EP1603539A1 - Method of producing small microspheres of sugar, microspheres thus obtained and applications thereof - Google Patents

Method of producing small microspheres of sugar, microspheres thus obtained and applications thereof

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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Withdrawn
Application number
EP04742280A
Other languages
German (de)
French (fr)
Inventor
Michel Duval
Patrick Sanial
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nouveaux Produits Pharmaceutiques
Original Assignee
Nouveaux Produits Pharmaceutiques
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nouveaux Produits Pharmaceutiques filed Critical Nouveaux Produits Pharmaceutiques
Publication of EP1603539A1 publication Critical patent/EP1603539A1/en
Withdrawn legal-status Critical Current

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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
    • 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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Abstract

The invention relates to a novel method of producing microspheres of sugar having a particle size of less than 500 µm. The invention is characterised in that it consists in alternating (i) phases in which a sugar syrup is finely sprayed onto a solid support comprising one or more sugars and (ii) drying phases, until the microspheres are produced.

Description

PROCEDE DE FABRICATION DE MICROSPHERES DE SUCRE DE PETITE TAILLE, LES MICROSPHERES SUSCEPTIBLES D'ETRE OBTENUES PAR CE PROCEDE ET LEURS APPLICATIONS PROCESS FOR THE MANUFACTURE OF SMALL SUGAR MICROSPHERES, THE MICROSPHERES LIKELY TO BE OBTAINED BY THIS PROCESS AND THEIR APPLICATIONS
La présente invention se rapporte à un nouveau procédé de fabrication de microbilles ou microsphères de sucre de petite taille, c'est-à-dire inférieures à 500 μm et de préférence comprises entre 100 et 500 μm en particulier utilisables dans l'industrie pharmaceutique comme supports pharmacologiquement neutre de principes actifs.The present invention relates to a new process for manufacturing microbeads or microspheres of small sugar, that is to say less than 500 μm and preferably between 100 and 500 μm in particular usable in the pharmaceutical industry as pharmacologically neutral carriers of active ingredients.
La présente invention se rapporte en outre aux microbilles ou microsphères ainsi obtenues dont la quasi parfaite sphéricité en font des produits de qualité pour la fabrication de produits absorbables par voie orale. Enfin, la présente invention concerne les utilisations qui peuvent être faites de tels produits, à la fois dans le domaine de l'industrie pharmaceutique, notamment pour la fabrication de microgranules fortement et ou faiblement dosés en principes actifs et dans le domaine de l'industrie agroalimentaire.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.
Le procédé conforme à l'invention implique une alternance de phases de pulvérisation fine et contrôlée, à la surface de microparticules solides de sucre, d'un sirop composé d'un ou plusieurs sucres identiques ou différents de celui des microparticules solides et de phases de séchage des différentes couches successives ainsi appliqués au cours de la formation des microgranules.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.
Les microbilles de sucre utilisées par exemple comme supports sphériques de principes actifs dans la fabrication de médicaments oraux à base de microgranules, sont également appelés "non pareils" ou plus généralement "neutres" du fait de leur neutralité pharmacologique.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.
Ces microbilles sont également désignées sous les termes anglo-saxons deThese microbeads are also known by the Anglo-Saxon terms of
"pellets" ou encore de "sugar sphères". Tous ces termes désignent des microsphères de sucre d'une taille généralement comprise entre 100 μm et 1500 μm. Dans la présente demande, les microsphères de sucre conformes à l'invention ont toujours une taille de particulees inférieure à 500 μm et seront indifféremment dénommées microsphères ou microbilles."pellets" or "sugar spheres". All these terms designate sugar microspheres generally between 100 μm and 1500 μm in size. In the present application, the sugar microspheres in accordance with the invention always have a particle size of less than 500 μm and will be indifferently called microspheres or microbeads.
On désignera par le terme général "sucre", toute substance, pharmacologiquement inactive appartenant à la classe chimique des oses, comportant entre 4 et 24 atomes de carbone.The general term "sugar" will denote any pharmacologically inactive substance belonging to the chemical class of oses, comprising between 4 and 24 carbon atoms.
On emploiera dans la présente demande le terme "support solide de sucre" pour désigner les particules solides de matière première sur lesquelles va être pulvérisé le sirop de sucre ou "suspension d'enrobage". Le terme "support solide de sucre", désignera donc, suivant les cas ou des cristaux de sucre ou des particules de sucre amorphe telles que des particules de sucre alvéolaire ou des particules agglomérées non cristallines telles que des microparticules recyclées en cours de procédé conforme à l'invention.The term “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”. The term “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.
On désigne par ailleurs par le terme "montage", l'opération qui consiste à appliquer à la surface des microbilles de sucre, une substance liquide, par exemple un principe actif en solution.The term “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.
On doit distinguer le montage par pulvérisation du montage par poudrage, ce dernier consistant à déposer à la surface des microbilles de sucre préalablement humidifiées, une poudre sèche, de principe actif par exemple. Enfin, on entend par pulvérisation l'opération qui consiste à projeter de manière contrôlée et diffuse, un liquide à la surface d'une entité solide telle qu'une microsphère de sucre par exemple. Dans la présente demande, on parlera également d'atomisation pour désigner une pulvérisation fine et homogène.A distinction must be made between assembly by spraying and assembly by dusting, the latter consisting in depositing on the surface microbeads of sugar previously moistened, a dry powder, of active principle for example. Finally, by spraying is meant the operation which consists in spraying, in a controlled and diffuse manner, a liquid on the surface of a solid entity such as a sugar microsphere for example. In the present application, we will also speak of atomization to designate a fine and homogeneous spray.
La présente invention se rapporte à un nouveau procédé de fabrication de microsphères de sucres ou "neutres", utilisés à la fois dans l'industrie pharmaceutique comme support de base à la fabrication de microgranules sphériques chargés de principes actifs, et dans l'industrie agroalimentaire, pour la fabrication de billes comestibles, montées ou non avec d'autres substances.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.
De telles microbilles sont en effet très utiles pour la synthèse de microgranules rentrant dans la composition de médicaments absorbables par voie orale. En effet, de tels microgranules sont destinées, suivant le besoin, soit au remplissage de capsules de gélatine soit à servir à la constitution de comprimés orodispersibles ou gastrodispersibles après une étape de compression.Such 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.
La fabrication de microgranules de sucre d'une taille comprise entre 500 et 1500 μm est très courante, principalement dans le domaine de la confiserie ou de tels microgranules entrent dans la constitution de desserts sucrés par exemple.The manufacture of sugar microgranules with a size of between 500 and 1500 μm is very common, mainly in the confectionery field where such microgranules are used in the constitution of sweet desserts for example.
La fabrication de telles billes de sucre s'effectue sur la base de particules de sucre solide, préférentiellement des cristaux de sucre d'une taille comprise entre 500 et 1000 μm sur lesquels on pulvérise une faible quantité d'une solution aqueuse destinée au "mouillage" des particules solides de sucre. Immédiatement après l'étape de mouillage, on procède alors à la phase de poudrage destinée à augmenter la taille des microsphères de sucre en formation. Cette étape de poudrage est une étape essentiellement manuelle dans laquelle on projette de façon non contrôlée une quantité de sucre sous forme de poudre sèche à la surface des cristaux préalablement mouillés. La poudre ainsi projetée s'agglomère à la surface des cristaux, dont le diamètre augmente ainsi. On réitère alors sur ces microgranules de sucre une nouvelle étape de mouillage qui sera suivie immédiatement d'une étape de poudrage jusqu'à l'obtention de microsphères de la taille recherchée.The manufacture of such sugar beads is carried out on the basis of solid sugar particles, preferably sugar crystals of a size between 500 and 1000 μm 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.
Un tel procédé a l'avantage de présenter un temps de séchage réduit et il permet en outre un grossissement relativement rapide des microsphères de sucre. Cependant, ce procédé n'est pas adapté à la fabrication de microsphères d'une taille inférieure à 500μm, du fait de la taille des cristaux de sucre de départ. De plus, le contrôle de la taille des microsphères est difficile, notamment à cause de la vitesse de grossissement des microsphères lors du poudrage. Ainsi, ce procédé est assez peu reproductible dans la mesure où le mode de fabrication manuel ne permet pas un contrôle précis des paramètres de poudrage notamment.Such a process has the advantage of having a reduced drying time and it also allows a relatively rapid magnification of the sugar microspheres. However, this process is not suitable for the manufacture of microspheres of a size less than 500 μm, due to the size of the starting sugar crystals. In addition, controlling the size of the microspheres is difficult, in particular because of the speed of magnification of the microspheres during dusting. Thus, this process is not very reproducible insofar as the manual manufacturing mode does not allow precise control of the powdering parameters in particular.
Enfin, ce procédé donne des microsphères de qualité médiocre sur le plan de la sphéricité et de la convexité, les rendant peu adaptées à un montage précis de principes actifs faiblement dosés.Finally, this process gives microspheres of mediocre quality in terms of sphericity and convexity, making them poorly suited to a precise assembly of low-dose active ingredients.
En effet, les microsphères de sucre sont également fabriquées en routine pour l'industrie pharmaceutique où elles servent de support à la synthèse de microgranules montés avec des principes actifs. Un tel montage s'effectue par pulvérisation de la substance active et /ou des excipients envisagés, préalablement dissous dans une solution aqueuse ou organique.Indeed, 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.
Ainsi, des "neutres" d'une taille avoisinant généralement 500 à 800 μm sont soumis à une telle pulvérisation, puis à une phase de séchage permettant le démarrage d'un nouveau cycle de pulvérisation. Le dépôt de principe actif s'effectue donc par cycles de pulvérisation / séchage successifs, jusqu'à ce que le neutre porte une quantité déterminée de principe actif.Thus, "neutrals" of a size generally around 500 to 800 μm 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.
Ce procédé appliqué au montage des principes actifs nécessite une pulvérisation fine encore appelée "atomisation" de la solution envisagée et par ailleurs une étape de séchage efficace avant d'entamer un nouveau cycle de pulvérisation / séchage.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.
Ce type de procédé est donc relativement long et coûteux.This type of process is therefore relatively long and expensive.
Un tel procédé se trouve enseigné par le brevet US 4,703,717 dans le quel des sphères de sucre d'une taille comprise entre 2 mm et 4 mm environ sont imprégnées par une solution aqueuse contenant un ou plusieurs agents actifs. Ces sphères de sucre ou "granules" sont destinées à l'industrie homéopathique. Le procédé d'imprégnation consiste à pulvériser la liqueur sur les granules vierges contenues dans une bonbonne en rotation à l'aide d'une première buse. Puis une étape de séchage des sphères ainsi imprégnées intervient par le biais d'une seconde buse soufflant de l'air sous pression.Such a process is taught by US patent 4,703,717 in which sugar spheres of a size between 2 mm and 4 mm approximately are impregnated with an aqueous solution containing one or more active agents. These sugar spheres or "granules" are intended for the homeopathic industry. The impregnation process consists of spraying the liquor onto the virgin granules contained in a rotating cylinder using a first nozzle. Then a step of drying the spheres thus impregnated intervenes by means of a second nozzle blowing pressurized air.
Ce procédé est bien adapté pour le "montage" de granules de sucre d'un diamètre relativement important, c'est-à-dire supérieur à 2 mm. En effet, les granules vierges ou imprégnés de cette taille n'ont pas tendance à s'agglomérer entre eux lors de l'imprégnation et sont maintenues en mouvement constant et relativement homogène par la rotation de la bonbonne les contenant.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.
En revanche, un tel procédé s'avère peu applicable à des produits de départ de faible taille et plus particulièrement de taille inférieure à 1000 μm. Ainsi, des particules tels que des microcristaux, vont avoir tendance à s'agglomérer ensemble une fois humidifiés par la solution pulvérisée et à former un amalgame compact, ne permettant pas la fabrication de microsphères individualisées. De plus, de tels cristaux ne sont généralement pas de forme sphéroïdale et présentent de ce fait une fluidité dans les appareillages de fabrication moins importante que les granules utilisés dans le brevet US 4,703,717.On the other hand, such a process proves to be hardly applicable to starting products of small size and more particularly of size less than 1000 μm. Thus, particles such as microcrystals will tend to agglomerate together when moistened by the sprayed solution and to form a compact amalgam, not allowing the manufacture of individualized microspheres. In addition, such crystals are generally not spheroidal in shape and therefore exhibit less fluidity in the manufacturing apparatus than the granules used in US Pat. No. 4,703,717.
La fabrication de microsphères d'une taille comprise entre 100 μm et 1000 μm est enseignée dans le brevet US 5,505,983.The manufacture of microspheres of a size between 100 μm and 1000 μm is taught in US patent 5,505,983.
Dans ce document, des microsphères composées d'au moins 50 % de cellulose microcrystalline fortement réticulée et d'éventuellement un sucre de type lactose sont obtenues par un mélange de la poudre contenant la cellulose et le sucre éventuel avec de l'eau. Ce mélange semi-solide est ensuite malaxé puis introduit dans une machine rotative qui va induire la formation des microsphères par effet de granulation. Les microsphères en formation sont simultanément à la rotation, soumises à une pulvérisation d'eau, puis séchées et tamisées.In this document, 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.
Ce procédé dit de "granulation humide" permet d'obtenir des microsphères de faible taille, c'est-à-dire d'un diamètre inférieur à 1000 μm, comprenant au moins 50 % de cellulose microcrystalline fortement réticulée.This so-called "wet granulation" process makes it possible to obtain microspheres of small size, that is to say of a diameter of less than 1000 μm, comprising at least 50% of highly cross-linked microcrystalline cellulose.
Cependant, ce procédé est limité à la cellulose microcrystalline et n'est pas transposable à des composés classiquement utilisés dans l'industrie pharmaceutique pour la fabrication de "neutres" tels que l'amidon de maïs ou le saccharose par exemple. En effet, un tel procédé de granulation humide appliqué à des poudres de sucre aboutit à une dissolution du sucre utilisé, puis à une recristallisation du sucre lors du séchage. De telles modifications structurelles conduisant à l'obtention des granules de sucre ne permettent pas un bon contrôle de la taille et de la forme de ces granules.However, this process is limited to microcrystalline cellulose and cannot be transposed to compounds conventionally used in the pharmaceutical industry for the manufacture of "neutrals" such as corn starch or sucrose for example. Indeed, such a wet granulation process applied to sugar powders results in a dissolution of the sugar used, then in a recrystallization of the sugar during drying. Such structural modifications leading to the production of sugar granules do not allow good control of the size and shape of these granules.
Par ailleurs, ce procédé nécessite une étape de triage des microsphères ainsi obtenues, du fait de l'hétérogénéité des tailles observées après granulation humide.Furthermore, this process requires a step of sorting the microspheres thus obtained, due to the heterogeneity of the sizes observed after wet granulation.
Ce procédé est donc limité à certains constituants et n'offre pas une qualité parfaite en terme de sphéricité, de convexité et d'homogénéité de taille.This process is therefore limited to certain constituents and does not offer perfect quality in terms of sphericity, convexity and uniformity in size.
Le document US 6,264,989, enseigne la fabrication de microsphères à base de sucre-alcools dont la taille est inférieure à 500 μm. Le procédé décrit consiste tout d'abord à effectuer une granulation humide des cristaux de la substance de base, par exemple le xylitol, en malaxant ensemble de la poudre cristalline de xylitol et une quantité suffisante d'eau. Les microgranules ainsi obtenus ont une taille inférieure à 300 μm environ et sont alors grossis par "poudrage" de la substance de base après humidification.Document US 6,264,989 teaches the manufacture of sugar-alcohol based microspheres whose size is less than 500 μm. The process described consists first of all in carrying out a wet granulation of the crystals of the basic substance, for example xylitol, by kneading together crystalline powder of xylitol and a sufficient quantity of water. The microgranules thus obtained have a size less than 300 μm approximately and are then magnified by "dusting" the basic substance after moistening.
Ce procédé de poudrage, comme cela a été énoncé plus haut ne permet pas d'obtenir des particules très homogènes et très convexes. De plus, il est limité à l'utilisation de certains sucre-alcools et non généralisable aux constituants habituellement utilisés pour la synthèse des "non pareils".This powdering process, as stated above, does not allow very homogeneous and very convex particles to be obtained. In addition, 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".
Le problème de l'obtention de microsphères d'une taille homogène est en partie résolu par le brevet US 6,056,949 qui enseigne la fabrication de microbilles porteuses d'une substance aromatique.The problem of obtaining microspheres of homogeneous size is partly solved by US patent 6,056,949 which teaches the manufacture of microbeads carrying an aromatic substance.
Dans ce document, des microsphères de sucre préformées de type "non pareil" sont mises en suspension dans un lit d'air fluidisé. On projette sur ces sphères par pulvérisation une solution d'agent aromatique. Les microsphères obtenues portent le composé aromatique projeté et présentent une homogénéité de taille assez élevée. Cependant, ce procédé utilise comme matière première des "neutres" qui sont l'objet de l'invention, et n'envisage pas la fabrication de microsphères d'une taille inférieure à 500 μm.In this document, preformed sugar microspheres of the "unlike" type are suspended in a fluidized air bed. An aromatic agent solution is sprayed onto these spheres. The microspheres obtained carry the projected aromatic compound and have a fairly high size homogeneity. However, this process uses as raw material "neutrals" which are the object of the invention, and does not envisage the manufacture of microspheres of a size less than 500 μm.
Le but de la présente invention est donc de fournir un nouveau procédé de fabrication de microsphères de sucre du type non pareil, d'un diamètre inférieur à 500 μm, d'une bonne homogénéité de taille et possédant une convexité et une sphéricité satisfaisantes.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 μm, of good size uniformity and having satisfactory convexity and sphericity.
La sphéricité correspond à une mesure en deux dimensions de la forme globale des microparticules. La sphéricité correspond au rapport du plus long diamètre sur le plus court diamètre mesuré sur la microparticule. La sphéricité est donc également une valeur comprise entre 0 et 1, une sphère parfaite ayant une sphéricité de 1, une tige ayant une sphéricité de 0. Pour des particules inférieures à 1 mm, la mesure des diamètres est effectuée au microscope. Dans la présente demande, on emploiera indifféremment les termes circularité et sphéricité.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. For particles less than 1 mm, the diameters are measured under the microscope. In the present application, the terms circularity and sphericity will be used interchangeably.
La sphéricité des microsphères conditionne la facilité avec laquelle on va pouvoir les utiliser à l'échelle industrielle. En effet, lors de la manipulation de gros volumes de microsphères, il est important que leur fluidité, ou indice d'écoulement, au sein des différentes machines (turbine, lit d'air, fondoir, tamis etc.) soit la plus importante possible. On évite ainsi les problèmes d'agglomération qui gênent l'emploi de tels produits.The sphericity of the microspheres conditions 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.
De plus, la sphéricité conditionne également la compression de telles particules. En effet, l'inconvénient d'utiliser des poudres, qui présentent une bonne fluidité, est qu'elles sont très difficilement compressibles, et donc peu sujettes à la fabrication de comprimés. La compression de poudre nécessite ainsi une étape de granulation préalable. Mais une telle granulation conduit à des particules dont les qualités de sphéricité et de convexité sont médiocres, de plus, la taille des particules obtenues n'est pas homogène. Par ailleurs, la convexité correspond à une mesure en trois dimensions de la forme de l'objet. Cette mesure consiste à faire le rapport entre la surface réelle de l'objet considéré et la surface d'une bande de caoutchouc imaginaire entourant cet objet.In addition, the sphericity also conditions the compression of such particles. Indeed, 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. Furthermore, 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.
Ainsi, plus un objet affecte une courbe convexe, tel qu'une sphère ou pseudo- sphère, plus les parois de cet objet vont avoir tendance à coller à cette bande imaginaire. De cette façon, le rapport entre les deux surfaces va tendre vers 1. Au contraire un objet de forme concave ne va pas suivre le contour imposé par la bande de caoutchouc, et de ce fait le rapport des deux surfaces va donc tendre vers 0.Thus, the more an object affects a convex curve, such as a sphere or pseudosphere, the more the walls of this object will tend to stick to this imaginary strip. In this way, the ratio between the two surfaces will tend towards 1. On the contrary, an object of concave shape will not follow the outline imposed by the rubber band, and therefore the ratio of the two surfaces will therefore tend towards 0.
Cette caractéristique est importante dans le cas de microsphères destinées à être montées par un principe actif faiblement dosé. En effet, plus la convexité de la particule servant de support est faible, c'est-à-dire qu'elle présente de nombreux creux et aspérités en surface, plus la quantité de matière se déposant sur cette surface va varier d'une particule à l'autre. En augmentant la convexité des particules, on diminue du même coup la variabilité entre les quantités de substance déposées à la surface de ces particules. Cela est particulièrement important dans le cas du montage de principes actifs faiblement dosés, où la quantité de substance active doit être absolument homogène d'un lot de particules à l'autre.This characteristic is important in the case of microspheres intended to be mounted by a low-dose active principle. In fact, 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. By increasing the convexity of the particles, 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.
On peut donc considérer que la sphéricité mesure la tendance globale d'un objet à tendre vers une forme sphérique parfaite sans tenir compte de l'état de surface de cet objet, alors que la convexité mesure la tendance à tendre vers une forme convexe et donc va tenir des comptes des aspérités et autres irrégularités de surface d'un tel objet. Le procédé conforme à l'invention a donc pour but de fournir des microsphères de sucre de taille inférieure à 500 μm dont la sphéricité et la convexité soit la meilleure possible et qui présentent de bonne capacités de compression et un indice d'écoulement élevé. La présente invention a également pour but d'améliorer le rendement de fabrication de telles microsphères habituellement obtenues par la méthode de "poudrage". En effet, le procédé conforme à l'invention est à la fois simple, ne nécessitant pas d'installations particulières et relativement peu coûteux.We can therefore consider that sphericity measures the overall tendency of an object to tend towards a perfect spherical shape without taking into account the surface state of this object, while convexity measures the tendency to tend towards a convex shape and therefore will keep accounts of roughness and other surface irregularities of such an object. The method according to the invention therefore aims to provide sugar microspheres of size less than 500 μm 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. In fact, the method according to the invention is both simple, does not require any particular installation and is relatively inexpensive.
De plus, la présente invention permet de résoudre le problème de la reproductibilité du procédé de fabrication de ces microsphères en décrivant un procédé dont les étapes sont pratiquement toutes automatisées et précisément paramétrables.In addition, 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.
Ainsi, la présente invention est particulièrement adaptée aux contraintes réglementaires de l'industrie pharmaceutique relatives à la qualité des excipients et de la matière première entrant dans la composition des médicaments.Thus, 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.
Enfin, la présente invention présente l'intérêt de permettre la fabrication de telles microsphères à partir des composants simples, habituellement utilisés pour la fabrication des "neutres" utilisés d'ordinaire dans l'industrie pharmaceutique, à savoir, notamment, le saccharose et l'amidon de maïs. De ce fait sa mise en œuvre est d'autant plus aisée et adaptée aux exigences de l'industrie.Finally, 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.
Ainsi, la présente invention présente tout d'abord l'avantage de permettre l'obtention de microsphères de taille inférieure à 500 μm, présentant à la fois une bonne uniformité de taille, c'est-à-dire qu'au moins 90% des microsphères de sucre ont la taille désirée et une convexité et une sphéricité satisfaisantes. Du fait de l'automatisation quasi-totale du procédé, les microsphères conformes à l'invention présentent en outre un prix de revient relativement faible et surtout une qualité de conception (absence d'impuretés, absence de solvants organiques) qui les rend propres à une utilisation approuvée par les standards de qualité des organisations régulatrices en matière de médicaments, telles que la FDA et l'agence européenne du médicament.Thus, the present invention firstly has the advantage of making it possible to obtain microspheres of size less than 500 μm, 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.
Les microsphères ou "neutres" de petite taille obtenues par le procédé objet de l'invention présente enfin l'avantage d'être un support de choix à des principes actifs "fortement dosés". En effet, leur faible diamètre permet de fabriquer des microgranules d'une taille conventionnelle permettant ainsi l'accumulation à leur surface de quantités d'autant plus importantes de principes actifs.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. In fact, 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.
Les microsphères de sucre conformes à l'invention sont donc particulièrement avantageuses pour la fabrication de médicaments sous formes de microgranules, à base de principes actifs fortement dosés.The 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.
Leur faible diamètre permet également d'envisager la fabrication de microgranules dosés de manière conventionnelle, et présentant un diamètre plus faible que les microgranules "classiques". De tels microgranules de 100 à 500 μm peuvent être employés dans la constitution de médicaments sous forme de comprimés, dont la taille réduite facilite leur absorption par le patient.Their small diameter also makes it possible to envisage the manufacture of microgranules dosed in a conventional manner, and having a smaller diameter than the "conventional" microgranules. Such microgranules of 100 to 500 μm can be used in the constitution of medicaments in the form of tablets, the reduced size of which facilitates their absorption by the patient.
Enfin, les caractéristiques physiques des microsphères conformes à l'invention, en particulier leur bonne sphéricité, avantageusement comprise entre 0,85 et l,leur bonne convexité, avantageusement comprise entre 0,9 et 1, et leur parfaite homogénéité de taille en font des supports de choix pour des principes actifs très faiblement dosés. En effet, des substances très actives telles que des hormones par exemple doivent être déposées à la surface des microsphères en quantité parfaitement contrôlée. De la qualité des microsphères dépend donc la qualité et la reproductibilité du dépôt à leur surface. En effet, pour des dosages faibles, de l'ordre du microgramme par exemple, il est nécessaire que le dosage conserve une bonne reproductibilté statistique. Cette reproductibilité est assurée par les microsphères obtenues selon le procédé conforme à l'invention qui présentent une parfaite homogénéité de taille et de forme.Finally, the physical characteristics of the microspheres in accordance with the invention, in particular their good sphericity, advantageously between 0.85 and 1, their good convexity, advantageously between 0.9 and 1, and their perfect homogeneity in size make them choice supports for very low-dose active ingredients. Indeed, 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.
Par ailleurs, le procédé objet de l'invention présente l'avantage d'être très rentable, en effet, la perte de matière observée, par rapport à un procédé classique de fabrication de neutres de taille comprises entre 100 et 500 μm par "poudrage" est relativement limitée, comme cela est représenté dans le tableau 1.Furthermore, 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 μm by "dusting "is relatively limited, as shown in Table 1.
Ainsi, pour un montage par poudrage, pour 150 kg de support de sucre et environ 234 litres de "suspension d'enrobage" on obtient environ 45 kg à 75 kg de microsphères de taille inférieure à 500 μm alors que pour la même quantité de produits de départ, on obtient entre 270 kg et 300 kg de produit fini. En effet, la matière composant les futurs microsphères étant pour la majeure partie pulvérisée de façon contrôlée à la surface des particules de sucre solide et préférentiellement des cristaux de sucre, la perte de matière est très réduite puisqu'on peut adapter le débit de la buse de pulvérisation à la vitesse de rotation de la turbine entraînant ces particules solides.Thus, for an assembly by powdering, for 150 kg of sugar support and approximately 234 liters of "coating suspension", approximately 45 kg to 75 kg of microspheres less than 500 μm in size are obtained, while for the same quantity of products from the start, between 270 kg and 300 kg of finished product are obtained. Indeed, the material making up future microspheres being for the most part sprayed in a controlled manner on the surface of solid sugar particles and preferably sugar crystals, the loss of material is very reduced since the flow rate of the nozzle can be adapted spraying at the speed of rotation of the turbine driving these solid particles.
Ce mode de fabrication, bien que plus lent que le procédé de poudrage, n'en demeure pas moins beaucoup plus précis et affiné, il est en outre responsable de la bonne sphéricité et de la bonne convexité des microsphères ainsi obtenues.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.
Par ailleurs, ce procédé de montage par pulvérisation d'un sirop concentré reste relativement simple puisque tant les turbines contenant les particules de sucre à enrober que les buses permettant la pulvérisation du sirop sont des outils connus et relativement peu complexes utilisés en routine dans l'industrie pharmaceutique. La particularité du procédé conforme à l'invention repose cependant sur la réalisation de multiples phases de pulvérisation contrôlées d'un sirop fortement concentré en sucre, c'est-à-dire de forte viscosité. Or, les sirops visqueux du type de ceux employés pour la réalisation de la présente invention se prêtent mal à la pulvérisation par atomisation car le contrôle du débit d'air à mettre en œuvre pour assurer une pulvérisation à la fois fine et homogène est très délicat. En effet, la pulvérisation du sirop conforme à l'invention consiste en la projection, au travers d'une buse pneumatique dite "à jet plat" d'une quantité de sirop déterminée et d'une quantité d'air destinée à nébuliser ledit sirop à la sortie de la buse. Ce système est donc totalement différent des systèmes de projection classique par pistolet, tels que ceux utilisés dans les montages par poudrage, où le liquide est pulvérisé seul. Ce dernier type de pulvérisation est nécessairement beaucoup plus grossier et moins précis que la pulvérisation par atomisation (ou nébulisation) utilisée pour la réalisation de la présente invention, dans laquelle on projette à la surface des microsphères en formation une très faible quantité de sirop, sous la forme d'une forme de "brouillard", assurant un grossissement très progressif et très homogène des microsphères. Une telle nébulisation n'est possible que si le contrôle, tant du débit d'air que du débit de sirop et de sa viscosité, est parfaitement contrôlée. De plus, la pulvérisation discontinue (alternance de phase de pulvérisation et de séchage) de tels sirops concentrés en sucre est difficile à mettre en œuvre de façon reproductible. En effet, il arrive fréquemment que des résidus de sirop attachés à la buse sèchent et obstruent partiellement l'orifice de pulvérisation de la buse. Cet inconvénient est particulièrement observé dans les cas où on projette un sirop comprenant à la fois du sucre et de l'amidon, ce dernier constituant ayant tendance à obstruer rapidement l'orifice de la buse dès l'arrêt de la phase de pulvérisation.Furthermore, this method of assembling by spraying a concentrated syrup remains relatively simple since both the turbines containing the sugar particles to be coated and the nozzles allowing the spraying of the syrup are known and relatively uncomplicated tools used routinely in the pharmaceutical industry. The peculiarity of the process according to the invention is however based on the realization of multiple controlled spraying phases of a syrup highly concentrated in sugar, that is to say of high viscosity. However, viscous syrups of the type used for carrying out the present invention do not lend themselves to spraying by atomization because the control of the air flow rate to be used to ensure a spray which is both fine and homogeneous is very delicate. . In fact, 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. Such nebulization is only possible if the control, both of the air flow rate and of the syrup flow rate and of its viscosity, is perfectly controlled. In addition, discontinuous spraying (alternating spraying and drying phases) of such syrups concentrated in sugar is difficult to implement in a reproducible manner. Indeed, it frequently happens that syrup residues attached to the nozzle dry and partially obstruct the spray orifice of the nozzle. This drawback is particularly observed in cases where a syrup is sprayed comprising both sugar and starch, the latter constituting a tendency to rapidly block the orifice of the nozzle as soon as the spraying phase is stopped.
Enfin, l'emploi de tels sirops concentrés en sucre en présence d'un flux d'air continu pose le problème du dépôt régulier du sirop à la surface des microsphères en formation. En effet, compte tenu de ces paramètres, le sucre liquide du sirop à tendance à recristalliser très vite une fois déposé à la surface des microsphères. Cette recristallisation rapide nuit à la convexité des microsphères, en créant à la surface des microsphères de sucre de multiples aspérités de sucre cristallisé.Finally, the use of such syrups concentrated in sugar in the presence of a continuous air flow poses the problem of regular deposition of the syrup on the surface of the microspheres being formed. Indeed, given these parameters, the liquid sugar in the syrup tends to recrystallize very quickly once deposited on the surface of the microspheres. This rapid recrystallization harms the convexity of the microspheres, creating on the surface of the sugar microspheres multiple asperities of crystallized sugar.
Le mérite de la demanderesse est donc d'avoir réussi à mettre au point un tel procédé de synthèse de microsphères de sucre par pulvérisation d'un sirop aussi visqueux. En effet, les sirops conformes à la présente invention ont une viscosité comprise entre 50 et 75 centipoises à 70 °C. Préférentiellement, on travaillera avec de sirops dont la viscosité est comprise entre 65 et 70 centipoises mesurée à 70°C, c'est-à-dire la température à laquelle la pulvérisation est effectuée. Une telle pulvérisation a été rendue possible en pulvérisant de façon très fine ledit sirop afin d'éviter les inconvénients décrits plus haut.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. In fact, the syrups in accordance with the present invention have a viscosity of between 50 and 75 centipoise at 70 ° C. Preferably, we will work with 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.
Enfin, le procédé objet de l'invention présente l'avantage d'être très reproductible car toutes les étapes de pulvérisation, de séchage et de sélection sont automatisées et paramétrables en fonction du produit fini désiré. Cette caractéristique permet de produire des microsphères très semblables d'un lot à l'autre, à la fois sur le plan de la forme et de la taille, donc parfaitement adaptées aux exigences et aux spécifications strictes des pharmacopées européenne, japonaise ou américaine par exemple.Finally, 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 .
La présente invention concerne ainsi un nouveau procédé d'obtention de microsphères de sucre ou "neutres", dont la caractéristique majeure est qu'il permet l'obtention de microsphères d'une taille inférieure à 500μm, de forme et de taille très homogène. Selon le procédé conforme à l'invention, on démarre la fabrication des microsphères à partir d'un support solide de sucre, sur lequel sera pulvérisée la suspension d'enrobage ou "sirop" de sucre liquide.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 μm, of very homogeneous shape and size. According to the process according to the invention, 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.
On entend par support de sucre, du sucre solide, soit sous forme de cristaux, soit de particules de sucre sous forme amorphe tel que le sucre alvéolaire ou le sucre glace amylacé, le sucre glace silice, le sucre alvéolaire et le COMPRES SUCRE®, soit encore sous forme de microparticules de sucre agglomérées entre elles au cours d'une première phase de fabrication du présent procédé et éliminées du cycle de fabrication par tamisage, du fait de leur trop faible taille. Ces dernières microparticules, de taille inférieure à 200 μm, aussi appelées Produit Semi-Oeuvré ont l'avantage de présenter une bonne sphéricité et une bonne convexité, ce qui facilite l'obtention de microsphères présentant ces mêmes caractéristiques.The term “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 μm, 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.
Selon une caractéristique particulière du procédé conforme à l'invention, les particules de sucre sous forme amorphe, constituant le support solide, ont une taille comprise entre 50 et 200 μm.According to a particular characteristic of the process according to the invention, the sugar particles in amorphous form, constituting the solid support, have a size of between 50 and 200 μm.
Selon une autre caractéristique du procédé de l'invention, lesdits cristaux de sucre sont constitués des sucres appartenant au groupe comprenant le saccharose, le maltose, le glucose, le dextrose, le mannose, le galactose, le fructose, le ribose, le lactose, le maltose, le mannitol, le sorbitol et le xylitol, et présentent avantageusement une taille comprise entre 50 et 200 μm, préférentiellement entreAccording to another characteristic of the process of the invention, 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 μm, preferably between
100 et 150 μm.100 and 150 μm.
Selon une autre caractéristique particulière du procédé conforme à l'invention, ledit sirop de sucre est composé d'un mélange d'un ou plusieurs sucre(s) et d'un liquide, le ou lesdits sucre(s) appartenant au groupe des sucres comportant entre 4 etAccording to another particular characteristic of the process according to the invention, 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
24 atomes de carbone.24 carbon atoms.
Selon une autre caractéristique du procédé de l'invention, ledit sirop de sucre est constitué d'un ou plusieurs sucre(s) et d'un liquide, le ou lesdits sucre(s) appartenant au groupe comprenant le saccharose, le maltose, le glucose, le dextrose, le mannose, le galactose, le fructose, le ribose, le lactose, le maltose, le mannitol, le sorbitol et le xylitol. Selon une autre caractéristique particulière du procédé conforme à l'invention, ledit liquide est un liquide pharmacologiquement acceptable, préférentiellement de l'eau.According to another characteristic of the process of the invention, 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. According to another particular characteristic of the process according to the invention, said liquid is a pharmacologically acceptable liquid, preferably water.
Selon une autre caractéristique particulière du procédé conforme à l'invention, ledit sirop contient en outre des additifs pharmacologiquement acceptables, tels que des colorants, des lubrifiants, des tensioactifs et des antioxydants.According to another particular characteristic of the process according to the invention, said syrup also contains pharmacologically acceptable additives, such as dyes, lubricants, surfactants and antioxidants.
Le procédé conforme à l'invention consiste à pulvériser de façon fine et contrôlée, à la surface de microparticules solides de sucre, un sirop à base d'un sucre identique ou différent, lesdites particules solides de sucre étant maintenues en mouvement dans une turbine en rotation.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.
Le procédé conforme à l'invention est donc principalement organisé en deux phases distinctes : une première phase de pulvérisation contrôlée, suivie d'une seconde phase de séchage des microparticules ayant reçu la pulvérisation de sirop.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.
La phase de pulvérisation conforme à la présente invention se décompose elle-même en deux étapes distinctes : une première phase dite de "prégranulation" et une seconde phase de granulation proprement dite. Dans les deux cas, la pulvérisation est réalisée de façon avantageuse par nébulisation au moyen d'une buse pneumatique à j et plat.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. In both cases, the spraying is carried out advantageously by nebulization by means of a pneumatic nozzle with j and flat.
La phase de prégranulation consiste à fabriquer des "amorces" utilisées ensuite comme support solide dans la phase de granulation proprement dite. Ces amorces correspondent ainsi à des microsphères de sucre de taille comprise entre 100 μm et 200 μm résultant de l'accumulation de sirop à la surface du support solide de sucre utilisé comme base de départ, c'est-à-dire, suivant le cas, soit des cristaux de sucre, soit du sucre sous forme amorphe, soit encore de microparticules issues du procédé, appelées aussi "produits semi-œuvrés" qui seront avantageusement recyclées.The pre-granulation phase consists in manufacturing "primers" which are then used as solid support in the granulation phase proper. These primers thus correspond to sugar microspheres of size between 100 μm and 200 μm 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.
La phase de prégranulation conforme au procédé selon l'invention est une phase primordiale puisque c'est elle qui va conditionner l'obtention d'amorces de sphéricité et de convexité acceptables, servant de base à la fabrication des microsphères conformes à l'invention. Ainsi, la phase de prégranulation doit être réalisée de façon précise pour disperser de façon homogène la suspension d'enrobage à la surface du support solide de sucre choisi. La pulvérisation ou atomisation est en effet réalisée à un faible débit et pendant de relativement longues périodes de temps. Cette étape est la plus longue du procédé.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. Thus, 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.
Avantageusement, la pulvérisation durant la phase de prégranulation est effectuée à un faible débit, avantageusement inférieur à 120 ml/min, et de préférence compris entre 60 ml et 120 ml par minute. D'une façon encore préférée, le débit choisi pour cette étape est de 80 ml par minute. Cette étape comporte ainsi de nombreux cycles de pulvérisation / séchage, la pulvérisation s'effectuant à un faible débit, le nombre de cycles nécessaires à l'obtention d'amorces de taille correcte est compris entre 2000 et 3000 suivant la taille des microsphères recherchées.Advantageously, 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.
D'une façon générale, on réalise environ 2500 cycles de pulvérisation / séchage, chaque cycle correspondant en fait à une phase de pulvérisation fine du sirop, suivi d'une phase dite de séchage des microsphères au cours de laquelle on stoppe la pulvérisation. Pendant cette phase, l'utilisation en continu du courant d'air puisé contribue à solidifier le sucre liquide préalablement pulvérisé. A chaque cycle, le diamètre des microsphères en formation augmente progressivement. D'une manière préférentielle, la durée d'un cycle de pulvérisation / séchage est d'une minute, au cours duquel 20 secondes sont consacrées à la pulvérisation proprement dite et 40 secondes sont consacrées au séchage (absence de pulvérisation). Bien entendu, de tels cycles peuvent être aisément adaptés en fonction de la taille et de la nature des matériaux utilisés pour la fabrication des microsphères conformes à l'invention. Ces intervalles de temps ne sont donc pas limitatifs.In general, approximately 2500 spraying / drying cycles are carried out, 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. During this phase, the continuous use of the pulsed air stream contributes to solidifying the liquid sugar previously sprayed. At each cycle, the diameter of the microspheres in formation gradually increases. Preferably, 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). Of course, 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.
Ainsi, la phase de prégranulation dure habituellement entre 30 heures et 60 heures, et plus généralement entre 40 heures et 50 heures, pour permettre un grossissement progressif et régulier des microsphères conformes à l'invention.Thus, 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.
La phase dite de granulation intervient à la suite de l'étape de prégranulation et consiste à utiliser les "amorces" fabriquées au cours de cette dernière étape et à augmenter leur diamètre par de nouveaux cycles de pulvérisation / séchage, à un débit de pulvérisation plus élevé. Ainsi, on effectuera pendant cette phase entre 350 et 500 cycles de pulvérisation / séchage sur les amorces issues de l'étape de prégranulation, à un débit de pulvérisation compris entre 100 ml et 300 ml par minute.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. Thus, during this phase, 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.
En effet, à ce stade du procédé, la sphéricité et la convexité des microsphères en formation sont pratiquement assurées car la forme des amorces présente déjà ces caractéristiques à un niveau satisfaisant.In fact, at this stage of the process, the sphericity and the convexity of the microspheres being formed are practically ensured since the shape of the primers already has these characteristics at a satisfactory level.
A l'issue de la phase de granulation qui dure, en général, entre 5 heures et 10 heures, les microsphères sont séchées et déshydratées.At the end of the granulation phase, which generally lasts between 5 hours and 10 hours, the microspheres are dried and dehydrated.
Cette phase ultime de séchage dure avantageusement entre 1 heure et 7 heures, de préférence de 2 heures à 4 heures suivant le type et la taille des microsphères fabriquées, le courant d'air puisé utilisé à cet effet étant porté à une température comprise entre 50°C et 80°C.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.
L'originalité du procédé tient au fait qu'on emploie un matériel de pulvérisation habituellement utilisé pour le "montage" de principes actifs en solution à la surface de "neutres" et non pas pour la synthèse des neutres proprement dits.The originality of the process is due to the fact that a spraying equipment usually used is used for the "mounting" of active principles in solution on the surface of "neutrals" and not for the synthesis of the neutrals themselves.
Un tel procédé est donc tout à fait innovant dans la fabrication de neutres habituellement obtenus par granulation humide, c'est-à-dire par mélange d'une poudre sèche de sucre avec une quantité d'eau suffisante.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.
Enfin, la particularité du procédé tient au fait qu'on pulvérise un liquide extrêmement visqueux et collant, dont la concentration en sucre est comprise entreFinally, the particularity of the process is due to the fact that an extremely viscous and sticky liquid is sprayed, the sugar concentration of which is between
700 grammes et 980 grammes par litre, à la surface de particules solides, par exemple de cristaux, dont la taille est très faible (comprise entre 50 μm et 200 μm) donc très sujettes à s'agglomérer entre elles.700 grams and 980 grams per liter, on the surface of solid particles, for example crystals, the size of which is very small (between 50 μm and 200 μm) and therefore very liable to agglomerate with one another.
Les cristaux de sucre pouvant être généralement employés pour la réalisation du procédé conforme à l'invention ont une taille comprise entre 50 μm et 200 μm, préférentiellement, entre 100 μm et 150 μm.The sugar crystals which can generally be used for carrying out the process according to the invention have a size of between 50 μm and 200 μm, preferably between 100 μm and 150 μm.
Les cristaux utilisables comme matériau de base dans le procédé conforme à la présente invention auront préférentiellement une forme polyédrique, c'est-à-dire présentant un nombre important de faces ce qui d'une part augmente leur fluidité au sein de la turbine en rotation et d'autre part améliore le coefficient de sphéricité des futurs "neutres" obtenus. En effet, plus le matériau de départ à une forme qui se rapproche de celle d'une sphère, plus le produit enrobé à partir de cette base sera sphérique.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.
La nature des cristaux servant de base aux futurs neutres est étendue. En effet, on peut utiliser aussi bien des cristaux de sucres appartenant à la famille des glucides et parmi eux, certains oses simples tels que les hexoses, comme le glucose, mannose ou le galactose par exemple ou les pentoses tels que le fructose ou le ribose par exemple.The nature of the crystals used as a basis for future neutrals is extensive. In fact, 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.
Mais on peut utiliser également des cristaux de sucres plus complexes, tels que le lactose, le saccharose ou le maltose par exemple, avec une préférence pour le saccharose qui est un produit couramment utilisé pour la synthèse de neutres et surtout approuvé par les différentes pharmacopées nationales.But we can also use more complex sugar crystals, such as lactose, sucrose or maltose for example, with a preference for sucrose which is a product commonly used for the synthesis of neutrals and especially approved by the various national pharmacopoeias .
On peut envisager également d'utiliser comme cristaux utilisables comme supports solides de sucre dans la présente invention, des cristaux de composés dérivés des oses, tels que ceux appartenant au groupe des sucres-alcools et parmi eux, notamment le sorbitol, le mannitol, et le xylitol.It is also conceivable to use, as 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.
Une forme amorphe de sucre, c'est-à-dire une forme non cristalline donc non organisée telle que le sucre glace pur, le sucre granulé ou le sucre alvéolaire, tel que celui vendu sous la marque Alvéosucre®. On peut également utiliser le sucre vendu sous la dénomination de "sucre glace amylacé" c'est-à-dire du sucre amorphe contenant une faible quantité (de l'ordre de 3%) d'amidon en tant qu'agent dit anti- mottant, c'est-à-dire empêchant la formation de "mottes" ou grains, due à la nature très hygroscopique de ces sucres. D'une même manière, les sucres vendus sous la dénomination "sucre silice", c'est-à-dire contenant environ 1% de silice comme agent anti-mottant et fluidifiant, peuvent également servir comme support solide de sucre, pour la réalisation de la présente invention. Là encore on utilisera des particules de taille comprise entre 50 μm et 250 μm.An 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. Likewise, 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. Here again, particles of size between 50 μm and 250 μm will be used.
Parmi les formes de sucre amorphes utilisables conformément à la présente invention, on pourra également utiliser le sucre amorphe vendu sous la marque Compressucre®, dont les particules obtenues par évaporation rapide d'une solution de saccharose dans un solvant, ont une taille comprise entre 50 μm et 250 μm. Le procédé de fabrication de microsphères de sucre conforme à l'invention peut également être réalisé à partir de produits semi-œuvrés issus de ce même procédé.Among the forms of amorphous sugar which can be used in accordance with the present invention, it is also possible to use 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 μm and 250 μm. 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.
Ainsi, ces microparticules qui ont été éliminées lors d'une première phase de fabrication du fait de leur trop faible taille, et qu'on appelle aussi PSO pour Produit Semi Œuvré, peuvent avantageusement être utilisées comme matière première solide de départ. Leur forme déjà sphérique et convexe et leur relativement grosse taille, par rapport aux cristaux de sucre bruts, en font des produits de départ avantageux pour la réalisation de la présente invention. Le sirop qui sera pulvérisé à la surface des particules solides de sucre et notamment des cristaux décrits ci-dessus peut être composé d'une solution d'un des sucres cités précédemment, préférentiellement un sucre appartenant à la famille des oses simples tels que le glucose ou le saccharose préférentiellement.Thus, these 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. Their already spherical and convex shape and their relatively large size, compared to the raw sugar crystals, make them advantageous starting materials for carrying out the present invention. 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.
Ce sirop est obtenu par une dissolution d'une poudre sèche du sucre précité dans une solution d'eau pure ou éventuellement additionnée d'agents tensioactifs, de sels ou d'agents conservateurs en faible quantité en fonction des besoins.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.
La concentration en sucre dans le sirop est un élément important de l'invention, en effet, la concentration conditionne à la fois le mode de pulvérisation, le temps de séchage et la vitesse de grossissement des microsphères.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.
C'est pourquoi, la demanderesse a déterminé, après de nombreux essais, la concentration idéale de sucre permettant le meilleur rendement de grossissement des microsphères. Cette concentration garantie permet d'éviter les problèmes liés à l'obstruction de la buse de pulvérisation, à la pulvérisation proprement dite et à la formation d'aspérités de cristallisation à la surface des microsphères.This is why, the applicant has determined, after numerous tests, the ideal concentration of sugar allowing the best magnification yield of the microspheres. This guaranteed concentration makes it possible to avoid the problems linked to the obstruction of the spray nozzle, to the actual spraying and to the formation of asperities of crystallization on the surface of the microspheres.
Cette concentration en sucre est avantageusement comprise entre 700 g/litre et 980 g/litre. Idéalement, on utilisera une concentration en sucre comprise entre 865 g/litre et 880 g/litre pour la réalisation des microsphères conformes à l'invention. D'une manière générale, les solutions de sucre liquide utilisées pour la préparation des sirops ou "suspension d'enrobage" conforme à l'invention, comporteront une quantité d'eau comprise entre 25 % et 40 % de la masse totale de solution liquide ce qui correspond à des valeurs de concentration en sucre comprises entre 700 g/litre et 980 g/litre.This sugar concentration is advantageously between 700 g / liter and 980 g / liter. Ideally, 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. In general, 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.
De façon préférentielle, la proportion d'eau des solutions liquides utilisées pour la préparation desdits sirops est comprise entre 20 % et 40 %. Avantageusement, une quantité de poudre d'amidon peut être incorporée à la solution de sucre, conformément aux standards de la pharmacopée américaine définissant les "sugar sphères".Preferably, the proportion of water in the liquid solutions used for the preparation of said syrups is between 20% and 40%. Advantageously, 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".
D'une manière préférée, la quantité de poudre d'amidon éventuellement ajoutée représente entre 10 % et 40 % de la poudre sèche utilisée pour la formation du sirop. D'une manière encore plus préférée, on travaillera pour la réalisation de la présente invention, avec des sirops dont la poudre d'amidon représente environ 20 % de la poudre sèche totale nécessaire à la constitution dudit sirop.Preferably, 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.
Bien que l'amidon de maïs soit l'amidon le plus communément utilisé dans l'industrie pharmaceutique, on peut également prévoir d'employer de l'amidon de blé, de pomme de terre ou de riz par exemple pour la réalisation du sirop conformément à la présente invention. " Turbine :Although corn starch is the most commonly used starch in the pharmaceutical industry, it is also possible to use wheat, potato or rice starch for example for the production of the syrup in accordance with to the present invention. "Turbine:
Pour la réalisation de la présente invention, on utilise avantageusement une turbine à fond plat de type classique, c'est-à-dire communément employée dans l'industrie pharmaceutique pour l'enrobage des microgranules par exemple. La réalisation de l'invention demande cependant l'utilisation d'une turbine non perforée, du fait de la faible taille des microsphères fabriquées à l'intérieur qui risquent de passer au travers des perforations lors du procédé de fabrication.For the realization of the present invention, 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.
De façon idéale, on pourra utiliser une turbine non perforée d'une capacité de 300 kg, dont la vitesse peut varier de 3 à 25 tours par minute.Ideally, 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.
En variante, les phases de pulvérisation peuvent être mises en œuvre en lit d'air fluidisé.As a variant, the spraying phases can be implemented in a fluidized air bed.
• Buse :• Nozzle:
La pulvérisation du sirop à la surface du support de sucre pourra être effectuée à l'aide d'une buse d'atomisation pneumatique telle que les buses du typeSpraying the syrup on the surface of the sugar support can be carried out using a pneumatic atomizing nozzle such as nozzles of the type
"Spraying System" à jet plat vendu sous la marque "Liquid 60100®" Fondoir : Le sirop à base d'un mélange de sucre et éventuellement d'amidon est réalisé dans un fondoir. Ce fondoir est une cuve à double enveloppe thermostatée munie d'un agitateur et reposant sur un peson ou balance permettant de mesurer de façon précise la quantité de poudre sèche introduite. ' Générateur :"Flat 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 :
Le sirop ou "suspension d'enrobage" ainsi préparé est ensuite stocké dans une cuve de stockage thermostatée. On pourra par exemple utiliser une cuve du type Cuve OserTech à double enveloppe, munie d'un agitateur. Système de Séchage : Pendant et après chaque phase de pulvérisation, les microsphères de sucre en formation sont séchées à l'aide d'un système de séchage permettant de puiser de l'air chaud à la surface des microsphères encore humides issues de la phase de pulvérisation. On pourra par exemple employer un système de séchage du type sécheur à vapeur Hydronic d'une capacité de 600m3/heure et par turbine. » Système de déshydratation:The syrup or "coating suspension" thus prepared is then stored in a thermostated storage tank. One could for example use 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. For example, a drying system of the Hydronic steam dryer type with a capacity of 600m 3 / hour and per turbine could be used. » Dehydration system:
A l'issue de l'étape de séchage, on parfait l'élimination de l'humidité à la surface des microsphères en formation en utilisant un système de déshydratation permettant d'éliminer toute trace d'humidité dans l'enceinte de fabrication des microsphères. On pourra par exemple utiliser un déshydrateur du type déshydrateur Munters MLT 1400, d'une capacité de 450 m3/heure et par turbine.At the end of the drying stage, 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. . One could for example use a dehydrator of the Munters MLT 1400 dehydrator type, with a capacity of 450 m 3 / hour and per turbine.
Système d'Extraction: La qualité des microsphères obtenues est par ailleurs assurée par un système d'extraction de poussières qui permet de garantir la pureté de l'air à l'intérieur de la turbine. On pourra par exemple utiliser un système d'extraction du type dépoussiéreur AAF d'une capacité de 750m3/heure et par turbine. • Automate : télé-mécaniqueExtraction 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. One could for example use an extraction system of the AAF deduster type with a capacity of 750m 3 / hour and per turbine. • PLC: tele-mechanical
L'automatisation de l'ensemble du procédé conforme à la présente invention est assurée à l'aide d'un automate télé-mécanique fabriqué par Magelis qui contrôle notamment les paramètres de vitesse, de pulvérisation, d'enrobage et de séchage du procédé.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.
Tamis Les microsphères obtenues à l'issu des phases de pulvérisation et séchage sont sélectionnées en fonction de la taille recherchée sur un tamis de sélection automatique muni de grilles superposées. Les microsphères de taille inférieure à 500 μm obtenues selon le procédé conforme à l'invention sont sélectionnées sur un tamis en inox composé de deux trames permettant d'éliminer d'une part les microsphères d'une taille supérieure 500 μm et plus généralement supérieure à la taille maximale choisie et d'autre part les microsphères de taille inférieure à 90 μm. Ces dernières pourront avantageusement être réutilisées dans le présent procédé comme support solide de sucre comme expliqué précédemment. D'une façon préférentielle, la trame supérieure permettant de retenir les particules de grosse taille comporte des ouvertures de 400 μm et est composée de fils de 180 à 250 μm de diamètre.Sieve The 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 μm 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 μm and more generally greater than the maximum size chosen and on the other hand the microspheres of size less than 90 μm. The latter can advantageously be reused in the present process as a solid sugar support as explained above. Preferably, the upper frame allowing the retention of large particles has openings of 400 μm and is composed of wires from 180 to 250 μm in diameter.
La trame inférieure, permettant d'éliminer les particules de taille inférieure à 90 μm possède des ouvertures de 90 μm de diamètre et de fils de 63 μm de diamètre.The lower screen, allowing particles smaller than 90 μm to be removed, has openings of 90 μm in diameter and wires of 63 μm in diameter.
Déroulement du procédé et conditions opératoiresProcedure and operating conditions
Préparation de la masse de particules solides à enroberPreparation of the mass of solid particles to be coated
Le support de sucre (cristaux de sucre ou forme amorphe ou encore produit semi-œuvré) servant de base aux futures microsphères de sucre est stocké au sein d'une turbine de type classique non perforée. On prépare ainsi un lit de 150 kg de sucre disposé au fond de la turbine. De façon préférentielle, on utilisera comme support solide de sucre, pour un même lot de microsphères, un produit unique plutôt qu'un mélange de support solide de plusieurs origines pour garantir une bonne homogénéité de taille aux microsphères en formation.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. Preferably, 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.
Cette masse de sucre est alors entraînée par la rotation de la turbine et préchauffée entre 37°C et 40°C pendant 20 à 30 minutes.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.
Préparation de la solution à pulvériser La solution destinée à être pulvérisée sur le support de sucre est préparée dans le fondoir à double enveloppe à une température de 70° ± 5°C par dispersion d'une proportion de 20% de poudre d'amidon de maïs dans 80% de saccharose liquide préalablement obtenue par dissolution d'une poudre sèche de saccharose dans une quantité d'eau représentant 33% de la masse du mélange.Preparation of the solution to be sprayed 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. corn in 80% liquid sucrose previously obtained by dissolving a dry sucrose powder in an amount of water representing 33% of the mass of the mixture.
Toutes ces quantités sont contrôlées par pesage.All these quantities are checked by weighing.
Bien entendu, la quantité de sirop est fonction de la quantité de microsphères envisagée et de la formule finale des microsphères.Of course, the quantity of syrup is a function of the quantity of microspheres envisaged and of the final formula of the microspheres.
La suspension obtenue est ensuite transférée dans un générateur à double enveloppe et est maintenue à température constante de 70 ±5°C tout au long du procédé de fabrication sous agitation continue.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.
Phases de pulvérisation d'enrobage et de séchageCoating spraying and drying phases
La durée possible d'un cycle de pulvérisation séchage est d'une minute. Dans ce cas, l'étape de pulvérisation dure 20 secondes et est en alternance avec la phase de séchage qui dure 40 secondes, et ce pour un débit de solution de pulvérisation de 80 ml/ minute. La phase de séchage correspondant à une projection continue d'air puisé à une température de 60°C.The possible duration of a drying spray cycle is one minute. In this case, 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.
Il est bien entendu évident que la durée et les paramètres de chacune de ces phases sont ajustables, et adaptés d'une part à la concentration en sucre du sirop et d'autre part au débit de pulvérisation de cette "suspension d'enrobage".It is of course obvious that the duration and the parameters of each of these phases are adjustable, and adapted on the one hand to the sugar concentration of the syrup and on the other hand to the rate of spraying of this "coating suspension".
Après les phases de prégranulation et de granulation, la vitesse de rotation de la turbine est réduite et l'étape de séchage finale des microsphères démarre et se poursuit pendant environ 3 heures.After the pregranulation and granulation phases, the speed of rotation of the turbine is reduced and the final drying stage of the microspheres starts and continues for approximately 3 hours.
Selon des programmes de tamisage définis par l'automate, le produit sec est tamisé et les tailles désirées sont sélectionnées.According to sieving programs defined by the automaton, the dry product is sieved and the desired sizes are selected.
Enfin, le produit conforme aux spécifications voulues, c'est-à-dire, le plus souvent, aux exigences de la pharmacopée en vigueur, est conditionné pour être commercialisé.Finally, the product conforming to the desired specifications, that is to say, most often, to the requirements of the pharmacopoeia in force, is conditioned to be marketed.
Exemple 1Example 1
100 kg de sucre cristallisé, comportant des cristaux de saccharose pur d'une taille moyenne comprise entre 90 et 120 μm et vendus sous la marque microcristal® tel que mentionné dans le tableau 1, et ayant une densité de 0.75, sont chargés dans une turbine classique d'enrobage. Puis 234,8 Litres de suspension d'enrobage ou sirop, sont pulvérisés selon les intervalles de temps optimaux pour chacune des phases de prégranulation et de granulation, aussi appelée "phase d'enrobage".100 kg of granulated sugar, comprising pure sucrose crystals with an average size of between 90 and 120 μm and sold under the brand microcrystal® as mentioned in table 1, and having a density of 0.75, are loaded into a turbine classic coating. Then 234.8 liters of coating suspension or syrup are sprayed at the optimum time intervals for each of the pre-granulation and granulation phases, also called "coating phase".
Les paramètres caractéristiques de ces deux phases de pulvérisation sont récapitulés ci-dessous :The characteristic parameters of these two spraying phases are summarized below:
Délai de pulvérisation (phase de prégranulation) : 20 secondes Délai pulvérisation (phase de granulation) : 40 secondes Vitesse de la turbine : 21 tours par minute Débit de pulvérisation : 80 ± 5 ml par minute Temps total de pulvérisation 49,5 heuresSpray time (pre-granulation phase): 20 seconds Spray time (granulation phase): 40 seconds Turbine speed: 21 rpm Spray rate: 80 ± 5 ml per minute Total spray time 49.5 hours
Vitesse de la turbine (séchage): 10 tours par minuteTurbine speed (drying): 10 revolutions per minute
Temps total de séchage: 6 heuresTotal drying time: 6 hours
Temps total de tamisage sélection 3 heuresTotal screening time selection 3 hours
Durée totale du procédé : 58,5 heuresTotal duration of the process: 58.5 hours
La caractérisation des sphères de sucre obtenues est décrite dans le Tableau III.The characterization of the sugar spheres obtained is described in Table III.
Tableau ITable I
Le tableau I donne un comparatif des rendements d'obtention de microsphères de sucre de petite taille par un procédé classique dit "par poudrage" et par le procédé par pulvérisation conforme à la présente invention.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.
Tableau IITable II

Claims

REVENDICATIONS
1) Procédé de fabrication de microsphères de sucre de taille de particules inférieure à 500 μm, caractérisé en ce qu'il implique l'alternance de phases de pulvérisation fine d'un sirop de sucre sur un support solide constitué par un ou plusieurs sucres, et de phases de séchage jusqu'à l'obtention finale des microsphères.1) Process for manufacturing sugar microspheres with a particle size of less than 500 μm, characterized in that it involves alternating fine spraying phases of a sugar syrup on a solid support consisting of one or more sugars, and drying phases until the microspheres are finally obtained.
2) Procédé selon la revendication 1, caractérisé en ce que ledit support solide de sucre(s) est choisi parmi les sucres comportant entre 4 et 24 atomes de carbone ainsi que leurs mélanges.2) Method according to claim 1, characterized in that said solid support of sugar (s) is chosen from sugars having between 4 and 24 carbon atoms as well as their mixtures.
3) Procédé selon l'une des revendications 1 ou 2, caractérisé en ce que ledit support solide de sucre(s) est constitué de cristaux de sucre.3) Method according to one of claims 1 or 2, characterized in that said solid support of sugar (s) consists of sugar crystals.
4) Procédé selon l'une des revendications 1 ou 2, caractérisé en ce que ledit support solide de sucre(s) est constitué de particules de sucre sous forme amorphe.4) Method according to one of claims 1 or 2, characterized in that said solid sugar support (s) consists of sugar particles in amorphous form.
5) Procédé selon l'une des revendications 1 ou 2, caractérisé en ce que ledit support solide de sucre(s) est constitué de particules de sucre semi-ouvrées de taille inférieure à 200 μm, obtenues à un stade intermédiaire de la mise en œuvre du procédé selon l'une des revendications 1 à 4.5) Method according to one of claims 1 or 2, characterized in that said solid sugar support (s) consists of semi-worked sugar particles of size less than 200 microns, obtained at an intermediate stage of the setting work of the method according to one of claims 1 to 4.
6) Procédé selon la revendication 4, caractérisé en ce que lesdites particules de sucre sous forme amorphe sont constituées d'un sucre appartenant au groupe comprenant le sucre glace amylacé, le sucre glace silice, le sucre alvéolaire et le COMPRESSUCRE®.6) Method according to claim 4, characterized in that said sugar particles in amorphous form consist of a sugar belonging to the group comprising starch icing sugar, silica icing sugar, alveolar sugar and COMPRESSUCRE®.
7) Procédé selon l'une des revendications 4 et 6, caractérisé en ce que lesdites particules de sucre sous forme amorphe ont une taille comprise entre 50 et7) Method according to one of claims 4 and 6, characterized in that said sugar particles in amorphous form have a size between 50 and
200 μm. 8) Procédé selon la revendication 3, caractérisé en ce que lesdits cristaux de sucre sont constitués des sucres appartenant au groupe comprenant le saccharose, le maltose, le glucose, le dextrose, le mannose, le galactose, le fructose, le ribose, le lactose, le maltose, le mannitol, le sorbitol et le xylitol.200 μm. 8) Method according to claim 3, characterized in that 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.
9) Procédé selon l'une des revendications 3 et 4, caractérisé en ce que lesdits cristaux de sucre ont une taille comprise entre 50 et 200 μm, préférentiellement entre 100 et 150 μm.9) Method according to one of claims 3 and 4, characterized in that said sugar crystals have a size between 50 and 200 microns, preferably between 100 and 150 microns.
10) Procédé selon l'une des revendication 1 à 9, caractérisé en ce que ledit sirop de sucre est composé d'un mélange d'un ou plusieurs sucres et d'un liquide, le ou lesdits sucre(s) appartenant au groupe des sucres comportant entre 4 et 24 atomes de carbone.10) Method according to one of claims 1 to 9, characterized in that said sugar syrup is composed of a mixture of one or more sugars and a liquid, the said sugar (s) belonging to the group of sugars with between 4 and 24 carbon atoms.
11) Procédé selon l'une des revendications 1 à 9, caractérisé en ce que ledit sirop de sucre est constitué d'un ou plusieurs sucres et d'un liquide, le ou lesdits sucres appartenant au groupe comprenant le saccharose, le maltose, le glucose, le dextrose, le mannose, le galactose, le fructose, le ribose, le lactose, le maltose, le mannitol, le sorbitol et le xylitol.11) Method according to one of claims 1 to 9, characterized in that said sugar syrup consists of one or more sugars and a liquid, the said sugar or sugars belonging to the group comprising sucrose, maltose, glucose, dextrose, mannose, galactose, fructose, ribose, lactose, maltose, mannitol, sorbitol and xylitol.
12) Procédé selon l'une des revendications 10 et 11, caractérisé en ce que ledit liquide est un liquide pharmacologiquement acceptable, préférentiellement de l'eau.12) Method according to one of claims 10 and 11, characterized in that said liquid is a pharmacologically acceptable liquid, preferably water.
13) Procédé selon l'une des revendications 1 à 12, caractérisé en ce que la concentration en sucre(s) dudit sirop est comprise entre 700 et 980 g par litre.13) Method according to one of claims 1 to 12, characterized in that the sugar concentration (s) of said syrup is between 700 and 980 g per liter.
14) Procédé selon l'une des revendications 1 à 13, caractérisé en ce que la concentration en sucre(s) dudit sirop est comprise entre 865 et 880 g par litre.14) Method according to one of claims 1 to 13, characterized in that the sugar concentration (s) of said syrup is between 865 and 880 g per liter.
15) Procédé selon l'une des revendications 1 à 14, caractérisé en ce que ledit sirop est constitué d'un mélange de saccharose et d'eau. 16) Procédé selon l'une des revendications 1 à 15, caractérisé en ce que ledit sirop contient en outre de l'amidon.15) Method according to one of claims 1 to 14, characterized in that said syrup consists of a mixture of sucrose and water. 16) Method according to one of claims 1 to 15, characterized in that said syrup also contains starch.
17) Procédé selon la revendication 16, caractérisé en ce que ledit amidon représente entre 10 et 40 % de la matière sèche composant ledit sirop.17) Method according to claim 16, characterized in that said starch represents between 10 and 40% of the dry matter making up said syrup.
18) Procédé selon l'une des revendications 16 et 17, caractérisé en ce que ledit amidon est choisi dans le groupe comprenant l'amidon de maïs, l'amidon de riz, l'amidon de blé, et l'amidon de pomme de terre.18) Method according to one of claims 16 and 17, characterized in that said starch is selected from the group comprising corn starch, rice starch, wheat starch, and apple starch Earth.
19) Procédé selon l'une des revendications 1 à 18, caractérisé en ce que ledit sirop contient en outre des additifs pharmacologiquement acceptables, tels que des colorants, des lubrifiants, des tensioactifs et des antioxydants.19) Method according to one of claims 1 to 18, characterized in that said syrup further contains pharmacologically acceptable additives, such as dyes, lubricants, surfactants and antioxidants.
20) Procédé selon l'une des revendications 1 à 19, caractérisé en ce que la pulvérisation dudit sirop est effectuée par une buse pneumatique à jet plat par nébulisation.20) Method according to one of claims 1 to 19, characterized in that the spraying of said syrup is carried out by a pneumatic nozzle with flat jet by nebulization.
21) Procédé selon l'une des revendications 1 à 20, caractérisé en ce que les phases de pulvérisation dudit sirop s'effectuent en une première étape dite de prégranulation à un faible débit (avantageusement inférieur à 120 ml par minute, et une seconde étape dite de granulation à un débit plus élevé.21) Method according to one of claims 1 to 20, characterized in that the spraying phases of said syrup are carried out in a first step called pre-granulation at a low flow rate (advantageously less than 120 ml per minute, and a second step called granulation at a higher flow rate.
22) Procédé selon la revendication 21, caractérisé en ce que les phases de pulvérisation dudit sirop s'effectuent à un débit compris entre 60 ml et 120 ml par minute lors de la phase de prégranulation.22) Method according to claim 21, characterized in that the spraying phases of said syrup are carried out at a flow rate between 60 ml and 120 ml per minute during the pre-granulation phase.
23) Procédé selon l'une des revendications 1 à 22, caractérisé en ce que les phases de pulvérisation sont mises en œuvre dans une turbine non perforée à fond plat ou en lit d'air fluidisé. 24) Procédé selon l'une des revendications 1 à 23, caractérisé en ce que les phases de séchage consistent en une projection continue d'air sur les microsphères de sucre en formation pendant l'arrêt des phases de pulvérisation.23) Method according to one of claims 1 to 22, characterized in that the spraying phases are implemented in a non-perforated turbine with a flat bottom or in a fluidized air bed. 24) Method according to one of claims 1 to 23, characterized in that the drying phases consist of a continuous projection of air on the sugar microspheres being formed during the stopping of the spraying phases.
25) Procédé selon l'une des revendications 1 à 24, caractérisé en ce qu'il comporte une phase finale de séchage et de déshydratation desdites microsphères durant de 1 à 7 heures, de préférence de 2 à 4 heures.25) Method according to one of claims 1 to 24, characterized in that it comprises a final phase of drying and dehydration of said microspheres lasting from 1 to 7 hours, preferably from 2 to 4 hours.
26) Microsphères de sucre présentant un indice de sphéricité compris entre 0,85 et 1, susceptible d'être obtenu par la mise en œuvre du procédé selon l'une des revendications 1 à 25.26) Sugar microspheres having a sphericity index of between 0.85 and 1, capable of being obtained by implementing the method according to one of claims 1 to 25.
27) Microsphères de sucre selon la revendication 26, caractérisées en ce qu'elles présentent en outre un indice de convexité compris entre 0,9 et 1.27) Sugar microspheres according to claim 26, characterized in that they also have a convexity index of between 0.9 and 1.
28) Microsphères de sucre selon l'une des revendications 26 et 27, caractérisés en ce que leur taille finale est comprise entre 100 et 500 μm.28) Sugar microspheres according to one of claims 26 and 27, characterized in that their final size is between 100 and 500 microns.
29) Utilisation des microsphères de sucre selon l'une des revendications 26 à 28 comme support neutre de principe actif pharmaceutique.29) Use of the sugar microspheres according to one of claims 26 to 28 as a neutral carrier of active pharmaceutical ingredient.
30) Utilisation des microsphères de sucre selon l'une des revendications 26 à 29 comme matière première dans la constitution d'aliments. 30) Use of the sugar microspheres according to one of claims 26 to 29 as a raw material in the constitution of food.
EP04742280A 2003-03-20 2004-03-18 Method of producing small microspheres of sugar, microspheres thus obtained and applications thereof Withdrawn EP1603539A1 (en)

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FR0303408A FR2852607B1 (en) 2003-03-20 2003-03-20 PROCESS FOR PRODUCING SMALL SIZE SUGAR MICROSPHERES, MICROSPHERES THAT MAY BE OBTAINED BY THIS PROCESS AND THEIR APPLICATIONS
FR0303408 2003-03-20
PCT/FR2004/000662 WO2004084863A1 (en) 2003-03-20 2004-03-18 Method of producing small microspheres of sugar, microspheres thus obtained and applications thereof

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