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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

• the present invention relates to a composition for the controlled release of one or more active compounds, especially biologically active compounds, from a degradable matrix material.
• a composition for the controlled release of one or more active compounds, especially biologically active compounds, from a degradable matrix material.
• Such a composition is known from WO 94/01092.
• This known composition contains the active substance, which may be a protein or other high molecular weight compound, in a matrix consisting of a helical, crystalline straight-chain ⁇ -glucan such as amylodextrin or crystalline amylose.
• a similar composition is known from WO
• the matrix further contains a glucan-degrading enzyme such as an ⁇ -amylase.
• a composition for the delayed release of an active substance can be produced by using a thermoplastic and/or crystalline fructan as a matrix material for said composition, together with one or more active substances.
• the composition of the invention and the process of producing it are defined in the appending claims.
• the fructan to be used is inulin (poly- ⁇ -2,1 -fructose terminated at the reducing end with 1-glucosyl).
• the inulin can have a varying chain length, from 3 up to as high as 3,000. Preferred chain length are from 3 to 70, particularly from 5 to 60, especially from about 7 to about 35.
• the inulin may be native inulin, or it may be physically and/or chemically modified.
• Such modifications include fractions having a lower or higher average chain length, hydrolysates, enzymatically shortened or lengthened treated inulins, partially oxidised inulins and the like.
• Inulins have the advantage of having a varying degree of crystallinity, depending on the processing of the inulin and on the water content.
• the degree of crystallinity can control the release pattern of the matrix material in an aqueous medium, as a higher crystallinity results in slower dissolution and hence in slower release.
• the crystallinity can be assayed by means of X-ray analysis.
• the inulin is partly crystalline, i.e. it has a structure between that of ⁇ -inulin (anhydrous, amorphous) and of ⁇ -inulin (hemihydrate or monohydrate, crystalline).
• the inulin contains 0.1-1.2 mol, in particular 0.3-1 mol, of crystal water per mol of anhydrofructose.
• the crystallinity and thus the release rate of encapsulated materials can also be influenced by using an inulin of varying polydispersity or by admixing other biopolymers, such as starch or hydrolysates or derivatives thereof, cellulose derivatives or protein hydrolysates in amounts of e.g. 0-40 wt.%, especially 1-25 wt.% with respect to the inulin weight. Another factor that can be used to influence the release rate is the chain length of the inulin.
• Active substances to be incorporated in the controlled-release composition include any substance which is introduced into an environment for performing a desired function.
• biologically active substances such as drugs, antigens, diagnostic agents, biocides, repellents an attractants (pheromones), flavours, fragrances, fertilisers, and other active substances such as colorants.
• the active substances can be relative simple inorganic (metals, metal compounds) or organic molecules, but also macromolecules, including carbohydrates, proteins (enzymes, antibodies, toxins), nucleotides, and biological systems including cells and microorganisms (bacteria, viruses).
• Plasticisers may be used to enhance the thermoplastic nature of the biopolymer.
• Plasticisers to be used include water, glycols and other polyols, partial esters thereof, citric acid and urea. Especially preferred is glycerol.
• Plasticisers other than water may be used at a level of 0-50 wt.% with respect to the biopolymer, especially 1-30 wt.%.
• compositions may further contain an emulsifier and/or a flow regulator, such as lipids, phospholipids, such as lecithin, glycerol monoesters, higher alkyl ammonium salts, and the like.
• lipids such as lipids, phospholipids, such as lecithin, glycerol monoesters, higher alkyl ammonium salts, and the like.
• phospholipids such as lecithin, glycerol monoesters, higher alkyl ammonium salts, and the like.
• These agents are commercially available, under the brand names Tween, Span, etc.
• These emulsifiers may be present at a level of from 0, especially from 0.1 to 15 wt.% with respect to the inulin.
• the process for producing the controlled-release compositions comprises mixing the inulin matrix material with the optional plasticiser and emulsifier and the active substance, and subjecting the mixture to a thermomechanical treatment.
• the thermo- mechanical treatment may comprise extrusion, rolling, kneading, injection-moulding, pelleting and similar treatments.
• This thermoplastic processing can be carried out at temperatures of 30-120°C, preferably using a plasticiser and/or a flow regulator.
• the active substance may be added after the thermomechanical treatment.
• the composition of the invention can be used to release the active substance(s) in a controlled manner.
• the release can be triggered by the presence of water, acid and/or heat.
• the release rate can be adjusted by adjusting the composition and the conditions of the thermomechanical treatment.
• the release rate can be adjusted by means of the average chain length (degree of polymerisation, DP) of the inulin. Inulins having a relatively low DP of, say, 3-10, will result in compositions with short release rate, whereas compositions with inulins having a relatively high DP, e.g. 15-60, as a matrix material will have slower rates.
• the release can further be controlled by means of the crystallinity (see above), the particle size, and the plasticiser content.
• the affinity of the encapsulated material with the matrix determines the release, and the rate can thus be adapted by slightly modifying the matrix material, e.g. by increasing hydrophobicity (acylation, alkylation).
• the composition can be used in medicine, i.e. as a medicament to be introduced into the gastro-intestinal tract of a mammal. It can also be used in horticulture and agriculture, where the composition can be applied to the soil or onto plants or be atomised in the air.
• Inulin used in the examples was commercially available Frutafit® from Suikerunie (NL). Glycerol was supplied by Chemproha BV (NL) and lecithin was supplied by Lucas
• Example 1 Eighty g of inulin (moisture content 5% w/w), 0-4.6 g of emulsifier (lecithin: L; tween
• Example 2 Inulin (moisture content 5% w/w) and 10 % (w/w to dry inulin) of Capsul-E emulsifier
• (C) were mixed with a Bear Narimixer for 10 minutes.
• the premix was fed into the extruder using a K-Tron K2M T85 volumetric feeder.
• the extruder had 7 zones with the following temperature profile (°C): 50-80-120-120-100-80-80.
• Glycerol (G) was pumped into the first zone.
• Orange (O) or apple (A) flavour was introduced into the fifth zone (at 20.8*D) using a pressure-independent volumetric pump.
• the inulin/emulsifier throughput was 7.1 kg/h.
• the flavour throughput was 0.3 and 0.6 kg/h and the glycerol throughput was 0.6 and 1.1 kg/h.
• the results are summarised in table 2.
• the flow rates (throughputs) are given in g min. Table 2
• inulin moisture content 5%
• G glycerol
• PN native potato starch
• the crystallinities of the samples were determined by X-ray diffraction.
• the samples were ground cryogenically and sieved to obtain a fine powder.
• the powdered samples were placed in sample holders and a smooth surface was created.
• the sample holders were placed in a Philips PC-APD PW 3710 mpd X-ray diffractometer supplied with a
• Fig. 1 depicts the crystallinity of inulin samples processed at 120°C with 20% glycerol
• FIG. 2 depicts the crystallinity of inulin samples processed at different temperatures (90-120-135-150°C) with 20% glycerol (w/w to dry inulin).

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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• 1998
  • 1998-12-18 EP EP98962692A patent/EP1039881A1/de not_active Withdrawn
  • 1998-12-18 AU AU17867/99A patent/AU1786799A/en not_active Abandoned
  • 1998-12-18 WO PCT/NL1998/000720 patent/WO1999030691A2/en not_active Application Discontinuation

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