H, 80H, 90G and 80G (American Lecithin Company, Oxford, Connecticut) and Lecinol (Nikken). The phospholipids can be modified using a modifying agent such as a cholesterol, stearylamine or tocopherol. The solvent is then evaporated, usually under reduced pressure, to produce a thin lipid film containing the active agent. The lipid film is then hydrated, with agitation, using an aqueous phase containing any desired electrolyte and lipid vesicles containing the active agent that was produced. The invention relates to a method and apparatus for producing a very reproducibly consistent, continuous and continuously variable output stream, composed of liposomes in the form of multilamellar lipid vesicles ("MLVs"), unilamellar lipid vesicles ("ULVs"). ) or oligolamellar vesicles ("OLVs") containing encapsulated active agents. As used herein, the terms "liposome" and "lipid vesicle" are used interchangeably and are proposed to include MLVs, ULVs and OLVs. The design of the equipment described herein is proposed to allow the constant monitoring of several factors that affect the size, distribution, structure, number and efficiency of drug encapsulation of the vesicles thus produced. The methods and embodiments described herein are typically capable of producing liposomal formulations at the rate of about 10 to 200 liters / hour, preferably 25 to 100 liters / hour. It should be understood that these rates are merely illustrative of the rates achievable by the method and apparatus described herein. Lower rates may be desirable under certain circumstances and higher rates may be achieved by standard optimization techniques, as they are well known in the art, both of which are encompassed by the invention. The MLVs, ULVs and OLVs produced by the state of the art methods, tend to include a wide distribution of sizes and shapes as well as a wide range of load volumes. Frequently, liposomal preparations include a substantial proportion of carrier vesicles without charge. The invention consists of several innovations proposed to monitor consistently and controllably and optimize the production of MLVs, ULVs and OLVs carriers of charge i.e. provided for encapsulation efficiency higher than the state of the methods of the art with highly reproducible results. The present invention pertains to an apparatus useful for the continuous production of a composition of matter by in-line mixing. In one embodiment of the invention, the apparatus comprises a first phase of storage means capable of being maintained at a set temperature and a first pressurized transfer means for transferring the first phase from the storage means together with a second phase of storage media. storage capable of being maintained at a set temperature and a second pressurized transfer medium for transferring the second phase from the storage means. In a preferred embodiment, the first phase is a lipid phase (optionally containing an active agent) and the second phase is an aqueous phase. The storage medium of the lipid phase is capable of being maintained at a set temperature by a first temperature control means, typically within the range of about 20 to 75 ° C. Similarly, the storage medium of the aqueous phase is capable of being maintained at a set temperature, by a second temperature control means, typically within the range of about 20 to 75 ° C. In one embodiment of the invention, the storage means of the lipid phase and the aqueous phase are equipped with a means for replenishing the lipid and aqueous phases continuously. In this way, the storage means function as a means of temperature stabilization in such a way that the lipid and aqueous phases are continuously fed to the storage measure, where the temperature of each phase is stabilized before being introduced into the media. of pressurized transfer that leaves each respective storage container. The apparatus also has a mixing device comprising a first measuring system for receiving the lipid phase from the first pressurized transfer medium, a second measuring system for receiving the aqueous phase from the second pressurized transfer medium, a pre-mixing system, and mixed to prepare a pre-mixed formulation, a third pressurized transfer medium for transferring the lipid phase from the first measurement system to a first inlet in the pre-mixing system and a fourth pressurized transfer medium to transfer the aqueous phase from the second measurement system to a second inlet in the pre-mixing system. The pre-mixing system comprises a pre-mixing chamber having a first and second inlet orifice. In one embodiment of the invention, the pre-mixing system further comprises a means for creating turbulence in the aqueous phase before entering the premixing chamber. The apparatus also has a mixer, such as a static mixer for preparing a mixed formulation comprising lipid vesicles, having a mixing chamber and an optional means for determining the optical properties of the mixed formulation, a fifth pressurized transfer medium for transferring the premixed formulation from the outlet orifice of the pre-mixing system to the mixing chamber or other suitable connection or fitting; and an optional means for applying ultrasonic energy to the pre-mixing system, the mixing chamber or both. In a preferred embodiment, the optical properties of the mixed formulations are measured with the medium to determine the optical properties of the mixed formulation, being configured in order to control the first and second temperature control means and the first and second measurement systems . Typically, the means for determining the optical properties will be in the form of an optical detector consisting of a light source such as an incandescent bulb, light emitting diode or other suitable apparatus that emits light, which is placed on one side of the camera with transparent parallel windows. A detector such as a photocell, phototransistor or photoresistor is placed on the other side of the camera opposite the light source. The purpose of the optical detector is to generate a signal or value, such as a resistance or voltage that will vary linearly in correlation with the opacity, transparency or other optical properties of the product, which vary with time, temperature, concentration and flow rates of the components of the lipid and aqueous phases. The signal thus derived, generated or measured, can then be used to activate transfer media, controls, pumps, motors, heaters and so on, through an interactive computer system, to maintain, alter or adjust the properties of the product with greater precision. The signal can also be used to control and direct the flow of the product either to a storage chamber, a means for packaging or to a waste receptacle, if for example, the product fails to meet the desired specifications. One embodiment of the optical detector may include a diode that emits UV light that is absorbed by a specific active agent. In this way, when the active agent is detected, the flow of the product is directed to a medium for packaging; if the active agent is absent or present in an undesirable quantity, the product flow can be directed towards a waste receptacle or the operation can be stopped in order to allow the evaluation and correction of any problem. The apparatus and method of the invention provide lipid phase and aqueous phase streams that are as unstimulated as possible and maintained at a constant pressure. This is achieved by the precise metering systems described herein, each of which is provided with a pump that operates under positive pressure and in such a manner so as to provide an accurate volumetric delivery. The mixer is preferably a static mixer, such as an in-line laminar division type mixer. The mixer may have a means for controlling the temperature of the mixing chamber, which typically is within the range of about 20 to 80 ° C. In addition, the mixer may also have a means for controlling the degree and rate of mixing within the mixing chamber. The mixing device of the apparatus may also have a means for controlling the temperature within the open space of the mixing device, which also typically falls within the range of about 20 to 80 ° C. Finally, the apparatus has a distributor means for transferring the mixed formulation from the mixing chamber to a storage chamber. This embodiment of the apparatus is particularly useful for the production of lipid vesicles and more particularly, lipid-lamellar vesicles. The apparatus of the invention is easily evaluated for its particular suitability for preparing lipid vesicles having a pre-specified composition and configuration. Typically, two measurements are used to evaluate a method of making lipid vesicles: the encapsulated mass, the amount of encapsulated material / lipid amount (material weight / lipid weight); and the volume captured, the amount of encapsulated aqueous phase / amount of the lipid in vesicles (aqueous volume / weight of the lipid). In another embodiment, the apparatus also has a means for homogenization or sonication that is located between the distribution means and the storage chamber. This latter mode is particularly useful for the production of unilamellar lipid vesicles. The apparatus may also have additional storage media for additional liquid phases such as a second lipid phase, a mixture of the lipid phase-pre-mixed aqueous phase and / or a phase of pre-formed lipid vesicles. In operation, the apparatus of the invention typically operates under pressures in the range of about 10 to 90 psia, more commonly about 40-80 psia. It should be understood that the apparatus and method of the invention does not necessarily operate under constant pressure and the actual pressure will vary between the components of the apparatus. The fluid flow rate of the lipid phase is usually about 3-200 cm3 / sec, more commonly 4 to 80 cm3 / sec. The fluid flow rate of the aqueous phase is usually about 5-300 cm3 / sec, more commonly about 10 to 100 cm3 / sec. The flow rate of the fluid in the various stages of the process and within the various components of the apparatus is determined by the initial flow rate such that the flow rate of the lipid and aqueous phases remain constant and the flow rate of the Mixed streams will be cumulative of incoming lipid and water rates. The fluid flow rate of the lipid phase is typically slower than that of the aqueous phase and will depend on the desired composition of the product, i.e., the mixed formulation, but will normally be about 20-30% of the aqueous phase. Therefore, for example, for a flow rate of the aqueous fluid of about 20 cm3 / sec one can select a lipid fluid flow rate of about 6 cm3 / sec which will then be provided for a combined phase flow rate of about 26 cm3 / sec. The dispensing means of the apparatus may have a means for controlling the rate at which the formulation is transferred from the mixing chamber into the storage chamber which may be part of the packaging machine. These rate control means maintain the rate at which the mixed formulation is transferred. In yet another preferred embodiment of the invention, each measurement system contained within the apparatus has a precise metering pump and a manifold. Each pump and manifold has a plurality of inlet and outlet means, wherein each pump inlet means communicates with a manifold outlet means and each pump outlet means communicates with a manifold inlet means. The manifold, together with having a plurality of inlet and outlet means, also has a manifold outlet orifice and a manifold inlet orifice. In operation, the inlet orifice of a first manifold is in communication with the first pressurized transfer medium and the outlet orifice of a first manifold is in communication with the third pressurized transfer medium, the inlet orifice of a second The collector is in communication with the second pressurized transfer medium and the outlet orifice of a second collector is in communication with the fourth pressurized transfer medium. The term "in communication with" is proposed to mean connections such as: an input means which is configured in order to adapt within an output means (or vice versa) an input means which is placed immediately adjacent to an output means and an inlet means which is connected to an outlet means by means of conduits, pipes or other suitable conduits that allow the flow of fluid and so on. The various embodiments of the method and apparatus of the invention should be understood with reference to the figures. Figure 1 is a schematic illustration of one embodiment of the apparatus of the invention for the production of compositions such as lipid vesicles, particularly MLVs and also illustrates the method by which the liposomal formulation is produced. The apparatus 10 has individual means for storing each component of the formulation, each component being stored at a set temperature. The storage means are illustrated in Figure 1 as containers or containers 12 and 14 which store the components of the formulation at specific temperatures, which are controlled by temperature controls 16 and 18. For example, a container may contain the lipid or phase similar to the lipid and the other container may contain an aqueous phase, either one of which may contain one or more of the active agents or other charge. It should be understood, however, that although only two containers are illustrated, the invention is not limited to that number and any number of storage means may be used and the actual number will vary depending on the number of components in the formulation. For example, a third container or container can be used to add an additional lipid phase component to the formulation. Such additional lipid phase would be added, for example, to facilitate the incorporation of one or more different active ingredients encapsulated separately or another form of phospholipid with a higher or lower melting point that would alter the properties of the mixture and could be added concurrently with, in advance or following the addition of the primary lipid phase to the aqueous phase in the pre-mixing system by means of an additional metering pump and a point where it could be introduced either before or after or simultaneously with the other streams . Similarly, an additional container (and metering pump) can be used to add a previously prepared two phase mixture, for example, to incorporate a second or third active agent in the formulation and would be added either simultaneously with, in advance or following the addition of the primary lipid phase to the aqueous phase in the pre-mixed chamber. The storage means useful in the method of the invention are typically containers, containers or tanks of any suitable configuration and can be made of any material that resists any temperature and pressure requirement and does not react with the components stored therein. Typically the materials include, by way of illustration and not limitation, stainless steel, glass, suitable plastics, fluoropolymers, etc. The storage means may be large enough to store a sufficient amount of components in order to allow the production of a specific amount of the formulation. On the other hand, the storage means 12 and 14 can function as medium-current storage containers that are continuously replenished from an external source such as such a large container, (not shown) as the components to be distributed. In that form, the amount of components stored within means 12 and 14 will remain relatively constant throughout the production cycle. The storage means may vary in size depending on the individual needs of the process to be executed, however, typically they will contain from 0.5 to 15 liters, preferably from 1 to 1.5 liters, more preferably approximately 1.5 liters for a system that is not replenished from a external source and from 0.5 to 10 liters, preferably from 1 to 5 liters, more preferably approximately 5 liters for a system that is replenished from an external source. As indicated above, it is desirable to maintain the components of the formulation at set temperatures that are controlled by the temperature controls 16 and 18. Those temperature controls can be commercially available separate controllers such as can be obtained from Omega Engineering, Inc. (Stanford , CT), programs that run on a computer or controllers of flow-controlled scale type and so on. The lipid and aqueous phases are typically maintained at a temperature within the range of 20-80 ° C. However, it may be desirable to maintain a slightly higher temperature for the lipid phase component. For example, a preferred range for the lipid phase could be about 55 to 65 ° C, more preferably about 60 ° C, while the corresponding temperature for the aqueous phase component would be within the range of about 50 to 60 ° C. C, more preferably about 55 ° C. The optimum differential temperature would be determined by the formulation itself and the characteristics of the desired product. Each component is supplied to the mixing device 20 by pressurized transfer means 22 and 24, each of which is fitted within a precise metering system 26 and 28 to control the amount of material transferred from the storage means to the mixing device. Each measurement system would typically comprise a pump, together with a manifold to control the pump's outlet and inlet in order to eliminate any pressure pulsation of the component stream that interferes with the precise mixing rates necessary for consistent product quality. . The mixing device 20 has a pre-mixing system such as a pre-mixer 29 having a pre-mixing chamber 30, wherein the individual components, i.e. the lipid phase and the aqueous phase are introduced under pressure by pressurized transfer means 23 and 25. The pressurized transfer means 22 and 24 transfer the components of the formulation from their respective containers 12 and 14, to the precise measurement systems 26 and 28. The pressurized transfer means 23 and 25 then transfer the formulation to the pre-mixing chamber 30. The mixing device may also be provided with means not shown to establish a gradient between the two component streams. It is critical that the lipid and aqueous phases are transferred to the pre-mixing system at sufficient rates so that turbulent flow is created in the pre-mixed chamber in order to provide shear mixing and to ensure that the lipid phase is hydrated. completely by the aqueous phase. For example, the lipid phase can be introduced into the aqueous phase by means of a hypodermic sized tube concentrically centered in the center of the tube carrying the aqueous phase. The interface between the two phases is such that the friction between the internal lipid stream and the external aqueous stream creates laminar turbulence and turbulence currents that will initiate the interfacial mixing process. The transfer means 22, 24, 23 and 25 are typically configured as flexible tubing, stainless steel tubing or as channels in a block of suitable material and can be made of any non-corrosive, non-reactive material including, by way of example and no limitation, plastic, rubber, aluminum, stainless steel, plastics, fluoropolymers such as Teflon and polyvinylidene fluoride (PVDF), etc. The pre-mixer 29 is used to prepare a pre-mixed formulation and is designed to create a turbulent vortex in a stream of components in which the second component stream is injected through high pressure. The combined component streams are then transferred through transfer means 32 and introduced into the mixer 33 having a high-pressure, high-shear, in-line mixing chamber 34. The transfer means 32 can be of a configuration and materials such as described above for the transfer means 22, 24, 23 and 25. The transfer means 32 is preferably a relatively short accessory which serves to connect the output of the mixer with the mixer inlet or may simply be the junction of the pre-mixer outlet and the mixer inlet such as when the pre-mixer outlet is placed adjacent and communicates with the inlet of the mixer. The length of the mixing chamber 34 can be varied to control the number of laminar divisions through which the current passes. The mixer 33 is preferably a static mixer. As used herein the term "static mixer" is used to refer to a mixer whose internal chamber creates turbulence in the fluid flow by the presence of, for example, a spiral or deflected inner tub, so that the movement The currents of components through the mixer create a mixed product, without the need for any moving parts in the mixer. The suitable static mixer includes in-line laminar-division type mixers or an online static mixing device ISG (Interfacial Surface Generator), which has either an interleaved spiral split or deflection design. Commercially available static mixers that are suitable for use in the present invention include the non-motion mixers in TAH Series 70, 85, 100, 120 and 160 sold by TAH Industries, Inc. (Robbinsville, NJ) and the non-motion ISG mixer. sold by Charles Ross S Son Company (Hauppauge, NY). The mixing chamber 34 is equipped with a means 36 for controlling the temperature of the chamber. It is preferable to maintain the temperature of the mixing chamber within the range of about 20 to 80 ° C, preferably 50 to 70 ° C, more preferably about 60 ° C. The temperature control means 36 is typically a separate thermocouple, a platinum thermocouple type automatic controller, a scale type controller or a control routine that operates in a computer. The mixing chamber 34 is also equipped with means 38 for controlling the degree and proportion of mixing within the chamber. This mixing controller means 38 is typically a means for moving the transfer medium of the lipid and / or aqueous phase in and out of the chamber to adjust the insertion point for the desired degree of turbulence. A means for adjusting the angle of the transfer medium relative to the wall of the mixing chamber may also be provided to increase or decrease the rotational turbulence induced therein. After the formulation was mixed, is supplied through the dispersion means 40 which is equipped with a control means 42 to control the proportion at which the formulation is transferred from the mixing chamber 34 to the storage chamber 44. The storage chamber may be part of a packaging machine, not shown. The mixed formulation can be used as it is without the need for any solvent removal. The dispensing means 40 is typically configured as a valved sanitary outlet and can be made of any non-corrosive, non-reactive material, including, by way of example and not limitation, plastic, rubber and aluminum. The flow rate control means 42 typically operates by adjusting the rate of graduation of the motors that control the pumps as well as the dimensions of the orifices in the manifolds and controls the flow rate so that it remains within the desired range . In conjunction with the supply of all the products of the storage chamber 44, the invention also contemplates that the device be equipped with a means for diverting the output current from the chamber 34 to any of the two or more chambers or channels, providing this is a mechanism by which the product can be diverted from the primary flow to the storage chamber 44 if the detectors determine that it is below acceptable quality levels, until the detectors can stop the device. The mixer 33 is also equipped with a determination means 46, which may be one or more detectors operating by using a feedback system so that each respective detector is connected or configured so as to control the temperature control means 16 and 18 and the measuring systems 26 and 28. Such a detector can be an optical sensor for determining the optical properties of the mixture within the chamber 34 for the purpose of adjusting the temperature and the flow rate of the components for the quality optimal product. A certain degree of opacity is the indication of successful mixing. If the material develops a transparency and transmits more light than expected, this is determined by a simple photoresistor or phototransistor detector circuit and the control mechanism is introduced to divert the current and / or stop the system. Another detector can be a rheometric device or viscometer that determines the viscosity of the mixture for additional monitoring of process quality and control. Like the optical sensor, the rheometric device may also be available to control the temperature control means 16 and 18 and the measuring systems 26 and 28 in order to adjust the temperature and the flow rate of the components. The mixing device 20 can be equipped with means 48 for applying ultrasonic energy in the pre-mixing chamber 30 and / or the mixing chamber 34. The use of ultrasonic energy in the formulation of lipid vesicles is described, for example in Gersonde et al. US Patent No. 4,452,747; Huang, Bi ochemi s try 8: 344 (1969); Papahodj opoulos et al., Bi ochim Bi ophysi ca Ac ta 135: 624 (1967); Schneider, Patent of E.U. No. 4,089,801; and Hsu, Patent of E.U. No. 5,653,996, the descriptions of which are incorporated herein by reference. The purpose of the ultrasonic energy is to facilitate the formation of a desirable vesicle size and / or a distribution size. Ultrasonic energy can be applied by means of a transducer that is in direct contact with several metal surfaces of the pre-mixed chamber. Depending on the placement of the transducer in relation to the point at which the lipid phase and the aqueous phase are in contact, the application of ultrasonic energy may be used either to aid in the formulation of multilamellar liposomes or to aid in the transformation of the multivitamin vesicles. ilaminar in unilamellar vesicles of certain constricted size ranges. The process by which the large unilamellar and multilamellar vesicles can be converted to smaller multilamellar and / or unilamellar vesicles is described by Gregoriadis.

(CRC Press) supra. The multilamellar liposomes produced by the method and apparatus of the invention are typically within the range of lOnm to lOOμm and are preferably from about 0.2 to 25μm, more preferably from about 0.5 to 20μm in diameter. Preferably the small unilamellar liposomes produced by the method and apparatus of the invention are from about 20 to 200 nm in diameter, while the large unilamellar liposomes produced by the method and apparatus of the invention are from about 200 nm to 2 μm in diameter. In addition, the application of ultrasound also serves to induce more uniformity in the size and distribution of the vesicles, in relation to the frequency in which the ultrasonic energy is being transmitted. Suitable means for accomplishing this include any means for generating high frequency electrical energy, such as generators, sonicators, ultrasonic homogenizers and tissue disruptors. For example, high frequency electric power is supplied from an electric generator, then converted to ultrasonic energy or vibrations and transmitted by an ultrasonic transmitter to one or both of the mixing chambers. The mixing device 20 is also equipped with a means 50 for controlling the temperature of the apparatus, in particular for controlling the temperature of the open space surrounding the various components of the apparatus such as the transfer means, pre-mixing system and mixer. The temperature control means 50 is similar in form and function to the temperature control means 36 described above. Preferably it is for maintaining the temperature within the interior of the mixing device within the range of about 20 to 80 ° C, preferably about 50 to 70 ° C, more preferably about 60 ° C, essentially a temperature close to that of the inside of the mixing chamber 58. The components of the mixing device 20 can be enclosed in a sealed container 52, which can reproduce a "sterile room" as is necessary for example in the production of pharmaceuticals. The container 52 could be likened to the inlet 54 and outlet 56 valves as a method of sterilizing and sanitizing the entire exterior surfaces of the components contained therein such as the measuring systems and the premixer and the components of the mixer such as their chambers. respective, together with the inner surface of the same container. The vapor, ethylene oxide or liquid sterilants are suitable for use as sterilization or sanitizing agents to be supplied by the inlet valve 54 and subsequently removed by the outlet valve 56. The device 20 could also be equipped with cleaning means 58 by means of which the interior of the components contained therein such as the measuring system and pre-mixing and mixing chambers could be cleaned by introducing heated cleaning agents such as chlorhexidine, sodium hypochlorite, soaps, detergents, mixtures of ethanol in water and so on. The apparatus 10 can also be equipped with heating / cooling means 60 placed on the outside of the mixing device 20. The delivery means 40 can be configured to extend beyond the periphery of the mixing device and adapted with such heating / cooling means. , which can be configured as a jacket surrounding the supply means that has a cold or hot fluid flowing inside. A slight modification of the schematic illustration of Figure 1 provides another embodiment of the apparatus of the invention for the production of liposomes, and is particularly suitable for the production of ULVs. After the formulation is mixed in the chamber 34, it is supplied through the supply means 40 and control means 42. However, before going to a storage chamber or packaging machine, the formulation is subjected to homogenization in high pressure line or sonication, thereby causing the vesicles to shrink or cause them to agglomerate, resulting in a uniform size . After this process is complete, the formulation is then directed to the storage chamber or packaging machine. One embodiment of the invention is illustrated in Figures 2 and 3, where Figure 2 is an exploded side view and Figure 3 is a plan view. The apparatus 100 has four main parts: individual means for storing each component of the formulation 112 and 114, a sealed container 152 enclosing the various parts of the mixing device and an open box 70 which maintains the control elements as will be described below . The large container 112 would typically be for storing a first liquid phase, such as an aqueous phase component, and the small container 114 would typically be used to store a second liquid phase, such as a lipid phase component. It is desirable to store each component at a set temperature and this is easily accomplished by means of temperature controls. The temperature control 118 that controls the temperature of the container 114 is shown in Figure 2. The temperature control 118 could be a separate thermocouple-based controller that is available for example from Omega Engineering, Inc. and could be connected to the source energy 172, for example an electrical output. Each component is supplied to the mixing device 120 by the pressurized transfer means 122 and 124, each of which is adapted with an accurate measurement system 126 and 128 to control the amount of material transferred from the storage medium to the chamber of mixing 130. The measuring system 128 is shown in Figure 2 as comprising an accurate metering pump 174, together with a manifold 176 for controlling the pump output and the inlet in order to eliminate any pressure pulsation of the current of components that could interfere with the precise mixing ratios necessary for the consistent quality of the product. Essentially, the collector serves to convert a pulsed input of the pump to an unpulsed output by means of phase compensation. The measuring system is driven by a motor 178 such as a stepper motor. The mixing device 120 has a pre-mixing system such as a pre-mixer 129 having a pre-mixing chamber 130, wherein the individual components are introduced under pressure by pressurized transfer means 123 and 125. According to the foregoing, the pre-mixed chamber has a first inlet orifice 136 connected to the transfer means 123 for the inlet of the aqueous phase, a second inlet orifice 138 connected to the transfer means 125 for the input of the lipid phase and an exit orifice 140 connected to the transfer means 132. The pre-mixer is designed to create a turbulent vortex, by which a stream of components is injected by means of high pressure into a second stream of components or both streams are injected by medium of high pressure. The pre-mixed formulation is then transferred by transfer means 132 and introduced into a mixer 133 having, for example, a high-shear design, laminar division 134 in-line mixing chamber 134. After the formulation is mixed, it is supplied through the supply means to a storage chamber or to a packaging means such as a packaging machine, not shown. In addition, the invention also contemplates the use of a means for further modification of the properties of the liposomes, which could be placed immediately after the delivery means. Such means for further modification may be, for example, a means for homogenization or sonication. This would allow the formulation of a formulation containing ULV from a formulation containing MLV or OLV. The modified formulation could then be supplied to a storage chamber or a packing medium, as indicated above for the mixed formulation. However, the modified formulation could also be used in a separate apparatus. It could be placed in a storage container and, with its own measurement system, used as a third component in another formulation. As indicated above, apparatus 100 includes a box 170 having an open end 180 to allow access to energy components, electrical systems, etc. Together with the temperature control 118, the power source 172 and the motor 178, this box also houses an indexer 186 which controls the motor 178, an index controller 182 for controlling the indexer 186 and a relay 184 for controlling the temperature control 118. Figure 2 shows only the components that are connected to the measurement system 128. The measurement system 126, shown in Figure 3, has similar components that relate to its performance. Figure 3 illustrates the temperature control 188, the power source 190, the engine 192 and the indexer (not shown) controlling the engine 192, an indexer controller 194 and a relay (not shown) all of which work with the system of measurement 126. There is also a relay (not shown) for controlling temperature control 150. Container 152 is sealed by means of a cover or lid 196 that is removable, but screwed in place and preferably includes a rubber seal, for example, to provide a hermetic sealing system during operation. The container can also be sealed by various means, including by way of example and without limitation, clamps, vacuum aspiration in the case of sensitive ingredients and by means of an edge and channel configuration. The mixing device 120 is equipped with a generator 110, as a means for applying ultrasonic energy to the pre-mixing chamber 130 and / or the mixing chamber 134. In the embodiment shown in Figures 2 and 3, the generator 110 is sample mounted in the pre-mixing chamber 130, an appropriate position when the ultrasonic energy is directed towards the pre-mixing chamber. However, it will be understood that the generator can be installed in the transfer means 132 if desired, to direct the energy to the mixing chamber 134. The latter configuration can be found in place or in addition to the generator installed in the premix chamber. Figure 3 provides another view of this embodiment of the invention. This view shows that the mixing device is also equipped with a means 150 for controlling the temperature of the device, and an energy source 198. Also shown in Figure 3, there is a plan view of the measuring system 126 comprising a precise measuring pump 200 together with a manifold 202. The measuring system is driven by a motor 194 as noted above. One skilled in the art will recognize other comparable parts that can be assembled in the manner shown in Figures 2 and 3 to produce a liposomal formulation in the manner described herein. In particular, suitable precision metering pumps are well known in the art. Particularly suitable for the method and apparatus of this invention is the Travcyl ™ metering pump (Encynova International, Inc., Broomfield, CO) which provides the accurate and efficient fluid delivery required by this invention. A simplified version of this pump is shown in Figures 4 and 5. Figure 4 shows an embodiment of the precision measuring system 128 of the invention, having an accurate metering pump 174 and a manifold 176. The pump and manifold are typically provide with a plurality of inputs and outputs. The collector has a plurality of inputs and outputs that correspond to the number of outputs and inputs in the pump. further, the collector has an inlet through which the lipid or aqueous phase from the storage container is transferred, and an outlet through which the components of the formulation are transferred to the pre-mixing system. The pump 174 having four inlets and four outlets is shown in Figure 5. The formulation component is transferred from its storage container 114 to the manifold 176 through the pressurized transfer means 124 before entering the pump. The component is transferred to the pump by the inlet means of the pump 300, 302, 304 and 306. The component is then returned to the manifold 176 by the outlet means of the pump 308, 310, 312 and 314, and then exits. of the manifold by the pressurized transfer means 125 for supply to the pre-mixing chamber 130. The pump inlet and pump outlet means are typically comprised of a flexible tubular material such as Teflon, PVDF, polypropylene, tubing stainless steel or reinforced polymer pipe. The pump inlet 300 and the pump outlet 308 are both connected to one of four cylinders in the pump 174. Similarly the input / output pairs 302/310, 304/312 and 306/314 are connected to the three remaining cylinders, respectively. Figure 6 illustrates one embodiment of a manifold 176 useful in combination with the pump 174 of Figure 5. Similarly to the pump, the manifold is provided with four inlets and four outlets, which are listed and identified separately. Each pump outlet means communicates with a collector inlet means, and each pump inlet means communicates with an outlet means of the manifold. In addition, the manifold has an inlet orifice communicating with the storage container and an outlet orifice communicating with the pre-mixer, as described in detail below. Referring now to FIG. 6 the component of the formulation is transferred from its storage container 114 to the manifold through the pressurized transfer means 124 in the inlet port of the manifold 141. The component is transferred to the pump by the means of collector input 324, 326, 328 and 330, where the collector outlet 328 is on the rear side. The component then returns from the pump to the manifold via the collector inlet means 316, 318, 320 and 322 where the collector inlet 318 is on the back side, and exits after the manifold by the pressurized transfer means 125 in FIG. the outlet orifice 142 of the manifold for delivery to the pre-mixing chamber. The collector can be, for example, a solid block in which the four input means are laterally perforated holes, as illustrated in FIG. 7. The same configuration is maintained for the four output means. An axially perforated orifice located at the junction of the four inlet means forms the outlet orifice of the manifold 142 by connecting the pressurized transfer means 125 to the manifold. Similarly, an axially perforated orifice located at the junction of the four outlet means forms the inlet opening of the manifold 141 by connecting the pressurized transfer means 124 to the manifold. This is illustrated in Figure 8. In the operation, the two components, i.e. the precursor phases foreseen in the formulation are prepared and heated each to the appropriate temperature, at which time they are transferred to the apparatus 100. Typically, Phase I of the mixture (the aqueous phase) is prepared and heated and enter into the larger of the two containers 112, which has been preheated to the required temperature before filling. Phase II of the mixture (the lipid phase) is prepared and heated, and is introduced into the smaller container 114 which has also been preheated to the required temperature. Once stored in the pre-heated containers 112 and 114, the phases are maintained at the required temperature, through individual feedback and control systems. The apparatus is equipped with two pumps 174 and 200, each of which is equipped with four positive displacement positive displacement pumping chambers.

The four inputs of each pump are combined through the use of the single collectors 176 and 202. The four outputs of each pump are then pumped through the same collector and are then transferred at a precise rate to the premix chamber 130. The result is an almost or virtually no pulse flow that allows the precise measurement ratios of the two components, ie, the lipid and aqueous phases that make up the liposomal formulation. The two components are each individually pumped through the use of the precise "no pulse" precise measurement pumps 174 and 200 in the premixing chamber 130 where they are introduced to each other in a precise ratio. The two phases are then introduced into the in-line mixing chamber 134 of length, diameter and composition appropriate for the specific product to be processed. The almost "no boost" action in the pump is achieved by the use of the four pump inlet means, each of which is 90 ° out of phase with the preceding inlet means and the successive inlet means. For example, referring to the pump 174 shown in Figure 5, there are four input means shown, 300, 302, 304 and 306. The operating curve of the input means 302, for example, is out of phase by 90. ° of the operating curve of the input means 300 and 304 and so on. In operation then, these curves are canceled to provide continuous "almost no-pulse" flows from the component from the container 114, to the manifold 176 to the pump 174, back to the collector 176, then to the pre-mixing chamber 130. The two phases can be intermixed slightly at an interfacial junction in the pre-mixing chamber 130, from which they are forced through the transfer means 132 to the static mixer 134. The design of the pre-mixing chamber incorporates surfaces that they create specific turbulence patterns that have very specific effects on the properties of liposomes during their formulation. In addition, several baffles can be added to the pre-mixing chamber or machined on the interior surface of the chamber, to increase turbulence. The design of the pre-mixing chamber 130 and the mixing device allows the use of an ultrasonic generator to be used in either or both of the chambers. The frequency and signal energy of the generator can be controlled by the same computer that monitors and controls the temperatures of the supply vessels, the temperatures of the housing and the mixing chambers and the flow rates of the two precise metering pumps . The length and internal components of the mixing chamber 134 are selected in order to maximize the effectiveness of the mixing process, as described above. The mixer feeds the product through a determination means 146 which can be a detection device or detector when the optical properties of the product are measured and the results are delivered to a process monitoring and control system, which is responsible for monitoring and adjust the temperature, flow rate and mixing ratios of each of the two phases based on the detected values, programmed responses and operator inputs. The process monitoring and control system typically includes suitable detectors and output reading deployment devices, and the necessary adjustments can be made manually by the operator or the entire system can be computerized easily by methods well known in the art.

Another embodiment of the invention is illustrated in Figures 9 and 10 where Figure 9 is an exploded side view and Figure 10 is a plan view. This embodiment illustrates some variations in the modality of Figures 2 and 3 and it is understood that the invention comprises other combinations of these two modalities. In particular the embodiment of Figures 9 and 10 illustrate a means by which the temperature of the storage containers can be monitored and maintained, an alternating manifold and an alternate pre-mixing system for the aqueous and lipid phases, together with the illustration of a mode of means by which the complete operation can be monitored and controlled. Referring now to Figures 9 and 10, apparatus 400 is equipped with individual means for storing each component of formulation 402 (the largest container for storing the components of the aqueous phase) and 404 (the smallest container for storing the component of the lipid phase), and a sealed container 406, which encloses the various parts of the mixing device 415 and the control elements. The temperature of each storage container is controlled by individual temperature sensors 408 and 410, together with heating elements 412 and 414. Each temperature sensor is inserted into the fluid contents of its respective containers. A preferred type of temperature detectors is a platinum resistant temperature sensing device, since such devices are well suited to accurately maintain the temperature of the contents at a set temperature. The heating element is configured to wind around the outside of the individual container and is typically a thermal sheet heater comprising a heater element encapsulated within a flexible silicone rubber sleeve. Each component is supplied to the mixing device 415 by the pressurized transfer means 416 and 418 to the individual precise measurement system 420 and 422 to control the amount of material transferred from the storage medium in a final manner to the pre-mixing chamber 424, and then to the in-line mixer 426. The precise measurement system 420 comprises a manifold 417 and a precise metering pump 419. The system also includes the housing 421, which contains a motor, or controller and a power supply. Similarly, the precise measurement system 422 comprises a manifold 423, a precise metering pump 425 and a similar housing 427. Details of this embodiment of the pre-blending system of the invention will be described in detail below. The pre-mixing system of this embodiment is best illustrated with reference to Figure 10. The aqueous phase leaves the precise measurement system 420 by the pressurized transfer medium 428, which is illustrated having a straight section 430, an adaptation section in L 432, and a T-shaped section 434, connected by the coupler flanges 436, 437, 438 and 439. The T-shaped section 434 is connected to the pre-mixed chamber 424 by the coupler flange 440 and the flange 441 coupler in the pre-mixed chamber, joined with a silicone gasket and clamp. The lipid phase exits the precise measurement system 422 by the pressurized transfer medium 442 having a straight section 444 having a diameter that approximates that of the sections of the pressurized transfer medium 428 and an injector section 446 having a diameter smaller than the sections of the pressurized transfer medium 428. The sections of the pressurized transfer medium 428 are joined together and joined to the section 434 by means of the coupler flange 448. The section of the injector 446 extends within the portion in T of section 434 and exits directly into the pre-mixed chamber 424. In operation, the aqueous phase leaving the straight portion of the T-shaped section 434 meets the outside length of the injector section 446 and creates turbulence before the aqueous phase enters the pre-mixing chamber 424, where it is mixed with the lipid phase entering the chamber through the injector section 446. This is illustrated in Figure 11 which shows a partial cross-section of the pre-mixing system 450. This configuration of the union of the pressurized transfer medium 428 of the Aqueous phase and pressurized transfer medium 442 of the lipid phase illustrates one embodiment of the invention whereby the lipid and aqueous phases can be accurately introduced and provided for temperature stabilization due to concentric flow. The turbulence is introduced into the aqueous phase within the branched portion 433 of the T-shaped section 434. The injector section 446 fits snugly in the recess of the flange 448 of the T-shaped section 434 and avoids the reflux of the aqueous phase in the straight section 434 of the pressurized transfer medium 442 of the lipid phase. The straight section 444 is connected to the T-shaped section by the coupler flange 443. The recursive flow of the aqueous phase into the chamber 435 of the branched portion 433 creates a steric effect. The ratio of (a) the internal cross-sectional area of the branched portion 433 that is not occluded by the injector section 446 to (b) the internal cross-sectional area of the injector section 446 is determined by the desired volumetric ratio from the aqueous phase to the lipid phase for any given formulation. Figure 11 also illustrates a cross-section of a suitable configuration of the in-line mixer 426, which has a plurality of baffles 452. However, it is understood that this invention is not limited to this configuration and any suitable configuration of the in-line mixer is comprised by the invention, while turbulent mixing of the aqueous and lipid phases is achieved. . Referring again to Figure 10, the apparatus 400 is provided with a heater 454, such as a resistive finned heater that serves to maintain the temperature within the mixing device 415, more specifically the temperature surrounding the pressurized transfer medium 428 and 442, the pre-mixed chamber 424 and the in-line mixer 426. The apparatus also comprises a temperature sensor 464, which serves to monitor the temperature inside the container 406 and adjust the heater 454 according to the above. Fig. 12 illustrates another embodiment of a manifold 423 useful in combination with pump 425 of Fig. 10. This mode of the manifold will be described in relation to the transfer of the lipid phase. However, a similar configuration can be used for the collector 417 and the pump 419, as it pertains to the transfer of the aqueous phase. Similar to the pump, the manifold is provided with four inputs and four outputs. In the pump / collector mode of Figure 4, there are transfer means that connect the inputs of the pump / collector output and the outputs of the pump / collector inputs. In the embodiment of Figure 9, the various inlets and outlets are placed on adjacent faces of the pump and manifold so that each outlet means of the pump communicates directly with an inlet means of the manifold, and each means of The pump inlet communicates directly with a collector outlet means. Furthermore the manifold has an inlet orifice communicating with the storage container and an outlet orifice communicating with the pre-mixing system, as described in detail below. Like the pump of Figure 5, the almost "no boost" action in the pump is achieved by using the four pump inlet means, each of which is 90 ° out of phase with the preceding inlet means and the successive inlet means. For example, referring to the pump 425 shown in Figure 13, there are four input means shown, 350, 352, 354 and 356. The operating curve of the input means 352, for example, is out of phase by 90. ° of the operating curve of the input means 352 and 356, and so on. In operation then, these curves cancel each other to provide continuous "almost no boost" flows from the container component, to the manifold 423 to the pump 425 back to the manifold 423 then to the pre-mixed chamber 424. Referring now to 12, the lipid phase is transferred from its storage container 404 to the manifold 423 through the pressurized transfer means 418 and the inlet port of the manifold 332. The lipid phase is then transferred to the pump 425 by the output means of the manifold 334, 336, 338 and 340 all of which are placed on the rear face 342 of the manifold. Fig. 14 illustrates the rear part of the manifold 423, which has the same configuration as the front face 344 of the precise metering pump 425, as shown in Fig. 13. The manifold and the pump are hermetically sealed together by means of of an O-ring and a plurality of fastening means, which can be screwed, for example. The bolts are secured through a plurality of perforated holes 346 that extend through the manifold 423 and engage with a plurality of perforated holes 348 located on the face of the pump 425. The pump is adjusted with four inlet means 350 , 352, 354 and 356 communicating with the collector outlet means 334, 336, 338 and 340. Like the embodiment of Fig. 4., the pump has four positive displacement, positive displacement pumping chambers or cylinders, not shown. Input 350 and output 358 of the pump communicate with a cylinder, input 352 and output 360 communicate with another cylinder, and so on. The lipid phase then leaves the pump via the pump outlet means 358, 360, 362 and 364, which communicate with the collector inlet means 366, 368, 370 and 372. The lipid phase subsequently leaves the collector through the outlet orifice of the manifold 374 located on the front face 376 of the manifold. The outlet orifice of the manifold 374 communicates with the pressurized transfer medium 442. The manifold 423 is manufactured as a solid block of metal such as stainless steel or a suitable alloy such as the nickel alloy Hastelloy ™. This collector is configured as a square or rectangular box as shown in FIG. 12, it has 6 sides or faces that are identified as the front face 376, the rear face 342, the upper face 378, the lower face 380, a first face lateral 382 and a second lateral face 384. The manifold is also configured to have two lateral planes each of which marks the location of a set of independent flow channels. The two planes are better illustrated by reference to Figures 15 and 16, which are cross-sectional views of the collector of Figure 12, taken along lines 15-15 and 16-16 respectively. Figure 15 illustrates a first side plane. A first and second sets of transverse flow channels, 385 and 386 are placed in order to intercept to form an "X". The first flow channel 385 is formed by drilling an angled hole from the side face 384 to a somewhat distant point before the side face 382 so that the channel 385 does not traverse the entire header. The end of the channel 385 is then connected to the connector 387 which prevents the flow from the collector and can be made of Teflon®, rubber, threaded plastic and any other suitable material that can be configured to securely fit into the channel. The second flow channel 386 is formed by drilling an angled hole from the upper face 378 to a somewhat distant point before the lower face 380 so that the channel 386 does not traverse the entire manifold. The end of the channel 386 is left open to form the inlet opening of the manifold 332.

Referring now to Figure 16, the second side plane is illustrated. A first and second set of transverse flow channels, 388 and 389 are placed in order to intercept to form an "X". The first flow channel 388 is formed by drilling an angled hole from the side face 382 to a somewhat distant point before the side face 384 so that the channel 388 does not traverse the entire manifold. The end of the channel 388 is then connected to the connector 390. The second flow channel 389 is formed by drilling an angled hole from the lower surface 380 to a somewhat distant point before the upper face 378 so that the channel 389 does not pass through. the complete collector. The end of the channel 389 is then connected to the connector 391. It is important to understand that the flow channels in a lateral plane are independent and do not communicate with the flow channels in the other lateral plane, ie, there is no flow fluid between channels 385, 386 in figure 15 and channels 388, 389 in figure 16. After drilling the flow channels in each lateral plane a plurality of means of inlet and outlet of the manifold is drilled into the manifold to a pre-defined depth. -specified. The manifold inlet means 366, 368, 370 and 372 are drilled in the rear face 342 to a depth sufficient to meet and communicate with the flow channels 388 and 389 in the lateral plane shown in Figure 16. Figure 17, which is a cross-sectional view of the collector taken along line 17-17 in FIG. 12, illustrate this even further. It can be seen that the inlet means of the manifold 370 is drilled to a depth to find the flow channel 389. The manifold outlet means 334, 336, 338 and 340 are drilled in the rear face 342 to a depth sufficient to be found and communicate with flow channels 385 and 386 in the lateral plane shown in Figure 15. Figure 17, which is a cross-sectional view of the collector taken along line 17-17 in Figure 12 illustrates this further . It can be seen that the manifold inlet means 338 are pierced at a depth to meet the flow channel 386. After the manifold inlet and outlet means are perforated, the manifold outlet orifice 374 is drilled into the manifold. the face 376 to a depth sufficient to meet and communicate with the flow channel 389, as shown in Figure 17. In operation, the lipid phase enters the manifold 423 through the inlet port 332 of the manifold. This flows through the flow channels 385 and 386 and then exits the flow channels by means of the collector outlet means 334, 336, 338 and 340, which communicate with the means 350, 352, 354 and 356 pump input, respectively. The fluid moves through the inlet 350 of the pump in one of the cylinders of the pump, then exits through the outlet means 358 and so on with all four pump inlets and outlets, such that the The lipid phase leaves the pump 425 as a current driven by the means 358, 360, 362 and 364 of the pump outlet communicating with the collector input means 366, 338, 370 and 372, respectively. The lipid phase then enters and flows through the flow channels 388 and 389 and exits the manifold through the outlet orifice 374 of the manifold. By means of the configuration of the collector and the almost "no impulse" action of the pump, which uses a plurality of inlet and outlet means, each of which is 90 ° out of phase, an input driven to the pre-mixing system as a flow with virtually no lipid phase or aqueous phase pulse. Figures 18-20 illustrate typical embodiments of a monitoring and process control system useful for the operation of the apparatus described herein and are exemplary for apparatus 400 of Figure 10. Figures 18 and 19 illustrate panels of control for the invention that fit with a plurality of connectors, indicator lights and controllers that are connected by appropriate wiring (not shown) to the parts of the apparatus they control, monitor or to which they provide power. Figure 18 illustrates a first control panel 456. The connector 458 of the temperature sensor is attached to the lipid phase resistance temperature device 410, while the power connector 460 provides power to the lipid phase heating element 414. The data communication terminal 462 is attached to a 466 computer, for example by means of a standard 9-pin serial port. The indicator light 468 indicates whether the heating elements 412 and 414 and the heater 454 are on or off. Similarly, the indicator light 470 indicates when the controllers (as described in Figure 19) and the precise measurement systems 420 and 422 are on or off. Figure 19 illustrates a second control panel 472. The connector 474 of the temperature sensor is attached to the aqueous phase resistance temperature device 408, while the energy connector 476 provides power to the aqueous phase heating element 412. The power connector 478 is attached to a remote communication port (not shown) that requires a converter or an interface card. The remote communication port serves as an interface between controllers 480, 482 and 484, and the computer used to interactively monitor, control and record the operation of the device and its component systems. The controllers 480, 482 and 484 serve to control the heating element 414, the heating element 412 and the heater 454, respectively. Figure 20 is the bottom view of a power distribution module 486 which is adjusted with a heat output 488. The module has an on / off switch 490 and an energy fuse 492 for the heating elements 414, 412 and heater 454. The module is also fitted with an on / off switch 500 and a 494 power fuse for controllers 480, 482 and 484 and precision measurement systems 420 and 422. In addition, there is a cooling fan with relay of heater 496 and a main power input connector 498. The present invention also contemplates methods for producing lipid vesicles using a continuous line mixing system. In one embodiment of the invention, the method includes first preparing a lipid phase, optionally containing an active agent, and storing the lipid phase in first storage media that are maintained at a set temperature, typically within the range of about 20 to 80 ° C. In a similar manner, an aqueous phase is prepared and stored in a second storage medium which is maintained at a set temperature, typically also within the range of about 20 to 80 ° C. In one embodiment of the invention, the first and second storage means are continuously replenished with the aqueous and lipid phases, respectively. The aqueous and lipid phases are then combined by means of a mixing device having a primary and secondary measuring system, a mixer and a pre-mixer. The mixer is typically maintained at a temperature within the range of about 20 to 80 ° C. The lipid phase is transferred from the first storage means to the first measurement system by first pressurized transfer means and the aqueous phase is transferred from a second storage means to the secondary measurement system by pressurized secondary transfer means. The lipid phase is then transferred from the first measurement system to a first inlet in the pre-mixing system by third pressurized transfer means. Similarly, the aqueous phase is transferred from the second metering system to the second inlet in the premixing system by fourth pressurized transfer means. In the operation of one of the embodiments of the invention, the lipid phase is transferred by the first and third pressurized transfer at a fluid flow rate of approximately 4 to 80 cm3 / sec. and the aqueous phase is transferred by the second and fourth pressurized transfer medium at a fluid flow rate of about 10 to 100 cm3 / sec. The lipid phase and the aqueous phases are transferred to the pre-mixing system with a high velocity, which creates a turbulence flow. Preferably, the lipid phase and the aqueous phases are transferred to the pre-mixing system at a precise ratio. In another preferred embodiment, the lipid phase and the aqueous phases are transferred to the premixing system in an almost no-pulse flow. The lipid and aqueous phases are then combined in the pre-mixed system by shearing mixing under conditions to ensure that the lipid phase is completely hydrated by the aqueous phase to form a pre-mixed formulation. The pre-mixed formulation is then transferred from the outlet orifice of the pre-mixing system to the mixer by a fifth pressurized transfer medium or other suitable connection or fitting. The mixed formulation, which contains lipid vesicles, is formed in the mixer by causing the pre-mixing formulation to traverse the static mixer. The optical properties of the lipid vesicles are optionally measured. This can be carried out by means of an optical transmission detection device using a photoresistor or phototransistor, which provides a control signal to a control computer or other process control device, which in turn functions to control or adjusting the temperatures of the first and second storage means, together with the control of the operation of the first and second measurement systems. In the final stage, the mixed formulation is distributed from the mixing chamber to a storage chamber within a medium for further modification of the properties of the lipid vesicles or to a packing medium of the mixed formulation. In another embodiment, the method includes a homogenization or sonication step after the distribution step. This last modality is useful for the production of unilamellar lipid vesicles. The method may also include the addition of a second lipid phase and / or a lipid phase of premixing-aqueous phase mixture. In yet another preferred embodiment of the invention, each measuring system in the method described above has a precise metering pump and a manifold. Each pump and manifold has a plurality of inlet and outlet means, wherein each pump inlet means communicates with an outlet means of the manifold and each outlet means of the pump communicates with an inlet means of the manifold. Each pump inlet means is 90 ° out of phase with the preceding inlet medium and the successive inlet medium. Along with a plurality of input and output means, the collector also has an outlet orifice of the collector and an orifice for entering the collector. In this embodiment, the method includes the steps of transferring the lipid phase to the inlet orifice of a first manifold by the first pressurized transfer medium and simultaneously transferring the aqueous phase to the inlet of a second manifold by the second transfer means pressurized; transferring the lipid phase from the plurality of exit means of the first collector to the plurality of input means of a first pump and simultaneously transferring the aqueous phase from the plurality of exit means of the second collector to the plurality of input means of the second pump; transferring the lipid phase from the plurality of outlet means of the first pump to the plurality of input means of the first manifold and transferring the aqueous phase from the plurality of outlet means of the second pump to the plurality of input means of the second collector; and transferring the lipid phase from the exit orifice of the first collector by means of the third pressurized transfer medium and simultaneously transferring the aqueous phase from the outlet of the second collector by means of the fourth pressurized transfer medium. For purposes of illustrating the method of the invention, two streams of components, one of lipid phase and one of aqueous phase, will be described. However, as described above for the apparatus of the invention, it is to be understood that additional single or mixed phase component streams may be added as desired. In addition, a stream of liposomes can also be included. By combining a liposome phase current with an aqueous phase stream and a lipid phase stream, the liposomes in the liposome stream can be further encapsulated using the method and apparatus of the invention. One of ordinary skill in the art will readily understand how such additional streams can be incorporated, for example by the addition of another storage container, measuring system, etc., as described above. As noted above, the present invention also pertains to a method for the continuous production of a composition of matter such as lipid vesicles by in-line mixing. In one embodiment of the invention the method comprises; (a) preparing a first phase, such as a lipid phase and storing the lipid phase in a first storage medium that is maintained at a set temperature; (b) preparing a second phase, such as an aqueous phase and storing the aqueous phase in a second storage medium which is maintained at a set temperature; (c) combining the lipid and aqueous phases by means of a mixing device having first and second measuring systems, a pre-mixing system and a mixer, by: transferring the lipid phase from the first storage medium to the first measuring system by means of a first pressurized transfer medium and transferring the aqueous phase from the second storage medium to the second measurement system by means of a second pressurized transfer medium; Transfer the lipid phase from the first measurement system to a first inlet in the premixing system by means of a third pressurized transfer medium and transfer the aqueous phase from the second measurement system to a second inlet in the pre-mixing system. - mixed by a fourth pressurized transfer medium; wherein the lipid phase and the aqueous phases transfer to the pre-mixing system with a high velocity that creates a turbulent flow; combining the lipid and aqueous phases in the pre-mixed system when mixing by shearing under conditions to ensure that the lipid phase is completely hydrated by the aqueous phase to form a pre-mixed formulation; and transferring the pre-mixed formulation from an exit orifice of the pre-mixing system to the mixer, such as by a fifth pressurized transfer medium or other suitable connection or accessory; (d) forming a mixed formulation containing lipid vesicles in the mixer by causing the premixed formulation to pass through a static mixer; (e) optionally measuring the optical properties of the lipid vesicles; and (f) distributing the mixed formulation from the mixing chamber into a storage chamber, in a medium for further modification of the properties of the lipid vesicles, or to a packing medium of the mixed formulation. This embodiment is further illustrated by the following discussion. First, the aqueous and lipid phases are prepared and heated to the appropriate temperatures. An exemplary aqueous phase may be sterile water, a physiological saline solution, a buffer solution, an aqueous solution of carbohydrate, deuterated water, or other isotopic forms of H20, regulated solutions of organic acids and bases, and the like or any combination thereof. same. In addition, the aqueous phase may also contain a water-soluble organic solvent such as by way of illustration and not limitation, polyhydric alcohols including glycerin, propylene glycol, polypropylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, etc .; alcohols such as benzyl alcohols, etc .; ethers; ketones; esters and glycerin esters such as monoacetin, diacetin, glycerophosphoric acid, etc.; and various aromatic and aliphatic hydrocarbons including fluorocarbons. Typically the aqueous phase will consist of from about 75 to 99% by weight of sterile water, preferably about 85 to 98% by weight. An exemplary lipid phase may consist, by way of illustration and not limitation, of phospholipids such as phosphatidyl clolines, lysophosphatidyl clolines, phosphatidyl serines, phosphatidyl ethanolamines, phosphatidyl inositols, cardiolipin and sphingomyelin; natural phospholipids such as egg yolk lecithin, soy lecithin and soybean oil based on phospholipids; glycolipids, synthetic dialkyl type surfactants; polar lipids and neutral lipids; fatty acids; and the similar; moreover the lipid phase may also contain materials such as stearylamine, phosphatidic acid, dicetyl phosphate, tocopherol, cholesterol, propylene glycol from lanolin extracts, polyethylene glycol, polypropylene glycol, glycol ethers, ethanol and the like. Typically the lipid phase will consist of about 5 to 20 weight percent (% by weight) of a phospholipid, preferably about 8 to 12% by weight. The lipid phase typically contains an active agent in the amount of about 0.01 to 35% by weight, more preferably about 2 to 25% by weight. However, it should be understood that if desired, the lipid vesicles can be made without any active agent contained therein. It may be desirable to prepare the aqueous phase in an amount in excess of what is needed to produce the desired formulation. This excess allows the stabilization of the temperatures of the collectors, of the precise measuring pumps together with the in-line mixing and premixing installation. Typically, one can produce the aqueous phase in an amount equal to 1 to 3, more typically 1.4 to 2 times the amount required for the formulation. On the other hand, the lipid phase is produced in an amount approximately to the amount necessary to produce the desired formulation. Once prepared, the lipid phase is placed in a storage medium and the aqueous phase is placed in another storage medium. These formulations are only provided to exemplify the methods of the invention and are not intended to be limiting in any way. It is expected that the method and apparatus described herein will work with any liposomal formulation that it is desired to produce, with the same result described herein. This current invention also relates to the lipid vesicles produced by the method and apparatus described herein. In accordance with the foregoing, the invention contemplates lipid vesicles, either multilamellar, oligolamellar or unilamellar produced by the various apparatus modalities described above. In a similar way, the invention contemplates lipid vesicles, either multilamellar, oligolamellar or unilamellar, produced by the various methods described above. Any of the aforementioned lipid vesicles may further comprise an active agent encapsulated in either the aqueous core of the lipid vesicles, within the lipid bilayer of the vesicles, or both. Of particular interest are the active agents ivermectin and diclofenac. As recognized by those skilled in the art, although certain materials and methods can give better results, the use of particular materials and methods are not critical to the invention and optimum conditions can easily be determined using routine tests. In addition, the invention also contemplates the inclusion of additional materials in the formulations to facilitate the delivery of drugs, the stability of the formulation and so forth. For example, some liposome formulations may acquire a gel-like consistency upon cooling to room temperature in the absence of some adjuvant. According to the above, conventional thickener and gelling agents would be added to provide a preparation having the desired consistency for topical application. Additionally, a preservative or antioxidant will be added frequently to the preparation. The amount of active agent to be included in the liposomal preparation is not critical, per se and may vary within wide limits depending on the proposed application and the lipid used. The level of the active agent in the final liposomal formulation of the invention may vary within the total range employed by those skilled in the art, eg, from about 0.01 to 99.99% by weight of the active agent based on the total formulation and about 0.01- 99.99% by weight of vehicle, etc. More typically the active agent will be present at a level of about 0.01-80% by weight. Preferably, the active agent may be included in an amount of between about 0.01 to 10% by weight of the liposomal preparation and more preferably may be included in an amount of about 0.01 to 7% by weight. By employing the active agent-liposome formulation produced with this invention for pharmaceutical use, any pharmaceutically acceptable mode of administration can be used. For example, products can be made to suit any accepted systemic or local administration route as is well known in the art, for example, parenterally, orally (particularly for formulations for infants), intravenous, nasal, bronchial inhalation (ie formulation aerosol), transdermal or topical routes, in the form of solid, semi-solid or liquid or aerosol dosage forms, such as for example tablets, pills, capsules, powders, liquids, lotions, solutions, emulsions, injectables, suspensions , suppositories, aerosols or similar. The formulations produced by the invention can also be made as sustained or controlled release dosage forms, including injections, osmotic pumps, pills, lotions in transdermal patches (including electrotransport), creams and the like, for the prolonged administration of an active agent to a predetermined rate, preferably in unit dosage forms suitable for the simple administration of precise doses. The formulations will include a conventional pharmaceutically acceptable carrier or excipient and the active agent and may also include other medicinal agents, pharmaceutical agents, vehicles, adjuvants, etc. The vehicles can be selected from various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferred liquid carriers are water, saline, aqueous dextrose and glycols, particularly for injectable solutions. Pharmaceutically acceptable excipients and vehicles also include starch, cellulose, talc, glucose, lactose, sucrose, mannitol, gelatin, povidone, malt, rice, flour, calcium carbonate, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, magnesium carbonate, sodium chloride, sodium saccharin, croscarmellose sodium, dehydrated skimmed milk, glycerol, glycols, such as propylene glycol, polyethylene and polypropylene glycol and their derivatives, esters, salts and combinations of glycols and other alcohols or fatty acids, water, low molecular weight alcohols such as ethanol, propanol and the like. The formulations of the invention also preferably contain an anti-oxidant such as, by way of illustration and not limitation, tocopherol, more specifically vitamin E (α-tocopherol), tocopherol derivatives, butylated hydroxyanisole and butylated hydroxytoluene. Other pharmaceutically suitable carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. If desired, the liposome formulation may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH regulating agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolanine oleate. , etc. Another aspect of the invention pertains to an improved method for producing compositions of matter such as emulsions, ointments and creams using the methods and apparatus described herein. The method and apparatus described above for the production of lipid vesicles are easily modified by one skilled in the art to produce any of a variety of other compositions by modifying the starting components and process parameters. Such compositions can also be formulated to include a payload. Emulsions are two-phase systems in which a liquid is dispersed through another liquid in the form of small droplets. When the oil is the dispersed phase and the aqueous phase is the continuous phase, the system is designated as an oil-in-water ("O / W") emulsion. Conversely, when the water or an aqueous solution is the dispersed phase and the oil or oleaginous material is the continuous phase, the system is designated as a water-in-oil ("W / 0") emulsion. Accordingly, the emulsions can be easily produced by using an aqueous phase optionally containing a surfactant, and an oil phase, optionally containing various other ingredients and excipients as a second phase. The ointments are semi-solid preparations that are proposed for external application to the skin or mucous membranes. It is generally recognized as oleaginous bases containing oil. Such ointments can be easily produced by the method and apparatus described herein using a viscous thixotropic phase as a first phase and a non-viscous oil phase as a second phase. The creams are viscous liquids or semi-solid emulsions and can also be designated as O / W or W / O. These can be formulated, for example, by using an emulsion phase and an aqueous phase. Each of the patent applications, patents, publications and other published documents mentioned or referred to for this specification herein are incorporated by reference in their entirety, to the same extent as each patent application, patents, publications and other published documents. Individuals will be specifically and individually indicated to be incorporated as a reference. Although the present invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes can be made and replaced with equivalents without departing from the spirit and scope of the invention and the appended claims. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process steps or stages., the purpose, spirit, and scope of the invention. All modifications are intended to be within the scope of the appended claims hereto.

Claims (57)

1. CLAIMS 1. An apparatus for the continuous production of lipid vesicles by in-line mixing, the apparatus comprising: (a) a lipid phase storage medium capable of being maintained at a set temperature and a first pressurized transfer medium for transferring the lipid phase from the storage medium; (b) an aqueous phase storage medium capable of being maintained at a set temperature and a second pressurized transfer medium for transferring the aqueous phase from the storage medium; (c) a mixing device comprising: a first measuring system for receiving the lipid phase from the first pressurized transfer medium; a second measuring system for receiving the aqueous phase from the second pressurized transfer medium; a pre-mixing system for preparing a premixed formulation; a third pressurized transfer medium for transferring the lipid phase from the first measurement system to a first entry port in the pre-mixing system and a fourth pressurized transfer medium for transferring the aqueous phase from the second measurement system to a second entry hole in the pre-mixing system; a mixer for preparing a mixed formulation comprising lipid vesicles, having a mixing chamber and optional means for determining the optical properties of the mixed formulation; means for transferring the pre-mixed formulation from the outlet orifice of the pre-mixing system to the mixing chamber; and an optional means for applying ultrasonic energy to the pre-mixing system, the mixing chamber or both; and (d) a distribution means for transferring the mixed formulation from the mixing chamber into a storage chamber.
2. 2. The apparatus of claim 1, wherein the lipid vesicles are multilamellar or oligolamellar.
3. The apparatus of claim 1, further comprising a means for homogenization or sonication located between the distribution means and the storage chamber.
4. 4. The apparatus of claim 2, wherein the lipid vesicles are unilamellar.
5. 5. The apparatus of claim 1, wherein the lipid phase comprises an active agent.
6. The apparatus of claim 1, wherein the storage medium of the lipid phase is capable of being maintained at a set temperature by a first temperature control means and the storage medium of the aqueous phase is capable of being maintained at a temperature established by a second means of temperature control.
7. The apparatus of claim 6, wherein the storage medium of the lipid phase is maintained at a temperature within the range of about 20 to 80 ° C.
8. The apparatus of claim 6, wherein the storage medium of the aqueous phase is maintained at a temperature within the range of about 20 to 80 ° C.
9. The apparatus of claim 1, wherein the means for determining the optical properties of the mixed formulation is configured in order to control the first and second temperature control means and the first and second measurement systems.
10. The apparatus of claim 1, further comprising an additional storage medium for a second lipid phase, a mixture of lipid phase-pre-mixed aqueous phase or a pre-formed lipid vesicle phase.
11. The apparatus of claim 1, wherein the storage medium of the lipid phase and the aqueous phase further comprises means for replenishing the lipid and aqueous phases.
12. 12. The apparatus of claim 1 operating under pressures in the range of about 10 to 90 psia.
13. The apparatus of claim 1 wherein the fluid flow rate of the lipid phase is approximately 3 to 200. cm3 / sec and the fluid flow rate of the aqueous phase is approximately 5 to 300 cm3 / sec.
14. 14. The apparatus of claim 1 wherein the mixer is a static mixer.
15. 15. The apparatus of claim 14 wherein the static mixer is an in-line mixer of the laminar splitting type.
16. 16. The apparatus of claim 1 wherein the mixer further comprises means for controlling the temperature of the mixing chamber.
17. The apparatus of claim 16 wherein the means for controlling the temperature of the mixing chamber maintains the temperature of the chamber within the range of about 20 to 80 ° C.
18. 18. The apparatus of claim 1 wherein the mixer further comprises means for controlling the degree and rate of mixing within the mixing chamber.
19. 19. The apparatus of claim 1 wherein the storage chamber is part of a packaging machine.
20. The apparatus of claim 1 wherein the dispensing means further comprises means for controlling the rate at which the formulation is transferred from the mixing chamber to the storage chamber.
21. The apparatus of claim 1 wherein the mixing device further comprises means for controlling the temperature of the device.
22. 22. The apparatus of claim 21 wherein the device is maintained at a temperature within the range of about 20 to 80 ° C.
23. 23. The apparatus of claim 1 wherein each measuring system comprises a precise metering pump and a manifold.
24. The apparatus of claim 23 wherein each pump and manifold have a plurality of inlet and outlet means wherein each pump inlet means communicates with an outlet means of the manifold and each pump outlet means communicates with a means of collector input; wherein each pump inlet means is 90 ° out of phase with the preceding pump inlet means and the successive pump inlet means and the manifold further comprises a manifold outlet orifice and a manifold inlet orifice.
25. 25. The apparatus of claim 24 wherein the inlet opening of a first manifold is in communication with the first pressurized transfer medium and the outlet orifice of a first manifold is in communication with the third pressurized transfer medium, the inlet orifice of a second manifold is in communication with the second pressurized transfer medium and the outlet orifice of a second manifold is in communication with the fourth pressurized transfer medium.
26. 26. The lipid vesicles produced by the apparatus of claim 1.
27. 27. The lipid vesicles of claim 26 wherein the lipid vesicles are multilamellar or oligolamellar.
28. 28. The lipid vesicles of claim 27 further comprising an active agent encapsulated in the aqueous core of the vesicles, within the lipid bilayer of the vesicles or encapsulated in the aqueous core and within the lipid bilayer of the vesicles.
29. 29. The lipid vesicles of claim 28 wherein the active agent is selected from the group consisting of ivermectin and diclofenac.
30. 30. The lipid vesicles produced by the apparatus of claim 3.
31. 31. The lipid vesicles of claim 30 wherein the lipid vesicles are unilamellar.
32. 32. The lipid vesicles of claim 31 further comprising an active agent encapsulated in the aqueous core of the vesicles, within the lipid bilayer of the vesicles or encapsulated in the aqueous core and within the lipid bilayer of the vesicles.
33. 33. The lipid vesicles of claim 32 wherein the active agent is selected from the group consisting of ivermectin and diclofenac.
34. 34. A method for the continuous production of lipid vesicles by in-line mixing, the method comprising: (a) preparing a lipid phase and storing the lipid phase in a first storage medium that is maintained at a set temperature; (b) preparing an aqueous phase and storing the aqueous phase in a second storage medium that is maintained at a set temperature; (c) combining the lipid and aqueous phases by means of a mixing device having a first and second measuring system, a pre-mixing system and a mixer, for: transferring the lipid phase from the first storage medium to the first measuring system by means of a first pressurized transfer medium and transferring the aqueous phase from the second storage medium to the second measurement system by means of a second pressurized transfer medium; transferring the lipid phase from the first measurement system to a first inlet in the pre-mixing system by means of a third pressurized transfer medium and transferring the aqueous phase from the second measurement system to a second inlet in the system of pre-mixing by means of a fourth pressurized transfer medium; wherein the lipid and aqueous phases are transferred to the pre-mixing system with a high velocity creating turbulence flow; combining the lipid and aqueous phases in the pre-mixing system by shearing mixing under conditions to ensure that the lipid phase is completely hydrated by the aqueous phase to form a pre-mixing formulation; and transferring the pre-mixed formulation from an exit orifice of the pre-mixing system to the mixer. (d) forming a mixed formulation containing lipid vesicles, in the mixer to cause the pre-mixing formulation to pass through the mixer. (e) optionally measuring the optical properties of lipid vesicles; and (f) distributing the blended formulation from the blender to a storage chamber, to a means for further modification of the properties of the lipid vesicles or to a packaging medium of the blended formulation.
35. 35. The method of claim 34, wherein the lipid vesicles are multilamellar.
36. 36. The method of claim 34, further comprising a step of homogenization or sonication after the distribution step.
37. 37. The method of claim 36, wherein the lipid vesicles are unilamellar.
38. 38. The method of claim 34, wherein the lipid phase comprises an active agent.
39. 39. The method of claim 34, wherein the first storage medium is maintained at a temperature within the range of about 20 to 80 ° C.
40. 40. The method of claim 34, wherein the second storage medium is maintained at a temperature within the range of about 20 to 80 ° C.
41. 41. The method of claim 34, wherein the step of measuring the optical properties is by means of an optical transmission detecting device using a photoresistor or a phototransistor that provides a control signal to a controller computer or other control device. process.
42. 42. The method of claim 34, further comprising the addition of a second lipid phase, a mixture of lipid phase-pre-mixed aqueous phase or a pre-formed lipid vesicle phase.
43. 43. The method of claim 34, wherein the first and second storage means are continuously replenished with the lipid and aqueous phases respectively.
44. 44. The method of claim 34 wherein the pressures are within the range of about 10 to 90 psia.
45. 45. The method of claim 34 wherein the fluid flow rate of the lipid phase is at about 3 to 200 cm3 / sec and the fluid flow rate of the aqueous phase is at about 5 to 300 cm3 / sec
46. 46. The method of claim 34 wherein the mixer is maintained at a temperature within the range of about 20 to 80 ° C.
47. 47. The method of claim 34 wherein each measuring system comprises a precise metering pump and a manifold, wherein each pump and manifold has a plurality of inlet and outlet means, each pump inlet means communicating with a collector outlet means and each pump outlet means communicates with a collector inlet means and the manifold further comprises a manifold outlet orifice and a manifold inlet orifice; the method further comprises: transferring the lipid phase to the inlet orifice of a first manifold by means of the first pressurized transfer medium and simultaneously transferring the aqueous phase to the inlet orifice of a second manifold by means of the second pressurized transfer medium. transferring the lipid phase from the plurality of exit means of the first collector to the plurality of input means of a first pump and simultaneously transferring the aqueous phase from the plurality of exit means of the second collector to the plurality of input means of the second pump; transferring the lipid phase from the plurality of exit means of the first pump to the plurality of input means of the first collector and transferring the aqueous phase from the plurality of exit means of the second pump to the plurality of input means of the second collector; and transferring the lipid phase from the outlet orifice of the first manifold by means of the third pressurized transfer medium and simultaneously transferring the aqueous phase from the outlet of the second manifold by means of the fourth pressurized transfer medium.
48. 48. The method of claim 47 wherein the lipid phase and the aqueous phase are transferred to the pre-mixer at a precise ratio.
49. 49. The method of claim 47 wherein the lipid and aqueous phases are transferred to the pre-mixer in an almost no-pulse flow.
50. 50. The lipid vesicles produced by the method of claim 34.
51. 51. The lipid vesicles of claim 50 wherein the lipid vesicles are multilamellar or oligolamellar.
52. 52. The lipid vesicles of claim 51 that further comprise an active agent encapsulated in the aqueous core of the vesicles, within the lipid bilayer of the vesicles or encapsulated in the aqueous core and within the lipid bilayer of the vesicles.
53. 53. The lipid vesicles of claim 52 wherein the active agent is selected from the group consisting of ivermectin and diclofenac.
54. 54. The lipid vesicles produced by the method of claim 46.
55. 55. The lipid vesicles of claim 54 wherein the lipid vesicles are unilamellar.
56. 56. The lipid vesicles of claim 55 further comprising an active agent encapsulated in the aqueous core of the vesicles, within the lipid bilayer of the vesicles or encapsulated in the aqueous core and within the lipid bilayer of the vesicles.
57. 57. The lipid vesicles of claim 56 wherein the active agent is selected from the group consisting of ivermectin and diclofenac.