MXPA00009914A - Incorporation of active substances in carrier matrixes - Google Patents
Incorporation of active substances in carrier matrixesInfo
- Publication number
- MXPA00009914A MXPA00009914A MXPA/A/2000/009914A MXPA00009914A MXPA00009914A MX PA00009914 A MXPA00009914 A MX PA00009914A MX PA00009914 A MXPA00009914 A MX PA00009914A MX PA00009914 A MXPA00009914 A MX PA00009914A
- Authority
- MX
- Mexico
- Prior art keywords
- process according
- aqueous phase
- emulsion
- fluid gas
- active principle
- Prior art date
Links
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- 239000000126 substance Substances 0.000 title claims abstract description 25
- 238000010348 incorporation Methods 0.000 title abstract description 5
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Abstract
A process for the incorporation of an active substance in a carrier system by forming an emulsion of the components and precipitating the system by the use of fluid gas technique.
Description
INCORPORATION OF ACTIVE SUBSTANCES IN CARRIER MATRICES
Field of the Invention The present invention relates to a process for the preparation of a formulation comprising an active substance associated with a carrier by forming an emulsion of the components and precipitating the system using a fluid gas technique. The invention also relates to the formulation obtained by this process.
BACKGROUND OF THE INVENTION Various solutions are suggested to the problem of the incorporation of active substances in carrier matrices in order to obtain particle systems. These systems can be used for example, in immediate release formulations, modified release formulations, sustained release formulations, pulsed release formulations, etc. Some examples of these techniques are:
Ref: 123 20
- interfacial polymerization (Birrenbach and Speiser, J. Pharm. Sci. 1976, 65, 1763, Thies, In Encyclopedia of Chemical Technology, 4 ed. Kirk-Othmer, 1996, 16, p.632) - methods of evaporation of Solvents (Cleland, In Vaccme Design, The subunit and adjuvant approach, Eds: Powell and Newman Plenum Press, New York, 1995, 439) - Solvent extraction (Cleland, In Vaccine Design, The sub? ni t and adjuvant approach, Eds: Powell and Newman Plenum Press, New York, 1995, 439) - spray dehydration (WO 94/15363) An important step in the preparation of these systems is the step of incorporating the active principle. The choice of the preparation method of the delivery system depends on the type of active ingredient to be incorporated and the desired release properties of the active ingredient from the delivery system. All the techniques listed above have their advantages and disadvantages. Therefore, the melt microencapsulation method is unsuitable for the thermo-weak active principles. A disadvantage with the interfacial polymerization method is that the monomers
highly reactive in the water-immiscible solvent, they can react with both the core material and the encapsulated active principle. One drawback of the solvent preparation process is that the method is time consuming and can only be carried out in batches. Like the solvent evaporation technique, the extraction method also requires a lot of time since it can only be carried out in batches. One drawback with the spray dehydration method is that it is difficult to produce particles in the nano-electric range. This method is also unsuitable for thermolabile substances or active substances sensitive to oxidation due to exposure to heat and air during the process. Supercritical fluid technology has advanced in recent years. In short, a supercritical fluid can be defined as a fluid in, or above, its critical pressure and its critical temperature, simultaneously. The physicochemical properties of supercritical fluids are flexible with respect to temperature and pressure and can be selected to suit a given application. There are different and new techniques currently being used, one of
these are known as rapid expansion of supercritical solutions (RESS) and the other is known as gas anti-solvent precipitation (GAS). In the GAS technique a substance of interest is dissolved, in a conventional solvent, a supercritical fluid such as carbon dioxide is introduced into the solution, which leads to a rapid expansion of the volume of the solution. As a result, the power of the solvent decreases dramatically over a short period of time, which triggers the precipitation of particles. C F N. W. Tom and P. G. Debenedetti in J. Aerosol Sci., 22 (1991), 555-584; P. G. Debenedetti et al in J. Controlled Reléase, 24 (1993), 27-44 and J. W. Tom et al in ACS Symp Ser 514 (1993) 238-257; EP 437 451 (Upjohn) and EP 322 687 / Schwarz Pharma). A modification of the GAS system has recently been developed (WO 95/01221 and WO 96/00610). It is called the SEDS technique (intensified dispersion of a solution by a supercritical fluid), which uses supercritical fluid technologies for the formation of particles. The protein can be incorporated in the carrier matrices, as in other active ingredients,
using the encapsulation methods mentioned above. The protein dissolves in an aqueous phase, is suspended or dissolved directly in the phase containing the carrier. A disadvantage with proteins that dissolve in organic solvents is the low solubility of proteins and organic solvents and supercritical fluids / modified supercritical expenditure (Stahl et al, "Dense Gas Results", Fluid Phase Balance, 1983, 10, 269) . Another disadvantage with proteins directly dissolved or suspended in an organic solvent is that the organic solvent can unfold or denature the protein. (Dill and Shortle Ann. Rev. Biochem., 1991, 60, 795-825). This can lead to a loss of the therapeutic effect, for example, of the immunological effect. In the supercritical fluid techniques, the proteins have been dissolved directly in DM? O for the preparation of pure protein particles (Winters et al., J. Pharm. Sci., 1996, 85, 586-594 and Pharm. Res. , 1997, 14, 1370-1378) or in coprecipitation with a polymer, with both, with the polymer and the protein dissolved in DMSO (W09629998 and Bertucco et al., In High Pressure Chemical Engineering, 1996, 217-222). Even a mixture of ethanol
and water has been used as a solvent for a protein and a polymer in SAS (EP0542314 and Tom et al., in Supercritical Technological Science, ACS Symposium Series, 1993, 514, 238-257). Protein particles have been prepared from aqueous solutions in the SEDS technique using a three-component nozzle, wherein the protein solution in water is first co-injected with ethanol and then mixed in the nozzle with supercritical carbon dioxide (WO9600610). Even if the contact time between the aqueous solution and the ethanol is very short, there may be destruction of the protein conformation. Low molecular weight substances have also been coprecipitated with polymers by supercritical fluid techniques. In EP332687, the preparation of a drug comprising an active substance and a carrier using anti-solvent and RESS techniques is presented (Kim et al., Biotechnol Prog 1996, 12, 650-661, Chou and Tomasko, The 4th Int. Symp. on Supercri tical Fl uids, Sendai, Japan, 1997, 55). Here, the antisolvent technique, the active principle and the carrier dissolve or disperse in the same liquid medium and combine with a fluid
supercritical. The examples included in these documents only refer to the incorporation of hydrophobic compounds in the L-PLA spheres. No mention is made of the compounds in the aqueous phase, as well as in other studies reported in PCA (Bosmeier et al., Pharm. Res., 1995, 12, 1211-1217), SAS (Bertucco et al. High Pressure Chemical Engineering, 1996, 217-222), GAS (Chou and Tomasko, The 4th Int. Symp. On Supercritical T uids, Sendai, Japan, 1997, 55) or ASES (Bleich and Muller, J. Microencapsulation, 1996 , 13, 131-139).
Description of the Invention It has been discovered that it is possible to associate an active principle or principles with a carrier system by forming an emulsion of the components and precipitating the system by using a fluid gas technique. The active principle or active ingredients are incorporated into and / or around the carrier system, which includes that the carrier may also surround the active ingredient or active principles. This improved method for preparing an active principle containing carrier systems is based on the use of emulsions. The emulsion is a mixture of two liquids or
non-irascible phases, where one liquid is finely dispersed in another liquid. One of the liquids has greater polarity, for example the water or the aqueous phase in comparison with the other liquid, for example an organic solvent or a mixture of solvents (oily phase, here called the non-aqueous phase). The emulsion can be either kinetically stable (macroemulsion), or thermodynamically stable (microemulsion), or a combination of these. In order to stabilize the emulsion, an emulsifier, either alone or in combination with other emulsifiers, such as but not limited to, surfactants, polymers and lipids, can be used. The emulsifiers are dissolved either in the aqueous phase and / or in the non-aqueous phase. The active principle or principles, which are / are being incorporated and / or associated with the carrier system, are dissolved, suspended or solubilized in the aqueous phase. The carrier material dissolves either in the non-aqueous phase, or in the aqueous phase. The aqueous phase is emulsified in a non-aqueous phase or vice versa. Nonionic surfactants may be, but are not limited to: esters of polyoxyethylene sorbitan fatty acids, fatty acid esters of
sorbitan, polyoxyethylene alkyl ethers, sucrose esters and n-octyl-b, D-glycopyranoside (n-OG). The anionic surfactants may be, but are not limited to: sodium dodecyl sulfate, sodium 1-bis (2-ethylhexyl) sulfosuccinate (AOT) and salts or fatty acids. The cationic surfactants can be, but are not limited to: alkyltrimethylammonium salts and dialkyldimethylammonium salts. Surfactant surfactants may be, but are not limited to: 3 ((3-colamidopropyl) dimethylammonium) -1-propane sulfonate, dodecyl-N-betaine. Polymeric emulsifiers can be, but are not limited to: poly (vinylpyrrolidone), polyglycerol polyricinoleate, poly (vinyl alcohol) and block copolymers. Liquid emulsifiers can be, but are not limited to: cholesterol, phosphatidylcholine, phosphtyldylethanolamine and phosphatidic acid. In this invention, the aqueous phase is defined as the aqueous solutions (not miscible with the non-aqueous phase) and / or other solutions which are non-irascible with the non-aqueous phase and which are more polar than the non-aqueous phase. The non-aqueous phase comprises, but is not limited to: conventional organic solvents, such as chloride
methylene, chloroform, ethylacetate, or mixtures of organic solvents. The material may be, but is not limited to, polymers, fillers, disintegrating agents, binders, solubility enhancers and other excipients and combinations thereof. The polymers can be synthetic or of a natural origin. They can be biodegradable or not, for example polystyrene. Polymer groups that can be used as carriers are, but are not limited to, polysaccharides, polyesters, polyethers, polyanhydrides and polypeptides. Examples of the polysaccharides are, but are not limited to, celluloses, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), pectin, alginates, cytosine, agar, hydroxyethylcellulose / HEC), xanthene, ethylhydroxyethylcellulose
(EHEC). Examples of the polyethers are, but are not limited to, polylactide (PLA), polyglycolide (PGA), their copolymers (PLG), polyhydroxybutyrate (PHB) and polycaprolactone.
Examples of the polyethers are, but are not limited to: polyethyleneoxide and pilipropyleneoxide. Examples of the polyanhydrides are, but are not limited to, poly (sebacic acid), poly (carbophenoxypropane), poly (fumaric acid) or copolymers thereof. Examples of the active ingredients are medicinal agents, toxins, insecticides, viruses, diagnostic supports, agricultural chemicals, commercial chemicals, fine chemicals, food products, dyes, explosives, paints, polymers or cosmetics etc. The active ingredients can have a high molecular weight (defined herein as more than 5,000 Daltons) such as, but not limited to, proteins, antigens, such as Helicobacter antigen, polypeptides, polynucleic acids, polysaccharides or a low molecular weight substance (defined herein as 5,000 Dalton or less) such as, but not limited to, Bodipy®. The enzymatic activity and the immunogenic activity of the proteins can be maintained by using the process according to the invention. In the present, the definition of a fluid gas includes the material in its supercritical and almost supercritical state as well as the compressed gases. The supercritical fluid
it may be, but is not limited to, carbon dioxide, nitrous oxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane. The quasi-supercritical state is defined herein, as the state where the pressure and / or temperature is below the critical values. For example, the lower level of the almost supercritical state with respect to carbon dioxide is 00.65 Tc (critical temperature) and for propane it is 0.30 Te. The described emulsion system may contain one or more additives, such as, but not limited to: buffers, for example phosphate, carbonate, tris (hydroxymethyl) aminoethane (TRIS) etc. - substances to increase the chemical and / or physical stability of the substance, for example trehalose and polyethylene glycol (PEG); adjuvants to further enhance the effect of the active substance, for example, stimulators of the immune response such as a lipid A and its derivatives, cholera toxin (CT), or absorption enhancers, for example, mono- or diglycerides, fatty acids, bile salts or enzyme inhibitors, for example, aprotonin, ethylenediaminetetraacetic acid, acid
polyacryl, or adjuvants for the selectivity of the active principle, for example, the antibodies; solubilization agents, such as n-octyl-b, D-glycopyranoside (n-OG). The present invention can be briefly described as a process for the preparation of a formulation comprising an active ingredient or active ingredients associated with a carrier, characterized in that - an emulsion is prepared by mixing a liquid, a non-aqueous phase and a liquid, a aqueous phase, the aqueous phase comprising the active principle or active principles and the carrier that is present in at least one of the phases, the emulsion is contacted with the fluid gas using an anti-solvent technique, - the units released from the liquid phase.
The process chosen to manufacture the carrier system is exemplified by the following general description, and in the experimental section below: In general, these procedures are based on the formation of the carrier system by the following steps:
- preparing an aqueous phase containing the active ingredient (s), - preparing a non-aqueous phase (not miscible with the aqueous phase), - dissolving the carrier material, emulsifier and / or additives in the non-aqueous phase and / or aqueous phase - forming the emulsion which is comprised of at least one aqueous phase and one non-aqueous phase; - use the fluid gas technique to form the carrier system with the active principle. The first step can be carried out by dissolving, dispersing and / or solubilizing the active principle (s) in the aqueous phase. The fourth step can be carried out using different techniques for emulsification, such as homogenization or ultrasonic or high pressure homogenization. The microemulsion or macroemulsion can also be called double-emulsion, in which the non-aqueous phase is dispersed in the aqueous phase (containing the active ingredients) which is dispersed in another non-aqueous phase or in which the aqueous phase (containing the
active) is dispersed in the non-aqueous phase which is dispersed in another aqueous phase. In the fifth step, the fluid gas techniques used for the formation of the carrier systems with the active principle are antisolvent techniques such as, but not limited to, SED ?, ASES, SAS, GAS and PCA. If the aqueous phase is the most extreme phase of the acroemulsion or microemulsion, a modifying agent may be needed to mix with the fluid gas or to be co-injected with the emulsion just before contact with the fluid gas.
This modifying agent is an organic solvent such as, but not limited to, ethanol and acetone. The carrier system containing the active ingredients according to the invention can be used for pharmaceutical purposes such as, but not limited to, therapeutic, prophylactic and diagnostic purposes. When the invention relates to pharmaceutical applications, the carrier system loaded with the active ingredient can be administered by different routes of administration, such as, but not limited to, oral, rectal, tonsillar, buccal, nasal, vaginal, parenteral,
intramuscular, subcutaneous, intraocular, pulmonary, transdermal, implant, or intravenous. The pharmaceutical dosage form that is prepared for use with this technique can be a solid, semi-solid, or liquid dispersion which is prepared by the use of well-known pharmaceutical techniques such as mixing, granulation, compression, coating, etc. In addition, the formulations may be monolithic, such as tablets, or capsules, or in the form of multiple formulations administered in a tablet, capsule or sachet. The size of the droplet can be affected by the emulsifiers, because the emulsifiers can dissolve to a certain extent in the continuous phase. Normally, the emulsifiers lower the surface energy, which contributes to a decrease in the size of the droplet. The emulsifiers can affect the agglomeration of the carrier systems because they can be located in the supercritical droplet / interface. When the droplet is transformed into a carrier system, the emulsifiers can still be located on the surface of the carrier system.
Therefore, the location of the emulsifier on the surface or in the carrier system, can decrease the degree of agglomeration that is formed in the carrier system, as previously described for the polymer particles (Mawson et al., Macromolecules, 1997, 30, 71).
In addition, the emulsifiers for the emulsion, which are incorporated in the carrier system as well as the substance or substances, can improve the characteristics of the release of the carrier system, for example, but not limited to, solubilization of the substance and further penetration. fast water in the carrier system.
EXPERIMENTAL SECTION Materials and Methods In this section, the materials, analytical methods and preparation techniques used in the following Examples are described below: Poly (3-hydroxybutyrate) (PHB, Astra Tech, Sweden, molecular weight (MW) 63500 g / mol) or the poly (DL-lactic-co-glycolic acid) 50:50 (PLG RG 502 H, Boehringer Ingelheim, Germany, MW 6000 g / mol) are used as carrier materials. The n-octyl-β-glucopyranoside (n-OG,
Sigma, MO, USA), poly (vinylpyrrolidone) (PVP, Aldrich, Germany, MW 10000 g / mol) and sodium 1,4-bis (2-ethylhexyl) sulfosuccinate (AOT, Sigma, MO, USA) are used. as stabilizers. Methylene chloride (99.5%) is used as a solvent and carbon dioxide as a supercritical fluid. Ethanol is used as a modifier in supercritical processing. Two different proteins are used: a carbonic anhydrase that is highly soluble in water (CA, Sigma, MO, USA) and lipidated Helicobacter pylori adhesion protein A, and insoluble in water, in stock solution (HpaA, CSL, Australia) . A fluorescent substance used as a low molecular weight model substance is Bodipy® (D3238, Molecular Probes Europe, The Netherlands). In the protein analysis, the SDS-Laemmli reactive solution is prepared by diluting a quarter of the stock solution consisting of 1.25 ml of the TRIS-HC1 2M buffer (pH 6.8), 5.05 g of glycerol (99%), 0.8 g of sodium dodecyl sulphate (SDS), 1 ml of 2-mercaptoethanol, 1 μl of bromophenol blue and 10 ml of water.
Analysis of the Particles The size, shape and morphology of the particle are analyzed when using scanning electron microscopy.
Determination of the Load of the Active Principles PHB Particles a) Total protein content: The particles (3-10 mg) are dissolved in 300 μl of chloroform. SDS-Laemmli (400 μl) is added and the protein is extracted from the organic phase into the aqueous phase. The samples are stirred at 60 ° C for 30 minutes. The aqueous phase is heated at 95 ° C for 15 minutes and the protein content is analyzed by means of polyacrylamide gel electrophoresis (SDS-PAGE). b) Bodipy content9 Water (5 ml) is added to 2 mg of particles containing Bodipy® (undissolved particles). The Bodipy® is released from the particles and the concentration is determined spectroscopically (absorptivity of 97000 M "1 cm3 GBC UV / VIS 920, Australia).
PLG particles a) Total protein content 1 ml of acetone is added to the PLG particles (3.10 mg). The polymer dissolves, while the protein precipitates. The protein precipitate is centrifuged for 15 minutes at 17530 x g and approximately 2/3 parts of the supernatant are removed by a Hamilton syringe. Pure acetone (1 ml) is added to wash the precipitate twice. The remaining acetone is evaporated by vacuum centrifugation. SDS-Laemmli (200 μl) is added and the sample is heated at 95 ° C for 15 minutes. The analysis of the protein content is carried out by SDS-PAGE. b) Analysis of the amount of the protein associated with the surface: The analysis of the amount of the protein associated with the surface is carried out according to Rafati et al. { Journal of Controlled Relay 1997 43, 89-102). 2 ml of 2% SDS (w / v) in water are added to 5-6 mg of PLG particles. The samples are stirred for 4 hours. The samples are then centrifuged at 2700 x g for 3 minutes and the supernatant is placed in a new tube. The water evaporates by means of
centrifugation under vacuum and add 1 ml of Laemmli (without SDS). The aqueous phase is heated at 95 ° C for 15 minutes and the amount of proteins is quantified by means of SDS-PAGE.
Preparation of the Particles The particles are prepared, in a SEDS equipment (Bradford Partióle Design, Bradford, UK) from the emulsion containing the active principle and the carrier (WO9501221 and WO 9600610). The emulsion and antisolvent (C02) are introduced into a coaxial nozzle that is located in a pressure vessel located in an oven. Under controlled conditions of pressure and temperature, antisolvent extracts the solvent from the droplets of the emulsion are formed. Therefore the concentration of the carrier in the droplets is increased, which allows a rapid formation of particles. The particles are collected in a container, while the antisolvent and the extracted solvent emerge through a back pressure regulator.
The nozzle uses a three-component nozzle that connects either in interleaved mode, or in a
two solutions, with an opening of 0.2 mm in diameter. In the intercalated mode, the supercritical fluid passes through the innermost passage, and in the outermost passageway, while the emulsion passes through the intermediate passageway. In the two-solution mode, the emulsion and the modifier, such as ethanol, are mixed before contact with the supercritical fluid. The supercritical fluid passes through the external passage, the modifier passes through the intermediate passage 10 and the emulsion passes through the internal passage.
Example 1. HpaA in PHB, water content of the emulsion: 20% (v / v) The PHB is dissolved in methylene chloride at 2 bar, 15-90 ° C. Equal volumes of PVP are mixed at 2% (w / w) (aq.) And a solution in the presence of HpaA [1.11 mg / ml HpaA in the buffer TRIS-HC1 (10 mM, pH8) and n-OG at 2 % (p / p)]. This mixture (3.8 ml) is injected (during the homogenization at 20,000 rpm) to 15.2 ml of methylene chloride containing 1% (w / w) PHB and 0.4% (w / w) AOT in a Kinematica container. 25 ml dispersion. The total homogenization time lasts 3 minutes. He
The homogenizer used is the Polytron PT300, Rotor PT-DA 3012/2 (Kinematica AG, Switzerland). All procedures are carried out under environmental conditions. Two series of this emulsion are made with different running conditions in the SEDS equipment. Series 1 is carried out using the three component nozzle in the two ethanol solution mode (flow rate 0.5 ml / min) as a modifier. In series 2, interleaved mode is used (Table 1).
Table 1. SEDS processing of the emulsion in Example 1
According to the SEM graphs, the particle size is 1-3 μm for both tests (series 1 and series 2).
The theoretical composition of the particles must be
55. 8% (w / w) of PHB, 43.5% (w / w) of surfactants, 0.6% (w / w) of HpaA. The quantification of the total amount of HpaA in the particles gives a result of 0.4% of HpaA for series 1 and series 2.
Example 2. Bodip-y ^ in PHB, water content in the emulsion: 33% (v / v) The purpose is to associate a molecule of low molecular weight to the carrier matrix using an emulsion with a water content of 33% ( v / v). The PHB is dissolved in methylene chloride at 2 bar, 90 ° C. Equal volumes of 2% (w / w) of PVP (aq) and 2% (w / w) of n-OG, 1.0 ml of Bodipy® are mixed in the TRIS-HC1 buffer (10 mM, pH 8). This solution (2 ml) is injected (during homogenization to
20000 rpm) to 4 ml of methylene chloride containing 1%
(p / p) of PHB and 0.4% (w / w) of AOT in a container
Kinematica of dispersion of 25 ml. The total homogenization time lasts 3 minutes. The homogenizer used is the Polytron PT3100, Rotor PT-DA 3012/2 (Kinematica AG,
Switzerland) . All procedures are carried out under environmental conditions. Ethanol is used as
modifier (the three-component nozzle connects in two-solution mode) with a flow velocity of
0. 5 ml / min. The conditions of the series are presented in Table 2.
Table 1. SEDS processing of the emulsion in Example 2
According to the SEM graphs, the particles are of a size of 1-3 μm. The remains of a fluorescent substance in the container can not be detected with the flow of carbon dioxide. This means that the Bodipy® is not extracted by the supercritical fluid or by the solvents used.
Example 3. Bodipy in PHB, water content of the emulsion: 20% (v / v)
The purpose is to associate a molecule of low molecular weight to a carrier matrix (as in Example 2) using an emulsion with a water content of 20% (v / v). Dissolve the PHB in methylene chloride at 2 bar, 90 ° C. 2% (w / w) of PVP (aq.) And 2% (w / w) of n-OG, 1.0 mg / ml of Bodipy® in the TRIS-HC1 buffer (10 M, pH 8) are mixed at equal volumes. ). This solution (2 ml) is injected (during homogenization at 20,000 rpm) into 8 ml of methylene chloride containing 1% (w / w) of PHB and 0.4% (w / w) of AOT in a dispersion Kinematic container of 25 ml. The total homogenization time lasts 3 minutes. The homogenizer used is the Polytron PT3100, Rotor PT-DA 3012/2 (Kinematica AG, Switzerland). All procedures are carried out under environmental conditions. The series 4 is carried out with SEDS equipment using a three-component nozzle in the two-solution mode with ethanol (flow rate 0.5 ml / min). In series 5, interleaved mode is used (Table 3).
Table 3. SEDS processing of the emulsion in Example 3
Both batches have a particle size between 1-3 μm, according to the SEM graphs. The theoretical composition of the particles is 55.8% (w / w) of PHB, 43.5% (w / w) of surfactants and 0.6% (w / w) of Bodipy®. The amount of Bodipy® associated with the particles of series 5 is 0.7% (w / w) according to the quantification.
Example 4. Carbonic anhydrase in PLG, water content of the emulsion 20% (v / v) An amount of 200 μl in 20mg / ml of carbonic anhydrase (93%) in the TRIS-SOß buffer (0.1M, pH 7.5) it is added to 800 μl of PLG at 8% (w / w), 0.4% (w / w) of Span
85 / Tween 80 (weight ratio of 80:20) during the
homogenization with an ultrasonic probe (CV26, Sonics S Materials Ine, USA), at approximately 30-50 W for 3 minutes. The emulsion is prepared in a 4 ml glass vessel on ice. Shifting conditions during the preparation of the particles are shown in Table 4. The series is carried out with the three-component nozzle in the interleaved mode.
Table 4. SEDS technique of the emulsion in example 3
According to the SEM graphs, the particles obtained have a particle size between 10-100 μm. The theoretical composition of the particles is 91.4% (w / w) of PLG, 4.6% (w / w) of surfactants and 4.0%
(w / w) of carbonic anhydrase. The quantification of the amount of proteins gives a result of 4% (w / w) of
carbonic anhydrase and there are no proteins associated with the surface of the particles.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (33)
1. A process for the preparation of a formulation comprising an active ingredient or active ingredients associated with a carrier, characterized in that: - an emulsion is prepared by mixing a liquid, an aqueous phase and a liquid, an aqueous phase, the aqueous phase includes the active ingredient or active ingredients and the carrier is present in at least one of the phases, the emulsion is brought into contact with the fluid gas using an anti-solvent technique, and - the units liberated from the aqueous phase are obtained.
2. A process according to claim 1, characterized in that the active principle is dissolved in the aqueous phase.
3. A process according to claim 1, characterized in that the active principle is dissolved in the aqueous phase.
4. A process according to claim 1, characterized in that the active principle is solubilized in the aqueous phase.
5. A process according to any of the preceding claims, characterized in that the active principle is a protein.
6. A process according to claim 5, characterized in that the active principle is an antigen.
7. A process according to claim 6, characterized in that the active principle is a Helicobacter antigen.
8. A process according to claim 7, characterized in that the active ingredient is protein A of adhesion of Helicobacter pylori, insoluble in water and lipidated.
9. A process according to claim 8, characterized in that the active principle is the specific, fully lipidated form of the adhesion protein A of Helicobacter pylori.
10. A process according to claims 1-4, characterized in that the active principle is a substance of low molecular weight.
11. A process according to any of the preceding claims, characterized in that the non-aqueous phase contains an organic solvent.
12. A process according to any of the preceding claims, characterized in that the non-aqueous phase contains a mixture of organic solvents.
13. A process according to any of the preceding claims, characterized in that the aqueous phase is more polar than the non-aqueous phase.
14. A process according to any of the preceding claims, characterized in that the emulsion is a macroemulsion.
15. A process according to any of the preceding claims, characterized in that the emulsion is a microemulsion.
16. A process according to any of the preceding claims, characterized in that the emulsion is a combination of a macroemulsion and a microemulsion.
17. A process according to any of the preceding claims, characterized in that the emulsion contains an emulsifier.
18. A process according to claim 17, characterized in that the emulsifier is a nonionic surfactant.
19. A process according to claim 17, characterized in that the emulsifier is an anionic surfactant.
20. A process according to claim 17, characterized in that the emulsifier is a cationic surfactant.
21. A process according to claim 17, characterized in that the emulsifier is a switerionic surfactant.
22. A process according to claim 17, characterized in that the emulsifier is a polymer.
23. A process according to claim 17, characterized in that the emulsifier is a lipid.
24. A process according to any of the preceding claims, characterized in that the carrier is poly (3-hydroxybutyrate).
25. A process according to any of the preceding claims, characterized in that the carrier is poly (DL-lactic-co-glycolic acid).
26. A process according to any of the preceding claims, characterized in that the emulsion makes contact with a fluid gas by the fluid gas technique.
27. A process according to claim 26, characterized in that the fluid gas technique used is SEDS.
28. A process according to claim 26, characterized in that the technique used for fluid gas is ASES.
29. A process according to claim 26, characterized in that the fluid gas technique used is SAS.
30. A process according to claim 26, characterized in that the fluid gas technique is GAS.
31. A process according to claim 26, characterized in that the fluid gas technique used is PCA.
32. A process according to any of the preceding claims, characterized in that the fluid gas is carbon dioxide.
33. A formulation prepared as described in any of the preceding claims.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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SE9801287-5 | 1998-04-14 |
Publications (1)
Publication Number | Publication Date |
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MXPA00009914A true MXPA00009914A (en) | 2001-07-31 |
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