Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
  • A61K36/282—Artemisia, e.g. wormwood or sagebrush
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/76—Salicaceae (Willow family), e.g. poplar
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials

Definitions

• Spheroids prepared from an isolated active ingredient of plant origin and a solution of plant origin containing the active ingredient or a precursor thereof.
• the present invention relates to medicinal compositions in the form of spheroids prepared from both an active ingredient of vegetable origin in an isolated form and a solution of plant origin containing the active ingredient or a precursor thereof. -this.
• It also relates to the process for preparing these spheroids by mixing an active ingredient of vegetable origin in an isolated form and a solution of vegetable origin containing the active principle or a precursor thereof, with an absorbent substance. , then extrusion and spheronization.
• One of the aims of the invention is to provide spheroids supporting pharmacologically activated substances of plant origin and more effective thanks to a synergistic effect and a better release in the digestive tract.
• the main object of the invention is to provide spheroids with a lower active ingredient titration than other conventional dry dosage forms in which this active ingredient is alone in isolated form, while maintaining comparable or even superior efficacy.
• the invention thus makes it possible to provide spheroids that are as effective as the other forms conventional dry galenics, but with reduced toxicity and lower cost.
• Another object of the present invention is to provide effective compositions in a dosage form much more convenient for patients and which is furthermore much more stable over time even under unfavorable storage conditions.
• the Western Pharmacopoeia recognizes the therapeutic action of many compounds derived from plants.
• This active ingredient purified and rid of unnecessary ancillary compounds that accompany it within the plant, is thus expected to have a maximum therapeutic activity. It is then mixed with one or more suitable excipients to make the drug.
• the active ingredient can continue to be extracted and isolated from the plant to make the drug. But most often, it is obtained chemically by hemisynthesis or total synthesis, which ensures a regular supply and consistent quality.
• the compound derived directly from the plant is not stable or does not have all the required qualities, particularly in terms of solubility for example, to be used as such in the manufacture of the drug.
• This compound is then generally converted chemically to give a suitable derivative of the plant compound precursor, then used as the active ingredient in the final drug.
• the recommended dose of active principle will be defined as an acceptable compromise between the desired efficacy on the one hand, and the risk and the dangerousness of the side effects that may result from it.
• the invention responds to this need particularly advantageously by providing drug formulations which, surprisingly, while being less dosed in active principles and therefore less toxic to the body, have a satisfactory efficiency, or even higher.
• the invention makes it possible to produce effective drugs from Artemisia Annuae whose cost is significantly lower than that of conventional drugs.
• the invention thus provides an answer to this humanitarian problem and provides hope for all the populations concerned.
• the spheroids according to the invention constitute a very stable galenic form, not requiring particular care for its storage and which supports very well the difficult climatic conditions.
• this dosage form is extremely convenient for patients and does not require the skills of trained personnel for its administration, unlike conventional injectable drugs.
• the general inventive idea consists in producing medicinal spheroids from two sources of an active principle of vegetable origin, on the one hand an active ingredient of vegetable origin in an isolated form and, on the other hand, a solution of vegetable origin containing the active ingredient or a precursor thereof. These two products are mixed with an absorbent and adsorbent substance. The whole is then extruded, then spheronized to give it the physical form of microspheres, also called spherules or spheroids.
• the invention thus provides a method for producing spheroids by mixing a solution of vegetable origin with an absorbent and adsorbent substance having plastic properties compatible with the process, wetting the mixture with a humidifying liquid if necessary. extruding the wet mixture and spheronizing the extruded product to form spheroids.
• the mixing operation comprises the following steps: . provide on the one hand an active ingredient of plant origin in an isolated form;
• spheroids which contain at least on the one hand an isolated active ingredient of plant origin and on the other hand a solution of vegetable origin containing the active principle or a precursor thereof, absorbed and / or adsorbed on an absorbent and / or adsorbent substance.
• compositions comprising an active ingredient of vegetable origin and being in a galenic form of spheroids obtained by the process according to the invention.
• the invention is not limited to its application to treat malaria, even if it is fundamental. It can be applied advantageously to many other active ingredients derived from plants to treat many other health problems or others.
• FIG. 1 is a simplified diagram of the essential steps of the method according to the invention; .
• FIG. 2 is a more detailed diagram of a first preferred variant of the method according to the invention: .
• Figure 3 is a diagram of a second variant of the method according to the invention with the addition of an auxiliary substance or a second active ingredient during the extrusion; .
• Figure 4 is a diagram of a third variant of the method according to the invention with the addition of a second active ingredient by coating; .
• Figure 5 is a diagram of a fourth variant of the method according to the invention combining the second and third variants;
• Figure 6 is a diagram illustrating an application of the method according to the invention for producing an antimalarial composition according to the invention from Artemisia Annuae; .
• Figure 7 is a diagram illustrating an application of the method according to the invention for producing a composition according to the invention based on aspirin.
• the spheroids according to the invention are made from two sources of an active ingredient of vegetable origin.
• the first of these sources corresponds to the incorporation of an isolated active ingredient which is obtained in a conventional manner.
• This active ingredient is originally derived from a plant, but may have been transformed chemically and no longer be identical to the molecule directly from the plant. For example, it is possible to obtain a molecule that is more stable or that has more suitable properties, in particular better solubility or other properties.
• This active ingredient can be extracted from the plant by any appropriate means known or to be discovered. It can also be obtained chemically, by total synthesis or semisynthesis.
• This active ingredient can be presented under a any physical form, especially solid, liquid, pasty or gel. Most frequently, it is at a pressure and ambient temperature in the form of a powder.
• the active ingredient is not necessarily the majority constituent, or the most characteristic or known of the plant. It is any compound derived from a plant, among the many compounds that can be extracted from it. In this application, active ingredient is understood to mean any compound having an effect which results in, participates in or promotes the overall result targeted by the composition for a therapeutic or other purpose.
• the second source of the invention is an active solution of plant origin containing the same active ingredient or a precursor thereof. It is preferably a liquid plant extract of the plant from which the active ingredient concerned or a precursor thereof can be extracted in the case of a chemically converted active ingredient.
• This active solution of plant origin can be obtained from the plant by any appropriate means and in particular by extraction, preferably aqueous, alcoholic or hydroalcoholic, by maceration, infusion, decoction, digestion, leaching or the like.
• mother tincture a dye or a liquid extract.
• a dry extract a dry extract, previously dissolved or suspended or used in combination with a wetting liquid in the first step of the invention.
• the first step of the process according to the invention consists in mixing the products resulting from these two enrichment routes, that is to say the isolated active ingredient on the one hand and the active solution of vegetable origin on the other hand. , to an absorbent and adsorbent substance.
• the absorbent and adsorbent substance is preferably of the natural or synthetic polymer type and is most often in the form of a powder. To be acceptable, this absorbent substance must also have plastic properties compatible with the extrusion and spheronization steps of the following process according to the invention.
• Suitable polymers having suitable absorbent and adsorbent properties and satisfactory plastic characteristics include, for example, microcrystalline celluloses, microfine celluloses, starches, modified starches and polysaccharides.
• a technical excipient formed of a dry homogeneous mixture of weakly substituted hydroxypropyl cellulosic polymer, in particular a hydroxypropyl cellulose ether weakly substituted at the level of the groups of the nucleus. ⁇ -O-glucopyranosile.
• This absorbing substance is particularly interesting when it is desired to obtain fast-dispersing spheroids of the active principles or more strongly titrated.
• any other solid substance having suitable absorbent and adsorbent properties and plastic properties compatible with the method of the invention.
• auxiliary substances such as for example other excipients commonly used with current techniques, including binders, slippery, lubricant compounds, surfactants or other.
• auxiliary substances may also be compounds intended to improve the results or the quality of the spheroids according to the invention or to give them new properties. It can thus be vitamins, minerals and / or other organic components. Examples that may be mentioned include simple sugars with a low energy content, and mineral and organic substances that may correspond in particular to lactose, sorbitol, mannitol, maltodextrins, carbonates, citrates, gelatin, polyvinylpyrrolidone or a cellulose derivative (ethyl, methyl or carboxy) and in particular sodium carboxymethylcellulose crosslinked.
• the mass of dry absorbent substance for example of microcrystalline cellulose
• a moistening liquid until a homogeneous and malleable paste is obtained that can undergo the steps following processes, ie extrusion and spheronization.
• the solution of plant origin from the natural route may advantageously serve as humidifying liquid for wetting.
• the addition of another liquid, aqueous or non-aqueous, may sometimes be necessary if the amount of liquid provided by the solution of plant origin is insufficient or for example in the case of a plant extract in dry form.
• the moistening liquid also serves as a vehicle for transporting and depositing the active substances to the heart of the absorbent and adsorbent substance in the microcavities of the polymer.
• the manufacturing process then consists of extruding the wet mass through a calibrated orifice die and then making the extruded product spherical (spheronized).
• This active ingredient, this auxiliary substance or this mixture can be incorporated into "extrudates" by coextrusion.
• it must have plasticity properties compatible with the coextrusion process.
• it may undergo beforehand any stage of preparation. It can in particular be mixed with a wetting liquid and / or with a suitable adsorbent / absorbent substance.
• the "extrudates" are placed in a cylindrical apparatus called “spheronizer” containing in its lower part a disc rotating at a variable and controlled speed. Under the effect of the centrifugal force exerted by the rotation of the rotating disk, the "extrudates" are fragmented regularly, then turn into spheres by a rolling-binding effect.
• the moistening liquid mass is preferably between 3 and 5 times the mass of absorbent substance used.
• a particular feature of the invention cited by way of example consists in preparing spheroids with a particle size of between 350 microns and 1250 microns, for a yield of at least 95% of the mass of spheroids produced.
• the die of the extruder has orifices of 1000 microns in opening diameter and 1000 microns in length (thickness of the die).
• the extrusion speed is 100 rpm for a twin screw or other type extruder apparatus.
• the spheronization cycle for a 25 cm diameter or other spheronization apparatus is then of 5 minutes duration with a speed of rotation of 1040 rpm.
• the spheroids can then undergo a drying step, preferably at a temperature in the region of 35-40 ° C. They can otherwise simply be left in the open air for a certain time. .
• the spheroids obtained are stable over time, easy to control and reproducible. They are of simple and practical use. They can be stored without precautions, nor particular care and are easily transportable because they are light, little bulky and not very fragile.
• the spheroids according to the present invention can be presented as such or coated in bulk, dosing dispenser, capsules, tablets, sachets or any other suitable form.
• capsules or capsules Preferably, they are grouped into capsules or capsules, corresponding to an amount of active ingredient determined according to the specific dosage of the composition and allowing easier uniting.
• these multiparticulate systems Prior to their packaging, for example in capsule form, these multiparticulate systems can be further dandruffed during an additional optional step of the process according to the invention.
• This operation consists in covering them with a resistant coating film making it possible to protect the molecules of active principle, for example sensitive to the low pH of the stomach or degraded by the enzymes of the intestinal lumen.
• the release can thus be delayed in order to deliver the active ingredient selectively to certain levels of the digestive system, for example at the gastric level and in the upper parts of the small intestine.
• the spheroids may also undergo an additional coating step which consists in producing an additional layer around the spheroids, once these have been formed by the mixing steps, extrusion and spheronization described above.
• the additional coating layer may be composed of one or more auxiliary substance (s) and even preferably of a second active ingredient, or of a mixture containing at least a second active ingredient, different from that provided in the initial mixing step and absorbed and adsorbed at the heart of the spheroids.
• This second active ingredient is any active substance useful for the application in question. It can for example come by its action to strengthen or complete the action of the first active ingredient. It can also have a different activity, preparing the action of the first active ingredient, acting on another aspect of the problem to treat or treating a side effect of the first active ingredient.
• This coating step is preferably performed after drying spheroids from the spheronization step.
• the coating layer is then deposited on the spheroids substantially without mixing with the first active ingredient present in the heart of the spheroids. This advantageously avoids the problems of interaction and physico-chemical incompatibility between the two active ingredients. These can coexist in parallel without harmful interactions, from the production of spheroids until their administration and even in case of long-term storage.
• the invention thus solves in a very simple and practical manner the problem of incompatibility between certain substances which makes their association impossible within conventional dosage forms, in particular tablets, and which traditionally leads to heavy and / or delicate treatments to be carried out. work based on multiple taps or in situ mixing.
• the coating step may also make it possible to obtain a delay or "double-expansion" effect between the two active principles, that is to say a release thereof that is delayed in time or at different points in the process. the body.
• This coating step may be repeated several times, so as to make as many successive layers as desired, each time using different active principles or alternating a number of them.
• the invention thus also provides spheroids coated with at least one coating layer containing at least a second active ingredient different from that absorbed and / or adsorbed on the absorbent and / or adsorbent substance.
• step or the coating steps according to the third variant of FIG. 4 can be combined with an introduction of auxiliary substance or of active principle during the extrusion according to the second variant illustrated in FIG. variant combining all these steps has been shown in Figure 5.
• the method according to the invention makes it possible to obtain a solid dosage form that is easy to use and in particular that can be administered orally without resorting to high temperatures that can alter the fragile active ingredients derived from the plants.
• this dosage form ensures the physical and chemical stability over time of the active ingredients used even under unfavorable storage conditions.
• the formulation according to the invention is accompanied by a reinforced activity of the active ingredient, which makes it possible to produce compositions which are more effective or of comparable effectiveness, but which are less dosed and therefore less toxic to the body.
• the combination of the two sources of active ingredient in the same composition achieves a synergy that increases the effectiveness of the active ingredient.
• the active solution of plant origin in addition to providing an additional amount of active ingredient, provides the composition according to the invention all the other compounds present in the plant and accompanying the active ingredient or its precursor in the natural state.
• the active ingredient thus enriched compounds initially present at its sides in the plant, sees its effectiveness enhanced by a real effect of synergy.
• the spheroids according to the invention constitute an original formulation and of great interest for preventive and curative medicine.
• the present invention will be better understood on reading the following examples.
• the first example is shown in Figure 6 and relates to a preferred application of the invention for the treatment of malaria.
• the active ingredient used is the artesunate molecule, for example in the form of sodium salt.
• This active ingredient is derived from the plant Artemisia Annuae in which it is in the form of a precursor. To improve its stability and solubility, this precursor is then chemically converted to dihydroartemisinin and artesunate.
• a liquid extract preferably a mother tincture, was obtained from Artemisia Annuae plants by extraction in alcohol and is the second source of active ingredient, in this case in the form of its precursor, according to the natural way.
• the artesunate powder and the mother tincture of Artemisia Annuae were mixed with an absorbent and adsorbent substance, for example microcrystalline cellulose powder according to the first step of the process according to the invention.
• the World Health Organization recommends for the treatment of malaria a useful dose of 200 mg artesunate twice a day for three days.
• the spheroids according to the invention most clinical tests have shown that with such an assay the parasite disappears into the blood in only forty-eight hours.
• spheroids grouped together for effective unit doses containing a dose less than or equal to 150 mg of artesunate can be produced with the invention. taken for an adult. If clinical trials confirm this, we hope achieve spheroids with sufficient efficacy when packaged in doses containing about 120 mg of artesunate for each dose. It is thus possible to reduce the toxicity of the treatment, but especially to reduce considerably the price, which is a crucial aspect for the countries struck by this disease.
• compositions of lower dosage intended for children and preferably packaged in doses containing less than or equal to 100 mg of artesunate per dose.
• FIG. 7 A second example of application of the invention has been shown in FIG. 7 and concerns the production of spheroids based on aspirin.
• acetylsalicylic acid powder usually called aspirin
• aspirin a commercial acetylsalicylic acid powder, usually called aspirin
• the natural route is provided by a liquid willow extract containing salicylic acid, a precursor of acetylsalicylic acid.
• the liquid willow extract is preferably a mother tincture of willow obtained by hydroalcoholic extraction or any other appropriate means.
• aspirin When administered in a conventional dosage form and in a usual dosage generally corresponding to an adult with 1 g acetylsalicylic acid per dose, aspirin is known to have troublesome side effects and in particular to cause inflammation of the stomach and digestive system.
• the invention makes it possible to produce aspirin-based spheroids of satisfactory efficacy with a significantly lower dose of acetylsalicylic acid.
• These spheroids can thus be grouped together for single shots containing for example a dose substantially equal to 0.1 g of acetylsalicylic acid per dose.
• the dose of active ingredient being greatly reduced, the toxicity of the composition is advantageously attenuated, which decreases and even in some cases eliminates the troublesome side effects.

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• Health & Medical Sciences (AREA)
• Natural Medicines & Medicinal Plants (AREA)
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• Medicinal Chemistry (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Tropical Medicine & Parasitology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Medicinal Preparation (AREA)

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• 2005
  • 2005-02-24 FR FR0501907A patent/FR2882255B1/fr not_active Expired - Fee Related
• 2006
  • 2006-02-23 US US11/816,945 patent/US20090123552A1/en not_active Abandoned
  • 2006-02-23 EP EP06709369A patent/EP1853226A2/de not_active Withdrawn
  • 2006-02-23 CA CA002598226A patent/CA2598226A1/fr not_active Abandoned
  • 2006-02-23 WO PCT/FR2006/000409 patent/WO2006090066A2/fr active Application Filing
  • 2006-02-23 RU RU2007134858/15A patent/RU2007134858A/ru not_active Application Discontinuation

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