EP0923312A1 - Hocheffizientes orales verabreichungssystem und verfahren zur herstellung desselben - Google Patents

Hocheffizientes orales verabreichungssystem und verfahren zur herstellung desselben

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Publication number
EP0923312A1
EP0923312A1 EP97922993A EP97922993A EP0923312A1 EP 0923312 A1 EP0923312 A1 EP 0923312A1 EP 97922993 A EP97922993 A EP 97922993A EP 97922993 A EP97922993 A EP 97922993A EP 0923312 A1 EP0923312 A1 EP 0923312A1
Authority
EP
European Patent Office
Prior art keywords
premix
mixture
emulsion
gel
delivery form
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Withdrawn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
EP97922993A
Other languages
English (en)
French (fr)
Inventor
Bernard Breton
Piotr Epler
Tomasz Mikolajczyk
Frans Ollevier
Ivo Roelants
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.)
Katholieke Universiteit Leuven
Institut National de la Recherche Agronomique INRA
AGRICULTURAL ACADEMY OF KRAKOW
Original Assignee
Katholieke Universiteit Leuven
Institut National de la Recherche Agronomique INRA
AGRICULTURAL ACADEMY OF KRAKOW
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 Katholieke Universiteit Leuven, Institut National de la Recherche Agronomique INRA, AGRICULTURAL ACADEMY OF KRAKOW filed Critical Katholieke Universiteit Leuven
Priority to EP97922993A priority Critical patent/EP0923312A1/de
Publication of EP0923312A1 publication Critical patent/EP0923312A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/184—Hormones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/28—Silicates, e.g. perlites, zeolites or bentonites
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/20—Shaping or working-up of animal feeding-stuffs by moulding, e.g. making cakes or briquettes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/25—Shaping or working-up of animal feeding-stuffs by extrusion
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic

Definitions

  • the present invention relates to a premix material for the production of an oral delivery form for animals, in particular fish, to a series of oral delivery forms per se, to methods for making the premix material and the delivery forms, and to the use of the premix material and the delivery forms in the treatment of animals.
  • the invention further relates to the use of the premix material, the delivery forms or at least some of their components for increasing the uptake of a bioactive agent in the intestinal tract.
  • oral administration When administering bioactive agents to animals, including humans, oral administration is usually preferred as compared to injections, intubation, suppositories and the like. Oral administration forms may be simply ingested, optionally after having been added to the food, whereas the other types of administration require handling of the animals. This generally causes stress which is not beneficial for the animals, and requires a high amount of work. It is for example known to administer bioactive agents, like hormones, to fish in order to produce a desired physiological effect, such as spawning. In practice, fish are individually treated by first catching them, followed by injection or parenteral administration of the bioactive agent. Being caught and handled is particularly stressful for the fish. Furthermore, this procedure is very labour intensive and thus not cost- effective.
  • a suitable delivery form may be prepared from a premix material, which is obtainable by a) preparing a first emulsion of at least one oily substance and optionally at least one watery substance; b) optionally adding a bioactive agent to the first emulsion to obtain a second emulsion; c) adding the preparation obtained so far to a solution of a colloid binding agent to obtain a liquid mixture; d) absorbing this mixture to a carrier mixture of hydrophobic and hydrophilic silica particles to obtain a cream or viscous liquid; e) gelling this cream or viscous liquid to obtain a premix gel; f) optionally drying the gel and grinding the dry substance obtained hereof to a particulate premix material .
  • the premix material is obtainable by a) preparing a first emulsion of at least one oily substance and optionally at least one watery substance; b) optionally adding a bioactive agent to the first emulsion to obtain a second emulsion; c) absorbing either of the emulsions to a carrier mixture of hydrophobic and hydrophilic silica particles to obtain a powder, a cream or a viscous liquid depending on the proportion of the ingredients; d) adding the preparation obtained so far to a solution of a colloid binding agent to obtain a mixture; e) gelling the mixture to obtain a premix gel; f) optionally drying the gel and grinding the dry substance obtained hereof to a particulate premix material .
  • the particulate premix material may then be used in combination with known granulation additives, such as AvicelTM (microcrystalline cellulose) or lactose to obtain granules.
  • known granulation additives such as AvicelTM (microcrystalline cellulose) or lactose
  • the bioactive agent can be added to the other ingredients during the granulation process instead of during the preparation of the premix.
  • the granules may be added to the feed or be brought in a separate dosage form such as capsules.
  • the liquid mostly water wets the particles effectively.
  • tensio-active substances are known to lower the interfacial tension between the liquid and the particles and thus have a negative impact on the strength between the primary particles. That is, by lowering the surface tension of the binding liquid, tensio-active substances make the formation of difficult. For granulation the use of tensio-active substances is therefore to be avoided
  • the absorption enhancer of the invention comprises a tensio-active substance. Therefore, again after extensive research it was found that when the silica powders having the oily and tensio-active substance absorbed thereon were incorporated in a colloid binding agent, after gelling, drying and milling, small particles were obtained that could be used for standard (micro)granulation.
  • the invention in a first aspect thus resides in the provision of this unique combination of process steps that surprisingly led to a particulate premix material that could be used in standard (micro)granulation techniques.
  • the invention in another aspect relates to the use of carrier mixtures of hydrophilic and hydrophobic silica as an additive for (micro)granulating oils, fats, fatty acids, tensio-active substances, or mixtures thereof, either with or without hydrophilic substances.
  • the first and second emulsion in the above described method may also be substituted by fats, oils, fatty acids or tensio-active substances per se.
  • the silica is preferably a mixture of Sipernat D17TM and/or Sipernat 22TM from the Degussa company.
  • the (bio)active substance might be a separate component that is added to the emulsion, fat, oil or fatty acid, the bioactive substance might as well be the oily or watery component itself. Step b) is therefore optional.
  • the colloid binding agent is preferably a hydrocolloid material, such as those originating from terrestrial plant (galactomannans, pectins) , seaweed (carrageenans, alginate) , animal (gelatin) or microorganism (xantan gum) , and is most preferably, for optimum results, an alcohol extracted kappa-carrageenan.
  • the dissolution of the binding agent is in the case of kappa-carrageenan preferably effected by heating or by removing K + from the kappa-carrageenan composition by alcohol extraction. Gelling is then effected by cooling or the addition of K + .
  • the final delivery form can be the premix gel before drying and grinding, but may also be the particulate premix material obtained after drying and grinding.
  • the particulate premix material is further processed into granules which are preferably substantially spherical, and have a diameter of between 150 ⁇ m and 10 mm, preferably between 250 ⁇ m and 1 mm, the optimal size of the granules being dependent on the application of the granules, such as the size of the animal to be treated.
  • the invention thus provides for four types of delivery forms, namely the powder of silica with the oil, fat, fatty acid or emulsion absorbed thereon, the premix gel, the particulate premix material and the granules.
  • the different delivery forms may optionally be encapsulated within a protective layer suitable for providing protection against breakdown thereof in the stomach or for targeting to particular areas in the intestine.
  • the protective layer comprises at least one enteric polymer, such as cellulose acetate trimellitate (CAT) , polyvinyl acetate phthalate (PVAP) , hydroxypropyl methylcellulose phthalate (HPMCP) , shellac or any other suitable polymer.
  • the enteric polymer is most preferably cellulose acetate phthalate (CAP) which was found to be very effective.
  • the core may be coated with other controlled release polymers.
  • it can be a hydrophilic swellable polymer responsible for a longer "lag phase" period by a delayed disintegration of the core over the intestinal transit time.
  • It can also be chemically modified glycosidase-sensitive carbohydrates.
  • the delivery forms may further comprise degradation decreasing agents for inhibiting degradation of bioactive agents in the digestive tract, such as enzyme inhibitors and/or chelating agents.
  • the delivery forms may comprise several other bioactive substances acting in combination, for example anti-dopaminergic compounds to enhance in fish the effect of GnRH.
  • the delivery forms according to the present invention can be simply fed to animals as part of a diet .
  • the granules after incorporation into the feed for example can be thrown onto the water whereby the need to individually treat fish is obviated.
  • Bioactive agents to be incorporated in one of the delivery forms of the invention are chemical compounds or compositions that have an effect on or create a response in living organisms, cells or tissues.
  • the bioactive agents can, for example, be polypeptides, hormonally active substances, antibodies, enzymes, oligo- or polynucleotides, like RNA, immuno-stimulators, (essential) nutrients, vitamins, carotenoids, therapeutics, and viral and bacterial antigens.
  • the bioactive agent may also be (modified) micro-organisms, for example for use in vaccines. All of these are biodegradable, which means that they are susceptible of degradation by biological processes, such as bacterial or other enzymatic action.
  • the bioactive agents may be naturally occurring, be synthetic or be derived from recombinant DNA technology.
  • Hormonally active compounds comprise a diverse group of chemical and biophysical identity but because of their functional specificity, they are conveniently grouped into discrete classifications by physiological effect.
  • GnRH-active polypeptides act through their receptors on the gonadotrops of the anterior pituitary gland to affect release of gonadotropic hormones, which affect the activity of reproductive organs. In most fish species this GnRH(-a) action is inhibited by dopamine. Simultaneously delivering anti-dopaminergic compounds can thus enhance the gonadotropin release stimulating effect of GnRH(-a) .
  • the delivery form of the invention may contain for example a gonadotropin hormone releasing hormone (GnRH) or analogue (GnRH-a) thereof which affect fertility and the physiological effects related thereto.
  • GH Growth hormones
  • somatomedines act on receptors in various tissues causing the release of somatomedines, the peptide factors responsible for skeletal growth and various other somatic and osmoregulatory processes.
  • Several studies have, also, provided evidence for a direct gonadal site of action for GH. In teleost fish GH and prolactines affect calcium metabolism and osmoregulation in specific ways.
  • Oligonucleotides are biodegradable compounds of a few nucleotides.
  • Antigens are substances which are capable, under appropriate conditions, of inducing the formation of antibodies and reacting specifically in some detectable manner with the antibodies produced.
  • Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells. They may be lipids, proteins, carbohydrates, proteoglycans, glycolipids, glycoproteins or lipoproteins such as the numerous lipopolysaccharides isolated from bacteria which function as specific haptens or as complete antigens in another individual or by cell culture.
  • Antibodies are immunoglobulin molecules that have a specific amino acid sequence by virtue of which they interact only with the antigen that induces its synthesis in lymphoid tissue, or with antigen closely related to it.
  • the meaning of entrapment of antibodies in the proposed delivery system of the invention is its usage a an immunotherapeutic for the modulation of the passive immunity of an individual, which passive immunity is conferred by administration of pre-formed antibodies (serum or gamma globulin) actively produced in another individual. They can also be used as vaccine in immuno- prophylaxis for prevention of disease and for any process of rendering a subject immune.
  • Enzymes are proteins capable of accelerating or producing by catalytic action some change in a substrate for which they are often specific.
  • Therapeutics are compounds that will heal and which will be used for treatment of diseases.
  • Prophylactic compounds will prevent disease, while immunostimulants are substances that activate the cellular or humoral immune system or possibly result in enhanced formation of antibodies and the specific reaction of the antibodies produced.
  • Essential nutrients are nutrients an animal requires for proper functioning.
  • bioactive, biodegradable compounds for administration of which this invention is intended, but merely sets out examples to illustrate the type of biodegradable macromolecules that may be used. All these bioactive, biodegradable substances have to be targeted from the intestinal lumen into the blood circulation.
  • the invention makes this possible by providing a delivery form that combines the bioactive agent with an absorption enhancer - these enhancers improve the uptake of the bioactive agent from the intestinal lumen into the blood - in a form which is suitable for oral administration.
  • the delivery form resists breakdown in the stomach if necessary.
  • the invention further relates to a method for producing the particulate premix material of the invention, comprising a) preparing a first emulsion of at least one oily substance and optionally at least one watery substance; b) optionally adding a bioactive agent to the first emulsion to obtain a second emulsion; c) adding the preparation obtained so far to a solution of a colloid binding agent to obtain a liquid mixture; d) absorbing this mixture to a carrier mixture of hydrophobic and hydrophilic silica particles to obtain a cream or viscous liquid; e) gelling this cream or viscous liquid to obtain a premix gel; f) optionally drying the gel and grinding the dry substance obtained hereof to a particulate premix material.
  • the method comprises the steps of a) preparing a first emulsion of at least one oily substance and optionally at least one watery substance; b) optionally adding a bioactive agent to the first emulsion to obtain a second emulsion; c) absorbing either of the emulsions to a carrier mixture of hydrophobic and hydrophilic silica particles to obtain a powder, a cream or a viscous liquid depending on the proportion of the ingredients; d) adding the preparation obtained so far to a solution of a colloid binding agent to obtain a mixture; e) gelling the mixture to obtain a premix gel; f) optionally drying the gel and grinding the dry substance obtained hereof to a particulate premix material.
  • the same principles apply as have been explained for the premix material which was defined by its method of preparation.
  • the invention further relates to the use of the premix material in the preparation of granules.
  • various standard techniques may be used such as "Pharmaceutics: The Science of Dosage Form Design”, Ed. Michael E. Aulton, Churchill Livingstone, Edinburgh London Melbourne and New York (1988) , pages 616-628, and “Pharmaceutical Pelletization Technology”, Ed. Isaac Ghebre-Sellassie, Marcel Dekker, Inc., New York and Basel (1989) , pages 101-122 and 187-216.
  • the invention further relates to method for producing the various delivery forms and premixes. Sometimes, a premix may at the same time be classified as a delivery form. However, a premix is also always a starting or intermediate material for the preparation of the delivery form.
  • the invention in another aspect relates to the use of the delivery forms and premixes in various (therapeutical) applications.
  • delivery form(s) and “administration form(s)” are used interchangeably.
  • bioactive agent and “ (bio) active substance” are used interchangeably.
  • “Oily substances” encompass a single substance or mixtures of substances having a hydrophobic character, e.g. oils, fats, fatty acids, tensio-active substances etc.
  • a “watery substance” is any watery compound or compound with a hydrophilic character.
  • “Powder” is used for the mixture of hydrophilic and hydrophobic silica having an oil, fat, fatty acid, tensio-active substance, emulsion or any combination of these absorbed thereon.
  • “Binding agent” encompasses every agent encapsulating the powder. The powder is added to a solution of the binding agent after which the solution is gelled. Thus, the “premix gel” or “gel” is obtained. After drying the gel and comminuting the dried gel in any way (grinding, milling, pulverizing etc.) a “particulate premix material” is obtained. “Granules” are obtained after (micro)granulation of the particulate premix material .
  • Absorption enhancer is used to indicate any substance or combination of substances that somehow stimulates the absorption of a bioactive agent by the intestine.
  • Oral delivery form is used to encompass any combination of a bioactive agent with one or more excipients.
  • Excipients as used herein are both the silica, binding agent, emulsion, tensio-active substance, fatty acid, fats, oils etc. and any other additive necessary for preparing the composition.
  • LHRHa or GnRHa as a model substance to show that absorption thereof by fish can be readily stimulated.
  • GnRHa or LHRHa absorption was estimated from its ability to stimulate ovulation and spermiation in African catfish, rainbow trout and carp and by the induced gonadotropin (GtH) release in these animals.
  • Second method for preparing a particulate premix material Delivery forms were prepared that allowed the inventors to entrap bioactive (poly)peptides and a dosage of Tween/oleic acid, necessary to enhance intestinal uptake, into a rigid gel of K-carrageenan. After producing the gel it was further treated to obtain a particulate premix material suitable for (micro) granulation.
  • the gel was formed as follows, K-carrageenan was added to water (up to 5 gram per 100 ml) , mixed vigorously, whereafter the mixture was warmed to 85°C to obtain a K-carrageenan solution in water.
  • K-carrageenan contains potassium salts. Potassium ions prevents ⁇ -carrageenan to solve in cold water. One has to heat such ⁇ -carrageenan up to 85°C in water to make a solution. Fast cooling results in immediate gelling.
  • bioactive compounds were added and mixed intensively by a (ultraturax) mixer. This mixture was cooled suddenly to obtain a rigid gel. Occasionally a KCl solution (2M) was added just prior to cooling to improve gelling.
  • the particulate premix material was made as follows.
  • the gel was cut in small pieces which were dried by freeze drying, fluidized bed drying or tray drying. This product was ground to a powder consisting of particles of less than 70 ⁇ m diameter.
  • K-carrageenan contains potassium ions it is not soluble in cold water. In the above procedure we therefore used an elevated temperature to effect dissolution. However when using alcohol extracted K-carrageenan it was possible by a cold procedure to make a solution which gelled immediately on addition of a KCl solution.
  • bioactive agents like GnRH analogues and/or Domperidone were added and mixed intensively.
  • KCl solution (2M) was mixed in this liquid.
  • the gel was cut into small pieces which were dried by freeze drying, fluidized bed drying or tray drying. This procedure was repeated to yield 7 particulate premixes (A-F and X) wherein the basic components were carrageenan, Tween + oleic acid, silica and bioactive agents.
  • hyfeel hydrophilic silica
  • hyfoob hydrophobic silica
  • CAP cellulose acetate phthalate
  • premixes were ground to a powder consisting of microbeads of diameter of less than 70 ⁇ m. Subsequently these premixes were subjected to granulation. The particulars of granulation are set out under 1.3. hereinbelow.
  • the above described particulate premixes were put into a spheronizer with the aim of producing spheres with a diameter of around- 250-750 ⁇ m. For granulation 200 gram of each premix was mixed (during 10 minutes) with 175 gram microcrystalline cellulose (AvicelTM) and 125 lactose. The mixtures A, B, C, D, E and F gave in the granulating machine a low yield of only some spheres (10%) . Phase separation of Tween (polyoxyethylene sorbitan surfactant) and the oleic acid (fatty acid) occurred.
  • Tween polyoxyethylene sorbitan surfactant
  • oleic acid fatty acid
  • premix X the inventors replaced a fraction of hydrophilic silica by hydrophobic silica, to yield a hydrophobic versus hydrophilic silica ratio of 1:1. Premix X was then used by the inventors to develop enteric microgranules. The formulation of the premix for encapsulation was shown in the above table.
  • Main carrier materials currently used in granulation processes are monohydrate lactose, micro crystalline cellulose and potato starch or lactose (Microencapsulation and related drug processes, Patrick B. Deasy, Marcel Dekker, Inc., New York and Basel, p 282) . These carrier materials, contribute to processes of attractive force between solid particles. These attractive forces may be molecular (Valence and Van der Waals) , electrostatic or magnetic in nature (Drug and the Pharmaceutical Science, Vol. 37, Marcel Dekker Inc, 1989, p.124) .
  • Extrusion is a process that initially mixes powders by forcing them through a mesh screen or plate through action of wiper mechanism.
  • Carrier materials such as lactose, micro crystalline cellulose and potato starch improve this process.
  • the irregular shaped granules (microbeads) of premix X were shaped, after addition of monohydrate lactose (FEDERA) and of micro crystalline cellulose (AVICEL, FEDERA) , into cylindrical extruded granules. After extrusion they were spheronized (300 ⁇ m diameter) in a marmurizer, from the Fuji Paudal Co. Ltd.
  • Aeromatic or the Freund type spheronizers like high speed mixer/granulators and also fluidized bed granulators, use wet granulation in which the powder microbeads are made to adhere and form larger particles.
  • the premix X and monohydrate lactose and microcrystalline cellulose were put into a centrifugal force granulating machine (Aeromatic rotorprocessor) to produce spherical pellets of 250 ⁇ m - 750 ⁇ m.
  • Coating was done in a fluidized bed with a 10% CAP salt solution and 25% (to CAP w/w) triacetin as plasticizer.
  • the CAP salts were produced from CAP (Eastman Kodak) . Coating condition in the fluidized bed were: - Income temperature: 50°C
  • An advantage of coating under these conditions is that no environmentally unfriendly organic solvents were used either for granulation or for enteric coating, furthermore coating with cellulose acetate phthalate in a fluidized bed has a large flexibility and the size of the coating layer can be easily controlled.
  • the capsules X were mixed together with different ratios of a mixture containing fat, hydrolysable sugar and proteins.
  • the overall mixture was introduced by forced feeding.
  • the treatment protocol is explained in table 1.
  • Table 2 shows the statistical analysis of data of the common carp experiment explained in table 1 and demonstrated in fig. 1.
  • Table 2 shows that there is no significant effect of diet (0 - 66,6%) on sGnRH-a induced GtH2 release.
  • the sGnRH-a loaded microcapsules were under the various nutritional conditions highly efficient in stimulating GtH2 release.
  • Lipids are certainly the nutrients which could interfere the most with enhancers. These enhancers, are more often tensio-active hydrophobic substances which can either be solubilised in lipids or form emulsions, thus reducing or inhibiting their action on the intestinal border. For that reason, special attention must be paid to the effects of lipids on the absorption of bioactive material from food entrapped microcapsules. Materials and methods
  • Micro-encapsulated sGnRH-a when delivered alone, did not stimulate significantly more the GtH secretion than when ingested together with low un-saturated fat concentrations of 1% to 5%. On the contrary in the presence of fat there was a tendency (but not significant) to induce a better stimulation. This indicated comparable bioavailabilities .
  • Table 4 shows the statistical analysis of this experiment on rainbow trout .
  • test diet was formulated as oral delivery medium for enteric microcapsules with the mixed micelle (polyoxyethylene sorbitan surfactant/oleic acid) and sGnRH analogue (sGnRH-a) 20 ⁇ g/g capsule.
  • This diet was moistened (50 ml water per 100 gram dry materials) and pelletised with CMC and Satagel (Sanofi Bioindustries) as binder and by the procedure of extrusion and of freeze drying. The pellets were floating which had the advantage that the food uptake could be checked.
  • the food composition is described in Table 7.
  • Table 7 Formulation of the test diet (A) gluten - 5 casein 25.5 yeast 20 silica 2 alpha starch 10 sucrose 15
  • Biomeerval The catfish had been raised on a commercial diet, "Biomeerval” (B) , they had to be weaned to the new dietary formulation. Biomeerval pellets were milled to a fine powder and after vitamin/mineral enrichment it was re-pelletized (formulation B) in a same procedure with the same binders.
  • the feeding rate was 1% of the body weight.
  • 104 gram of enteric microcapsules had been mixed into 520 gram of nutrients.
  • Fourteen broodstock fish (11 females and 3 males) were kept in a 1000 litre flow-through holding facility at 27°C. On day eleven they were fed a diet enriched with s-GnRH-a loaded microcapsules.
  • the delivery dose for sGnRH-a was only 40 ⁇ g/kg body weight . This is only twice more than what is currently administered by intraperitoneal injection to obtain spawning in catfish. These results are very promising. Firstly, because they made prove that the formulation, which had been changed to make granulating of the premix possible was still an efficient absorption enhancement medium. And secondly, because this is also the first record of an efficient sGnRH-a enriched spawning diet .
  • Goldfish Carassius auratus
  • the sGnRH-a loaded enteric microcapsules were incorporated into food pellets and were fed to the goldfish.
  • 40 goldfish (mean body weight around 48 gram) were separated into 2 groups over 4 aquaria of 300 litre water at 24°C to these conditions during 2 weeks. No male goldfish were present.
  • the fish were adapted to the experimental food which consisted of a sticky past from boiled fine wheat grains. After cooling little pellets of a diameter of approximately 1 mm were hand made and fed to the fish.
  • the experiments started after two days of starvation.
  • the microcapsules coated with 10% CAP were mixed with the paste in a 1/1 ratio dry weight and the pellets were formed as described. This preparation was given to the fish in the morning. The food uptake was confirmed and after 12 hours ovulation was checked.
  • Group 1 was fed a diet containing blank control microcapsules.
  • Groups 2 was fed at 40 ⁇ g sGnRH-a per kg fish by microcapsules (containing 20 ⁇ g sGnRH-a/g) in the food pellets .
  • Ovulation rates were 1/14, 3/14, 10/14 and 8/14 in the groups that were respectively fed control capsules, 50 ⁇ g sGnRH-a/kg, 100 ⁇ g sGnRH-a/kg, 150 ⁇ g sGnRH-a/kg.
  • the Fisher exact test revealed that a dietary delivery dosage of 50 ⁇ g sGnRH-a /kg b.w. was not enough to affect significantly spawning in mature barbells (P > 0.05) .
  • a dietary delivery system of 100 ⁇ g sGnRH- a/kg b.w. (P ⁇ 0.005) or 150 sGnRH-a/kg b.w. (P ⁇ 0.007) highly significantly induced ovulations as compared to the control group.
  • a dietary delivery of 100 ⁇ g sGnRH- a/kg b.w. was significantly more affective than the 50 ⁇ g sGnRH-a/kg dietary delivery form (P ⁇ 0.05) . There were no significant differences between the highest dose delivery forms.
  • Different delivery forms liquid, powdered premix & enteric microcapsules containing the same absorption enhancer and s-GnRH-a were administrated orally to groups of 10 carps at the dosage of 20 ⁇ g sGnRH-a/kg b.w. (experiment 1) and at the dosage of 40 ⁇ g sGnRH-a /kg b.w. (experiment 2) .
  • Plasma samples collected at 0, 1, 3, 6, 12, 32 and 48 hours after delivery were analysed for GtH2. And the AUC (area under the curve) was calculated to estimate the bioavailability of GtH2 in the different conditions.
  • the 40 ⁇ g sGnRH-a delivery experiment revealed that there was no significant difference in efficiency between the powdered premix , the microcapsules and intraperitoneal injection (figures 4 and 5) .
  • the premix X containing no bioactive agent, was ground to a powder of diameter less than 90 ⁇ m. This powder was subsequently subjected to granulation, using the agitation method (Aeromatic rotorprocessor; see example 1, 1.3.2.) . Monohydrate lactose (FEDERA) and micro crystalline cellulose were used as granulating additives.
  • the bioactive agent, the GnRH-analogue Azagly- nafarelin was dissolved in the water, serving as binder liquid in the granulation process. Thereafter, the obtained granules were dried and coated (see example 1, 1.4.) .
  • the final concentration of Azagly-nafarelin in the capsules was 40 ⁇ g beadlets.
  • Plasma samples were collected immediately before administration and 6, 12, 24, 36, 48 and 72 hours later.
  • the plasma GtH II levels, as a response to the GnRH-a were determined in both groups. 2 .

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EP97922993A 1996-04-29 1997-04-29 Hocheffizientes orales verabreichungssystem und verfahren zur herstellung desselben Withdrawn EP0923312A1 (de)

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GB9723615D0 (en) * 1997-11-08 1998-01-07 Ewos Ltd Sinkable fish food pellets having good palatable properties
DE60003633T2 (de) * 1999-01-12 2004-06-03 Merck Sharp & Dohme Ltd., Hoddesdon Sphäronisiertes selbstemulgierendes system für hydrophobe und wasserempfindliche wirkstoffe
WO2001026481A1 (en) * 1999-10-13 2001-04-19 Ewos Limited Fish feed with increased nucleotide content
KR20030009344A (ko) * 2000-01-27 2003-01-29 아쿠아 솔루션 인코포레이티드 장내 전달용 조성물
EP1414561A2 (de) * 2001-08-03 2004-05-06 Maripro AS Verbesserungen an einkapselungsverfahren
CN103549213B (zh) * 2013-11-14 2016-04-27 苏州市相城区新时代特种水产养殖场 一种无污染缓释肥效鲤鱼肥料及其制备方法
CN107801865A (zh) * 2017-09-18 2018-03-16 佛山市信豚生物科技有限公司 鳜鱼专用复合预混合饲料及其制备方法与应用
JP2022172573A (ja) * 2021-05-06 2022-11-17 孝太朗 雨澤 産卵誘発用の経口製剤

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