EP1603539A1 - Procede de fabrication de microspheres de sucre de petite taille et leurs applications - Google Patents
Procede de fabrication de microspheres de sucre de petite taille et leurs applicationsInfo
- Publication number
- EP1603539A1 EP1603539A1 EP04742280A EP04742280A EP1603539A1 EP 1603539 A1 EP1603539 A1 EP 1603539A1 EP 04742280 A EP04742280 A EP 04742280A EP 04742280 A EP04742280 A EP 04742280A EP 1603539 A1 EP1603539 A1 EP 1603539A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- sugar
- microspheres
- syrup
- spraying
- size
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- the present invention relates to a new process for manufacturing microbeads or microspheres of small sugar, that is to say less than 500 ⁇ m and preferably between 100 and 500 ⁇ m in particular usable in the pharmaceutical industry as pharmacologically neutral carriers of active ingredients.
- the present invention also relates to the microbeads or microspheres thus obtained, the almost perfect sphericity of which make them quality products for the manufacture of products which can be absorbed orally. Finally, the present invention relates to the uses which can be made of such products, both in the field of the pharmaceutical industry, in particular for the manufacture of microgranules highly and or weakly dosed in active principles and in the field of industry. food.
- the process according to the invention involves alternating fine and controlled spraying phases, on the surface of solid microparticles of sugar, of a syrup composed of one or more sugars identical or different from that of solid microparticles and of phases of drying of the various successive layers thus applied during the formation of the microgranules.
- Sugar microbeads used, for example, as spherical carriers of active principles in the manufacture of oral medicaments based on microgranules, are also called “not the same” or more generally “neutral” because of their pharmacological neutrality.
- pellets or “sugar spheres”. All these terms designate sugar microspheres generally between 100 ⁇ m and 1500 ⁇ m in size. In the present application, the sugar microspheres in accordance with the invention always have a particle size of less than 500 ⁇ m and will be indifferently called microspheres or microbeads.
- sucrose will denote any pharmacologically inactive substance belonging to the chemical class of oses, comprising between 4 and 24 carbon atoms.
- solid sugar support will be used in the present application to designate the solid particles of raw material onto which the sugar syrup will be sprayed or “coating suspension”.
- solid sugar support will therefore denote, depending on the case, sugar crystals or amorphous sugar particles such as cellular sugar particles or non-crystalline agglomerated particles such as microparticles recycled during the process in accordance with the invention.
- assembly also denotes the operation which consists in applying to the surface of the sugar microbeads, a liquid substance, for example an active principle in solution.
- the present invention relates to a new process for the manufacture of sugar or "neutral" microspheres, used both in the pharmaceutical industry as a basic support for the manufacture of spherical microgranules loaded with active ingredients, and in the food industry , for the manufacture of edible marbles, mounted or not with other substances.
- microbeads are indeed very useful for the synthesis of microgranules used in the composition of drugs absorbable by the oral route. Indeed, such microgranules are intended, as necessary, either for filling gelatin capsules either to be used to form orodispersible or gastrodispersible tablets after a compression step.
- Such sugar beads is carried out on the basis of solid sugar particles, preferably sugar crystals of a size between 500 and 1000 ⁇ m on which a small amount of an aqueous solution intended for "wetting" is sprayed. "solid particles of sugar. Immediately after the wetting step, we then proceed to the dusting phase intended to increase the size of the sugar microspheres being formed.
- This dusting step is an essentially manual step in which an amount of sugar, in the form of dry powder, is sprayed in an uncontrolled manner onto the surface of the previously wetted crystals. The powder thus projected agglomerates on the surface of the crystals, the diameter of which thus increases. Then reiterating on these sugar microgranules a new wetting step which will be immediately followed by a dusting step until microspheres of the desired size are obtained.
- Such a process has the advantage of having a reduced drying time and it also allows a relatively rapid magnification of the sugar microspheres.
- this process is not suitable for the manufacture of microspheres of a size less than 500 ⁇ m, due to the size of the starting sugar crystals.
- controlling the size of the microspheres is difficult, in particular because of the speed of magnification of the microspheres during dusting.
- this process is not very reproducible insofar as the manual manufacturing mode does not allow precise control of the powdering parameters in particular.
- sugar microspheres are also routinely manufactured for the pharmaceutical industry where they serve as a support for the synthesis of microgranules mounted with active ingredients. Such an assembly is carried out by spraying the active substance and / or the envisaged excipients, previously dissolved in an aqueous or organic solution.
- neutrals of a size generally around 500 to 800 ⁇ m are subjected to such a spraying, then to a drying phase allowing the start of a new spraying cycle.
- the deposition of active principle is therefore carried out by successive spraying / drying cycles, until the neutral carries a determined quantity of active principle.
- This method applied to the assembly of the active ingredients requires a fine spraying also called “atomization" of the envisaged solution and moreover an effective drying step before starting a new spraying / drying cycle.
- This process is well suited for the "assembly" of sugar granules with a relatively large diameter, that is to say greater than 2 mm. Indeed, the blank or impregnated granules of this size do not tend to agglomerate with one another during the impregnation and are kept in constant and relatively homogeneous movement by the rotation of the cylinder containing them.
- microspheres of a size between 100 ⁇ m and 1000 ⁇ m is taught in US patent 5,505,983.
- microspheres composed of at least 50% of highly cross-linked microcrystalline cellulose and possibly a lactose-type sugar are obtained by mixing the powder containing the cellulose and the optional sugar with water. This semi-solid mixture is then kneaded then introduced into a rotary machine which will induce the formation of microspheres by granulation effect. The microspheres being formed are simultaneously rotated, sprayed with water, then dried and sieved.
- microspheres of small size that is to say of a diameter of less than 1000 ⁇ m, comprising at least 50% of highly cross-linked microcrystalline cellulose.
- this process requires a step of sorting the microspheres thus obtained, due to the heterogeneity of the sizes observed after wet granulation.
- This process is therefore limited to certain constituents and does not offer perfect quality in terms of sphericity, convexity and uniformity in size.
- This powdering process does not allow very homogeneous and very convex particles to be obtained.
- it is limited to the use of certain sugar-alcohols and not generalizable to the constituents usually used for the synthesis of "not the same".
- the object of the present invention is therefore to provide a new process for manufacturing sugar microspheres of the non-similar type, with a diameter of less than 500 ⁇ m, of good size uniformity and having satisfactory convexity and sphericity.
- Sphericity corresponds to a two-dimensional measurement of the overall shape of the microparticles.
- the sphericity corresponds to the ratio of the longest diameter to the shortest diameter measured on the microparticle.
- the sphericity is therefore also a value between 0 and 1, a perfect sphere having a sphericity of 1, a rod having a sphericity of 0.
- the diameters are measured under the microscope.
- the terms circularity and sphericity will be used interchangeably.
- microspheres condition the ease with which we will be able to use them on an industrial scale. Indeed, when handling large volumes of microspheres, it is important that their fluidity, or flow index, within the different machines (turbine, air bed, melter, sieve etc.) is the most important possible. This avoids agglomeration problems which hinder the use of such products.
- the sphericity also conditions the compression of such particles.
- the drawback of using powders, which have good fluidity is that they are very difficult to compress, and therefore not very subject to the manufacture of tablets. Powder compression thus requires a prior granulation step. But such granulation leads to particles whose qualities of sphericity and convexity are poor, moreover, the size of the particles obtained is not homogeneous.
- the convexity corresponds to a three-dimensional measurement of the shape of the object. This measurement consists in making the ratio between the real surface of the object considered and the surface of an imaginary rubber band surrounding this object.
- This characteristic is important in the case of microspheres intended to be mounted by a low-dose active principle.
- the lower the convexity of the particle serving as a support, that is to say that it has numerous recesses and asperities on the surface the more the amount of material depositing on this surface will vary by particle. to the other.
- the variability between the quantities of substance deposited on the surface of these particles is reduced at the same time. This is particularly important in the case of the assembly of low-dose active ingredients, where the amount of active substance must be absolutely homogeneous from one batch of particles to another.
- the method according to the invention therefore aims to provide sugar microspheres of size less than 500 ⁇ m whose sphericity and convexity is the best possible and which have good compression capacities and a high flow index.
- the present invention also aims to improve the production yield of such microspheres usually obtained by the "dusting" method.
- the method according to the invention is both simple, does not require any particular installation and is relatively inexpensive.
- the present invention makes it possible to solve the problem of the reproducibility of the process for manufacturing these microspheres by describing a process the steps of which are practically all automated and precisely configurable.
- the present invention is particularly suited to the regulatory constraints of the pharmaceutical industry relating to the quality of the excipients and of the raw material used in the composition of the drugs.
- the present invention has the advantage of allowing the manufacture of such microspheres from simple components, usually used for the manufacture of "neutrals" usually used in the pharmaceutical industry, namely, in particular, sucrose and l 'corn starch. As a result, its implementation is all the easier and adapted to the requirements of the industry.
- the present invention firstly has the advantage of making it possible to obtain microspheres of size less than 500 ⁇ m, having both good size uniformity, that is to say at least 90% sugar microspheres have the desired size and satisfactory convexity and sphericity. Due to the almost total automation of the process, the microspheres in accordance with the invention also have a relatively low cost price and above all a design quality (absence of impurities, absence of organic solvents) which makes them suitable for use approved by the quality standards of regulatory organizations in the field of medicines, such as the FDA and the European Medicines Agency.
- the small microspheres or "neutrals” obtained by the process which is the subject of the invention finally has the advantage of being a choice support for principles "highly dosed” active ingredients.
- their small diameter makes it possible to manufacture microgranules of a conventional size, thus allowing the accumulation on their surface of even greater quantities of active principles.
- sugar microspheres in accordance with the invention are therefore particularly advantageous for the manufacture of medicaments in the form of microgranules, based on highly dosed active principles.
- microgranules dosed in a conventional manner, and having a smaller diameter than the "conventional" microgranules.
- microgranules of 100 to 500 ⁇ m can be used in the constitution of medicaments in the form of tablets, the reduced size of which facilitates their absorption by the patient.
- the physical characteristics of the microspheres in accordance with the invention make them choice supports for very low-dose active ingredients.
- very active substances such as hormones for example must be deposited on the surface of the microspheres in a perfectly controlled amount.
- the quality of the microspheres therefore depends on the quality and reproducibility of the deposit on their surface. Indeed, for low dosages, of the order of micrograms for example, it is necessary that the dosage retains good statistical reproducibility. This reproducibility is ensured by the microspheres obtained according to the process according to the invention which exhibit perfect homogeneity in size and shape.
- the process which is the subject of the invention has the advantage of being very profitable, in fact, the loss of material observed, compared with a conventional process for manufacturing neutrals of size between 100 and 500 ⁇ m by "dusting "is relatively limited, as shown in Table 1.
- This manufacturing method although slower than the powdering process, remains much more precise and refined, it is also responsible for the good sphericity and the good convexity of the microspheres thus obtained.
- the spraying of the syrup according to the invention consists in spraying, through a pneumatic nozzle called "flat jet", a determined quantity of syrup and a quantity of air intended to nebulize said syrup at the outlet of the nozzle.
- This system is therefore completely different from conventional spray gun projection systems, such as those used in powdered assemblies, where the liquid is sprayed alone.
- This latter type of spraying is necessarily much coarser and less precise than the spraying by atomization (or nebulization) used for carrying out the present invention, in which a very small amount of syrup is sprayed onto the surface of the formation, under the shape of a "mist" form, ensuring a very gradual and very homogeneous magnification of the microspheres.
- the plaintiff's merit is therefore to have succeeded in developing such a process for the synthesis of sugar microspheres by spraying such a viscous syrup.
- the syrups in accordance with the present invention have a viscosity of between 50 and 75 centipoise at 70 ° C.
- syrups whose viscosity is between 65 and 70 centipoise measured at 70 ° C, that is to say the temperature at which the spraying is carried out.
- Such a spraying was made possible by spraying said syrup very finely in order to avoid the drawbacks described above.
- the process which is the subject of the invention has the advantage of being very reproducible since all the spraying, drying and selection steps are automated and can be configured as a function of the desired finished product.
- This characteristic makes it possible to produce very similar microspheres from one batch to another, both in terms of shape and size, therefore perfectly suited to the strict requirements and specifications of the European, Japanese or American pharmacopoeias for example .
- the present invention thus relates to a new process for obtaining sugar or "neutral" microspheres, the major characteristic of which is that it makes it possible to obtain microspheres of size less than 500 ⁇ m, of very homogeneous shape and size.
- the manufacture of the microspheres is started from a solid sugar support, onto which the coating suspension or "syrup" of liquid sugar will be sprayed.
- sugar support is understood to mean solid sugar, either in the form of crystals, or of sugar particles in amorphous form such as alveolar sugar or starch icing sugar, icing sugar silica, alveolar sugar and COMPRES SUCRE®, or again in the form of sugar microparticles agglomerated together during a first manufacturing phase of the present process and eliminated from the manufacturing cycle by sieving, due to their too small size.
- These latter microparticles, of size less than 200 ⁇ m, also called Semi-Worked Product have the advantage of having good sphericity and good convexity, which facilitates the obtaining of microspheres having these same characteristics.
- the sugar particles in amorphous form, constituting the solid support have a size of between 50 and 200 ⁇ m.
- said sugar crystals consist of sugars belonging to the group comprising sucrose, maltose, glucose, dextrose, mannose, galactose, fructose, ribose, lactose, maltose, mannitol, sorbitol and xylitol, and advantageously have a size between 50 and 200 ⁇ m, preferably between
- said sugar syrup is composed of a mixture of one or more sugar (s) and a liquid, the said sugar (s) belonging to the group of sugars comprising between 4 and
- said sugar syrup consists of one or more sugar (s) and a liquid, said sugar (s) belonging to the group comprising sucrose, maltose, glucose, dextrose, mannose, galactose, fructose, ribose, lactose, maltose, mannitol, sorbitol and xylitol.
- said liquid is a pharmacologically acceptable liquid, preferably water.
- said syrup also contains pharmacologically acceptable additives, such as dyes, lubricants, surfactants and antioxidants.
- the method according to the invention consists in spraying in a fine and controlled manner, onto the surface of solid sugar microparticles, a syrup based on the same or different sugar, said solid sugar particles being kept in motion in a turbine in rotation.
- the process according to the invention is therefore mainly organized in two distinct phases: a first controlled spraying phase, followed by a second drying phase of the microparticles having received the syrup spraying.
- the spraying phase in accordance with the present invention is itself broken down into two distinct stages: a first phase known as “pre-granulation” and a second phase of granulation proper.
- the spraying is carried out advantageously by nebulization by means of a pneumatic nozzle with j and flat.
- the pre-granulation phase consists in manufacturing "primers” which are then used as solid support in the granulation phase proper.
- primers thus correspond to sugar microspheres of size between 100 ⁇ m and 200 ⁇ m resulting from the accumulation of syrup on the surface of the solid support of sugar used as starting base, that is to say, as the case may be. , either sugar crystals, or sugar in amorphous form, or else microparticles resulting from the process, also called “semi-finished products” which will advantageously be recycled.
- the pre-granulation phase in accordance with the process according to the invention is an essential phase since it is this which will condition the obtaining of primers of acceptable sphericity and convexity, serving as a basis for the manufacture of the microspheres in accordance with the invention.
- the pre-granulation phase must be carried out precisely to disperse the coating suspension uniformly on the surface of the solid support of sugar chosen. Spraying or atomization is in fact carried out at a low flow rate and for relatively long periods of time. This step is the longest in the process.
- the spraying during the pre-granulation phase is carried out at a low flow rate, advantageously less than 120 ml / min, and preferably between 60 ml and 120 ml per minute. More preferably, the flow rate chosen for this step is 80 ml per minute.
- This step thus comprises numerous spraying / drying cycles, the spraying being carried out at a low flow rate, the number of cycles necessary for obtaining primers of correct size is between 2000 and 3000 depending on the size of the microspheres sought.
- each cycle corresponding in fact to a fine spraying phase of the syrup, followed by a so-called microsphere drying phase during which the spraying is stopped.
- the continuous use of the pulsed air stream contributes to solidifying the liquid sugar previously sprayed.
- the diameter of the microspheres in formation gradually increases.
- the duration of a spraying / drying cycle is one minute, during which 20 seconds are spent on the actual spraying and 40 seconds are spent on drying (no spraying).
- such cycles can be easily adapted according to the size and nature of the materials used for the manufacture of the microspheres in accordance with the invention. These time intervals are therefore not limiting.
- the pre-granulation phase usually lasts between 30 hours and 60 hours, and more generally between 40 hours and 50 hours, to allow a gradual and regular magnification of the microspheres in accordance with the invention.
- the so-called granulation phase occurs after the pre-granulation stage and consists in using the "primers" manufactured during this last stage and in increasing their diameter by new spraying / drying cycles, at a spraying rate more Student.
- 350 to 500 spraying / drying cycles will be carried out on the primers from the pre-granulation step, at a spraying rate of between 100 ml and 300 ml per minute.
- the microspheres are dried and dehydrated.
- This final drying phase advantageously lasts between 1 hour and 7 hours, preferably from 2 hours to 4 hours depending on the type and size of the microspheres manufactured, the stream of pulsed air used for this purpose being brought to a temperature between 50 ° C and 80 ° C.
- Such a process is therefore entirely innovative in the manufacture of neutrals usually obtained by wet granulation, that is to say by mixing a dry powder of sugar with a sufficient quantity of water.
- the sugar crystals which can generally be used for carrying out the process according to the invention have a size of between 50 ⁇ m and 200 ⁇ m, preferably between 100 ⁇ m and 150 ⁇ m.
- the crystals which can be used as basic material in the process according to the present invention will preferably have a polyhedral shape, that is to say having a large number of faces which on the one hand increases their fluidity within the rotating turbine. and on the other hand improves the sphericity coefficient of the future "neutrals" obtained. Indeed, the more the starting material has a shape which closer to that of a sphere, the more the product coated from this base will be spherical.
- sugar crystals belonging to the carbohydrate family can be used as well and among them, certain simple dares such as hexoses, such as glucose, mannose or galactose for example or pentoses such as fructose or ribose for example.
- certain simple dares such as hexoses, such as glucose, mannose or galactose for example or pentoses such as fructose or ribose for example.
- sucrose is a product commonly used for the synthesis of neutrals and especially approved by the various national pharmacopoeias .
- crystals which can be used as solid sugar carriers in the present invention crystals of compounds derived from oses, such as those belonging to the group of sugar alcohols and among them, in particular sorbitol, mannitol, and xylitol.
- amorphous form of sugar that is to say a non-crystalline and therefore unorganized form such as pure icing sugar, granulated sugar or cellular sugar, such as that sold under the brand Alvéosucre®. It is also possible to use the sugar sold under the name "starch icing sugar”, that is to say amorphous sugar containing a small amount (of the order of 3%) of starch as an agent known as anti- clumping, that is to say preventing the formation of "lumps” or grains, due to the very hygroscopic nature of these sugars.
- the sugars sold under the name "silica sugar”, that is to say containing about 1% of silica as an anti-caking and thinning agent, can also serve as a solid sugar support, for the production of the present invention.
- particles of size between 50 ⁇ m and 250 ⁇ m will be used.
- amorphous sugar which can be used in accordance with the present invention
- the amorphous sugar sold under the brand name Compressucre®, the particles of which obtained by rapid evaporation of a solution of sucrose in a solvent, have a size of between 50 ⁇ m and 250 ⁇ m.
- the process for manufacturing sugar microspheres in accordance with the invention can also be carried out using semi-processed products resulting from this same process.
- microparticles which were eliminated during a first manufacturing phase due to their too small size, and which are also called PSO for semi-processed product can advantageously be used as solid starting raw material.
- the syrup which will be sprayed on the surface of the solid sugar particles and in particular of the crystals described above may be composed of a solution of one of the sugars mentioned above, preferably a sugar belonging to the family of simple sugars such as glucose or sucrose preferentially.
- This syrup is obtained by dissolving a dry powder of the aforementioned sugar in a solution of pure water or optionally supplemented with surfactants, salts or preservatives in small quantities as required.
- the sugar concentration in the syrup is an important element of the invention, in fact, the concentration conditions both the method of spraying, the drying time and the speed of magnification of the microspheres.
- This sugar concentration is advantageously between 700 g / liter and 980 g / liter.
- a sugar concentration of between 865 g / liter and 880 g / liter will be used for the production of the microspheres in accordance with the invention.
- the liquid sugar solutions used for the preparation of the syrups or "coating suspension" according to the invention will comprise an amount of water of between 25% and 40% of the total mass of liquid solution which corresponds to sugar concentration values between 700 g / liter and 980 g / liter.
- the proportion of water in the liquid solutions used for the preparation of said syrups is between 20% and 40%.
- a quantity of starch powder can be incorporated into the sugar solution, in accordance with the standards of the American pharmacopoeia defining the "sugar spheres".
- the amount of starch powder optionally added represents between 10% and 40% of the dry powder used for the formation of the syrup. Even more preferably, we will work for the realization of the present invention, with syrups whose starch powder represents about 20% of the total dry powder necessary for the constitution of said syrup.
- a flat-bottom turbine of conventional type is advantageously used, that is to say commonly used in the pharmaceutical industry for coating microgranules for example.
- the realization of the invention however requires the use of a non-perforated turbine, because of the small size of the microspheres produced inside which risk passing through perforations during the manufacturing process.
- an unperforated turbine with a capacity of 300 kg can be used, the speed of which can vary from 3 to 25 revolutions per minute.
- the spraying phases can be implemented in a fluidized air bed.
- Spraying the syrup on the surface of the sugar support can be carried out using a pneumatic atomizing nozzle such as nozzles of the type
- melt Spraying System sold under the brand name "Liquid 60100®” Melter: The syrup based on a mixture of sugar and possibly starch is made in a melter. This melter is a thermostatic jacketed tank fitted with an agitator and resting on a load cell or balance allowing precise measurement of the quantity of dry powder introduced. ' Generator :
- the syrup or "coating suspension” thus prepared is then stored in a thermostated storage tank.
- a tank of the OserTech double jacket type provided with an agitator.
- Drying System During and after each spraying phase, the sugar microspheres in formation are dried using a drying system allowing hot air to be drawn from the surface of the still wet microspheres from the spray.
- a drying system of the Hydronic steam dryer type with a capacity of 600m 3 / hour and per turbine could be used. » Dehydration system:
- the elimination of the moisture on the surface of the microspheres in formation is perfected by using a dehydration system making it possible to eliminate any trace of moisture in the enclosure for manufacturing the microspheres.
- a dehydrator of the Munters MLT 1400 dehydrator type with a capacity of 450 m 3 / hour and per turbine.
- Extraction system The quality of the microspheres obtained is also ensured by a dust extraction system which guarantees the purity of the air inside the turbine.
- a dust extraction system which guarantees the purity of the air inside the turbine.
- PLC tele-mechanical
- the entire process in accordance with the present invention is automated using a tele-mechanical automaton manufactured by Magelis which notably controls the speed, spraying, coating and drying parameters of the process.
- microspheres obtained at the end of the spraying and drying phases are selected according to the size sought on an automatic selection screen fitted with superimposed grids.
- the microspheres of size less than 500 ⁇ m obtained according to the process in accordance with the invention are selected on a stainless steel sieve composed of two screens making it possible to eliminate on the one hand the microspheres of size greater than 500 ⁇ m and more generally greater than the maximum size chosen and on the other hand the microspheres of size less than 90 ⁇ m.
- the latter can advantageously be reused in the present process as a solid sugar support as explained above.
- the upper frame allowing the retention of large particles has openings of 400 ⁇ m and is composed of wires from 180 to 250 ⁇ m in diameter.
- the lower screen allowing particles smaller than 90 ⁇ m to be removed, has openings of 90 ⁇ m in diameter and wires of 63 ⁇ m in diameter.
- the sugar support (sugar crystals or amorphous form or even semi-processed product) serving as a basis for future sugar microspheres is stored in a turbine of the conventional non-perforated type.
- a 150 kg bed of sugar is thus prepared which is placed at the bottom of the turbine.
- a single product will be used as the solid sugar support, for the same batch of microspheres, rather than a mixture of solid support from several origins to guarantee good homogeneity in size to the microspheres being formed.
- This sugar mass is then driven by the rotation of the turbine and preheated between 37 ° C and 40 ° C for 20 to 30 minutes.
- the solution intended to be sprayed onto the sugar support is prepared in the jacketed melter at a temperature of 70 ° ⁇ 5 ° C by dispersion of a proportion of 20% starch powder.
- the quantity of syrup is a function of the quantity of microspheres envisaged and of the final formula of the microspheres.
- the suspension obtained is then transferred to a double jacket generator and is kept at a constant temperature of 70 ⁇ 5 ° C throughout the manufacturing process with continuous stirring.
- the possible duration of a drying spray cycle is one minute.
- the spraying step lasts 20 seconds and alternates with the drying phase which lasts 40 seconds, and this for a spraying solution flow rate of 80 ml / minute.
- the drying phase corresponding to a continuous projection of air drawn at a temperature of 60 ° C.
- the speed of rotation of the turbine is reduced and the final drying stage of the microspheres starts and continues for approximately 3 hours.
- the dry product is sieved and the desired sizes are selected.
- Spray time (pre-granulation phase): 20 seconds
- Spray time (granulation phase): 40 seconds
- Spray rate 80 ⁇ 5 ml per minute Total spray time 49.5 hours
- Table I gives a comparison of the yields for obtaining small sugar microspheres by a conventional process called “dusting” and by the spraying process according to the present invention.
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- Polymers & Plastics (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0303408 | 2003-03-20 | ||
FR0303408A FR2852607B1 (fr) | 2003-03-20 | 2003-03-20 | Procede de fabrication de microspheres de sucre de petite taille, les microspheres susceptibles d'etre obtenues par ce procede et leurs applications |
PCT/FR2004/000662 WO2004084863A1 (fr) | 2003-03-20 | 2004-03-18 | Procede de fabrication de microspheres de sucre de petite taille et leurs applications |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1603539A1 true EP1603539A1 (fr) | 2005-12-14 |
Family
ID=32922308
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04742280A Withdrawn EP1603539A1 (fr) | 2003-03-20 | 2004-03-18 | Procede de fabrication de microspheres de sucre de petite taille et leurs applications |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1603539A1 (fr) |
FR (1) | FR2852607B1 (fr) |
WO (1) | WO2004084863A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160242432A1 (en) * | 2013-10-01 | 2016-08-25 | Bühler AG | Spherical particle, and food suspensions and consumable masses having spherical particles |
US20180056261A1 (en) * | 2016-08-30 | 2018-03-01 | Allergan, Inc. | Method of manufacturing coated beads |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201130428A (en) * | 2010-01-25 | 2011-09-16 | Japan Tobacco Inc | Method for making flavoring pellets |
WO2013043828A1 (fr) * | 2011-09-20 | 2013-03-28 | Grain Processing Corporation | Microsphères |
GB201418422D0 (en) * | 2014-10-17 | 2014-12-03 | Mars Inc | Confectionary production |
AU2016361838B2 (en) | 2015-11-30 | 2020-12-24 | Société des Produits Nestlé S.A. | Amorphous porous particles for reducing sugar in food |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0452862B1 (fr) * | 1990-04-18 | 1995-07-19 | Asahi Kasei Kogyo Kabushiki Kaisha | Noyaux des germes sphériques, granules sphériques et procédé de leur préparation |
PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
WO1997016078A1 (fr) * | 1995-10-27 | 1997-05-09 | Givaudan-Roure (International) S.A. | Granules d'aromes |
JP3447042B2 (ja) * | 1997-07-23 | 2003-09-16 | フロイント産業株式会社 | 単一物質球形粒の製造方法 |
ES2157731B1 (es) * | 1998-07-21 | 2002-05-01 | Liconsa Liberacion Controlada | Preparacion farmaceutica oral de un compuesto de actividad antifungica y procedimiento para su preparacion. |
FR2796840B1 (fr) * | 1999-07-26 | 2003-06-20 | Ethypharm Lab Prod Ethiques | Comprimes faiblement doses et procede de preparation |
-
2003
- 2003-03-20 FR FR0303408A patent/FR2852607B1/fr not_active Expired - Fee Related
-
2004
- 2004-03-18 WO PCT/FR2004/000662 patent/WO2004084863A1/fr active Application Filing
- 2004-03-18 EP EP04742280A patent/EP1603539A1/fr not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
None * |
See also references of WO2004084863A1 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160242432A1 (en) * | 2013-10-01 | 2016-08-25 | Bühler AG | Spherical particle, and food suspensions and consumable masses having spherical particles |
US11452302B2 (en) * | 2013-10-01 | 2022-09-27 | Buehler Ag | Spherical particle, and food suspensions and consumable masses having spherical particles |
US20180056261A1 (en) * | 2016-08-30 | 2018-03-01 | Allergan, Inc. | Method of manufacturing coated beads |
Also Published As
Publication number | Publication date |
---|---|
WO2004084863A8 (fr) | 2004-12-09 |
FR2852607A1 (fr) | 2004-09-24 |
WO2004084863A1 (fr) | 2004-10-07 |
FR2852607B1 (fr) | 2006-07-14 |
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