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WO2008067573A2 - Système d'administration de médicament - Google Patents

Système d'administration de médicament Download PDF

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Publication number
WO2008067573A2
WO2008067573A2 PCT/ZA2007/000083 ZA2007000083W WO2008067573A2 WO 2008067573 A2 WO2008067573 A2 WO 2008067573A2 ZA 2007000083 W ZA2007000083 W ZA 2007000083W WO 2008067573 A2 WO2008067573 A2 WO 2008067573A2
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Prior art keywords
chitosan
drug
polycarbophil
solution
cross
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Ceased
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PCT/ZA2007/000083
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WO2008067573A3 (fr
Inventor
Josias Hendrik Hamman
Zhilei Lu
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Tshwane University of Technology
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Tshwane University of Technology
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Publication of WO2008067573A2 publication Critical patent/WO2008067573A2/fr
Publication of WO2008067573A3 publication Critical patent/WO2008067573A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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 invention relates to a drug delivery system.
  • the inventor is aware that drug delivery systems are critical to effective treatment of many diseases.
  • a drug delivery system including an interpolyelectrolyte complex of chitosan and polycarbophil.
  • the complex may be used as an excipient in swellable matrix drug delivery systems.
  • the polymeric complex may exhibit swelling properties when formulated into a compressed matrix system.
  • the polymeric complex may exhibit controlled drug release.
  • the controlled drug release may be zero order release.
  • the invention extends to a drug dosage form including a polymeric complex of the invention.
  • the drug dosage form may be a solid dosage form.
  • the solid dosage form may be a tablet, a capsule, a caplet, or the like, whether coated or uncoated.
  • the invention extends to a sustained release drug delivery system including a polymer complex of the invention.
  • Matrix tablets consisting of the IPEC between chitosan and polycarbophil, without the drug or excipients exhibited extremely high swelling properties that are completely reversible upon drying.
  • the drug release from the matrix systems depended on the concentration of the chitosan-polycarbophil IPEC in the formulation and some formulations approached zero order release kinetics for all the model drugs tested in this study.
  • the chitosan-polycarbophil IPEC has therefore demonstrated a high potential as an excipient for the production of swellable matrix systems with controlled drug release properties.
  • the drug release rate and mechanism can be controlled by varying the composition of the excipients (i.e. Avicel and Explotab) as well as that of the chitosan-polycarbophil IPEC in the matrix tablet.
  • the concentration of Avicel and Explotab By increasing the concentration of Avicel and Explotab, the matrix system changes from a swellable system to one that shows surface erosion, which may disintegrate totally in a relatively short period of time.
  • IPECs Interpolyelectrolyte complexes between chitosan or TMC and polyanionic polymers including Eudragit® L100-55, Eudragit® L100, Eudragit® S100, tripolyphosphate (TPP), polycarbophil, polyvinyl acetate phthalate (PVAP) and poly(lactide-co-glycolic acid) (PLGA) were prepared.
  • IPECs were characterised by using differential scanning calorimetry (DSC), infrared spectrometry (IR) and their effects on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers.
  • the IPEC between chitosan and polycarbophil showed excellent properties as an excipient for use in swellable controlled release matrix systems.
  • this IPEC was compressed into a tablet matrix system, it exhibited superior swelling properties in both pH 5.8 and pH 7.4 buffer solutions.
  • matrix systems containing this IPEC were capable of releasing drugs with different physicochemical properties in a sustained manner. It was demonstrated that the concentration of the chitosan-polycarbophil IPEC in the matrix tablet formulation plays an important role in the ability of the drug delivery system to control the release of the model drug.
  • Insulin release from matrix tablet formulations was also influenced by the quantity and combination of excipients (i.e. chitosan, polycarbophil, Avicel® and Explotab®) in relation to the quantity of chitosan-polycarbophil IPEC.
  • excipients i.e. chitosan, polycarbophil, Avicel® and Explotab®
  • the results obtained with the dissolution studies and swelling experiments showed that the matrix tablets that released insulin only by means of swelling showed a relatively low rate of drug release, while it was possible to improve this by addition of excipients.
  • Some formulations showed insulin release in a concentration independent way, i.e. approaching zero-order release over an extended period of time.
  • An absorption enhancer such as TMC was successfully loaded and released from these matrix systems.
  • IPEC IPEC between chitosan and polycarbophil that was produced and characterized in this study showed excellence properties to manufacture monolithic matrix tablet systems such as good compressibility, swelling and gel forming characteristics.
  • the use of this IPEC in matrix systems has been shown to offer zero-order drug release properties for model drugs with different physicochemical properties such as good water-solubility, poor water-solubility and macromolecular compounds.
  • the method used to produce the drug loaded complexes, i.e. the addition of the cross-linking polymer and drug in a solid powder form provided certain advantages such as very high drug loading efficiencies.
  • TMC N - trimethyl chitosan chloride
  • polyanionic substances such as Eudragit ® L100-55, Eudragit ® L100, Eudragit ® S100, tripolyphosphate (TPP), polycarbophil, polyvinyl acetate phthalate (PVAP) and ⁇ oly(lactide-co-giycolic acid) (PLGA).
  • DSC differential scanning calorimetric
  • FIG. 4-1 Schematic illustration of the chemical reaction between chitosan and methyl iodide (i.e. reductive methylation of chitosan) and ion exchange with sodium chloride to produce ⁇ /-trimethyl chitosan chloride (TMC).
  • methyl iodide i.e. reductive methylation of chitosan
  • TMC ⁇ /-trimethyl chitosan chloride
  • the product that formed during the chemical reaction was precipitated with ethanol and isolated by c ⁇ ntrifugation. After washing with ethanol and diethyl ether, the product was dissolved in 40 ml of a 10% w/v aqueous sodium chloride solution to exchange the iodide ion with a chloride-ion. The resultant polymer was precipitated with ethanol and isolated by centrifugation. Lastly, the product was dissolved in 60 ml water and then precipitated with ethanol to remove the remaining sodium chloride from the material.
  • Second reaction step The product that was obtained from step one was dissolved in 160 ml ⁇ /-methylpyrrolidone, 9.6 g of sodium iodide and 22 ml of a 15% w/v aqueous sodium hydroxide solution was added to the solution under magnetic stirring for 10 min. Lastly, 23 ml of methyl iodide was added to react for a period of 45 min at 60 0 C.
  • the product was precipitated with ethanol and isolated by centrifugation.
  • the iodide ion was exchange with a chloride-ion and access sodium chloride was then removed as described for reaction step one.
  • step two The product that was obtained from step two was dissolved in 160 ml W-methylpyrrolidone, 9.6 g of sodium iodide and 22 ml of a 15% w/v aqueous sodium hydroxide solution was added to the solution under magnetic stirring for 10 min. At lastly, 23 ml of methyl iodide was added to react for a period of 45 min at 6O 0 C.
  • the product was precipitated with ethanol and isolated by centrifugation.
  • the iodide ion was exchange with a chloride-ion and access sodium chloride was then removed as described for reaction step one.
  • NMR is a form of absorption spectrometry and is based on the theory that under appropriate conditions in a magnetic field, a sample can absorb electromagnetic radiation in the radio frequency region at frequencies governed by the characteristics of the sample. This absorption is in fact a function of certain nuclei in the molecule.
  • a plot of the frequencies of the absorption peaks versus peak intensities constitutes an NMR spectrum (Silverstein et a/., 1991:165). The absorption peaks on the spectrum can be used to determine molecular structures and to quantify certain chemical groups within molecules.
  • the degree of quaternisation of the synthesised TMC polymer was determined from a 1 H-NMR spectrum obtained with a 500 MHz BRUKER DAX500 spectrometer (Karlsruhe, 76189 Germany) in D 2 O at 80 0 C with suppression of the water peak.
  • the degree of quaternisation of the synthesised TMC polymer was calculated from the data obtained from the NMR spectrum according to the following equation:
  • % DQ degree of quaternisation as a percentage
  • DSC is a technique in which the difference in energy output of a substance and a reference material is measured as a function of temperature, while the substance and reference materials are subjected to a controlled temperature program (Botha, 1985:56).
  • DSC thermograms of chitosan and the synthesised TMC were recorded with a Shimadzu DSC50 (Kyoto, Japan) instrument by sealing 2 mg samples in aluminium crimp cells and heating it at a rate of 10 °C/min under the flow of nitrogen at rate of 20 ml/min.
  • IPEC INTERPOLY-ELECTROLYTE COMPLEXES
  • IPECs with chitosan and TMC, respectively, which include Eudragit ® L100-55, Eudragit ® L100, Eudragit ® S 100 (R ⁇ hm GmbH & Co., Darmstadt, Germany), tripolyphosphate (TPP, Sigma-Aldrich, USA), polycarbophil (Noveon, USA), polyvinyl acetate phthalate (PVAP, Colorcon Limited, England) and poly(lactide-co-glycolic acid) (PLGA 1 Sigma-Aldrich, inc., USA).
  • a quantity of 1.0 g of chitosan was added to 33.3 ml of a 2% v/v acetic acid solution and stirred with an overhead stirrer at 800 rpm for 10 min to dissolve the chitosan.
  • a solution of 1.5 g of Eudragit ® L100-55, Eudragit ® L100 and Eudragit ® S 100, respectively, in 70.0 ml ethanol were prepared and the chitosan solution was added slowly to each Eudragit ® solution using a syringe under homogenisation for 20 min and the mixture was then mechanically stirred for an additional 1 h at 800 rpm.
  • the resultant cross-linked hydrogel was separated by centrifugation for 5 min at 3000 rpm and washed twice (i.e. once with ethanol and once with a 2% v/v acetic acid solution) to remove any un-reacted material.
  • IPEC IPEC was finally freeze-dried at -49 0 C for 48 h (Jouan LP3, France) followed by screening the powder through a 25 ⁇ m sieve.
  • a solution of 1.5 g Eudragit ® L100-55 in 40.0 ml 1.0 M NaOH was prepared under magnetic stirring. This Eudragit ® L100-55 solution was adjusted to a pH value of 8.0 by addition of small volumes of acetic acid.
  • a solution of 1.0 g TMC in 20.0 ml distilled water that was pre-adjusted to a pH of 8.0 usi ⁇ giM NaOH solution was prepared under magnetic stirring.
  • the TMC solution was added slowly to the Eudragit ® L100-55 solution under magnetic stirring over a period of 1 h.
  • the resultant cross-linked hydrogel was separated by centrifugation for 5 min at 3000 rpm and was then washed twice with a 0.1 M NaOH solution.
  • IPECs between TMC and Eudragit ® L100 and Eudragit ® S100, respectively.
  • IPEC IPEC was finally freeze-dried at -49 0 C for 48 hours (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a quantity of 1.0 g chitosan was dissolved in a 2% v/v acetic acid solution (33.3 ml) under mechanical stirring at 800 rpm for 10 min.
  • a quantity of 1.5 g TPP was dissolved in 70 ml distilled water.
  • the chitosan solution was slowly added to the TPP solution using a syringe under homogenisation for 20 min and the mixture was then mechanically stirred for an additional 1 hour at 800 rpm to allow for complete cross-linking to take place between the chitosan chains.
  • the resultant cross-linked hydrogel was separated by centrifugation for 5 min at 3000 rpm and was then washed twice with distilled water to remove any un-reacted materials.
  • the hydrogel was freeze-dried at -49 0 C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • TMC Trigger-dried styrene resin
  • 50.0 ml distilled water 50.0 ml distilled water
  • 50.0 ml ethanol 50.0 ml ethanol
  • a 1.5 g TPP solution in 70 ml distilled water was prepared.
  • the TMC solution was added slowly to the TPP solution using a syringe under homogenisation for 20 min and then under mechanical stirring for 1 h at 800 rpm to allow cross-linking between the TMC chains.
  • the cross-linked hydrogel was separated by centrifugation for 5 min at 3000 rpm and then gels were washed twice by using distilled water.
  • the hydrog ⁇ l was freez ⁇ -dried at -49 0 C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a quantity of 1.0 g chitosan was dissolved in 33.3 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 10 min.
  • a quantity of 1.5 g polycarbophil was dissolved in 70 ml of a 2% v/v acetic acid solution.
  • the chitosan solution was added to the polycarbophil solution using a syringe under homogenisation for 20 min and was then mechanically stirred for 1 h at 800 rpm to allow cross-linking between the oppositely charged polymer chains.
  • the cross-linked hydrogel was separated by centrifugation for 5 min at 3000 rpm and washed 10 times with a 2% v/v acetic acid solution to remove any un-reacted materials.
  • the hydrogel was freeze-dried at -49°C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a quantity of 1.0 g TMC was dissolved in 30.0 ml distilled water under mechanical stirring at 800 rpm for 10 min.
  • a polycarbophil solution was prepared by dissolving 1.5 g polycarbophil in 70 ml of a 2% v/v acetic acid solution.
  • the TMC solution was added to the polycarbophil solution with a syringe under homogenisation stirring for 20 min and the mixture was then mechanically stirred for 1 h at 800 rpm to allow cross-linking between the oppositely charged polymer chains.
  • a quantity of 1.0 g chitosan was dissolved in 33.3 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 10 min.
  • a PVAP solution was prepared by dissolving 1.5 g PVAP in 70.0 ml of a 1:1 mixture of ethanol and acetone.
  • the chitosan solution was added to the PVAP solution with a syringe under homogenisation at 5000 rpm for 20 min and the mixture was then mechanically stirred for 1 h at 800 rpm.
  • the cross-linked gel was centrifuged for 5 min at 3000 rpm and then washed twice with ethanol to remove any un-reacted material.
  • the hydrogel was finally freeze-dried at -49 0 C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a quantity of 1.0 g TMC was dissolved in 15 ml distilled water under magnetic stirring for 20 min.
  • a PVAP solution was prepared by dissolving 2.0 g PVAP in 50 ml of a 1 :1 mixture of ethanol and acetone. The TMC solution was added slowly to the PVAP solution with a syringe under magnetic stirring for 20 min and the mixture was then mechanically stirred for 1 h at 800 rpm.
  • the product was finally freeze-dried at -49°C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a PLGA solution was prepared by dissolving 0.5 g PLGA in 10 ml glacial acetic acid under magnetic stirring. A quantity of 0.5 g chitosan was dissolved in 20 mi of a 2 % v/v acetic acid solution under magnetic stirring. The chitosan solution was added to the PLGA solution under magnetic stirring for 1 h to allow cross-linking between the polymer chains.
  • a PLGA solution was prepared by dissolving 0.5 g PLGA in 10 ml glacial acetic acid under magnetic stirring. A quantity of 0.5 g TMC was dissolved in 10 ml distilled water under magnetic stirring. The TMC solution was added to the PLGA solution under magnetic stirring for 1 h to allow cross-linking between the polymer chains.
  • the product was finally freeze-dried at -49 0 C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 ⁇ m sieve.
  • a 3% w/v dispersion of polycarbophil (Noveon, USA) was prepared in 500 ml of a 2% v/v acetic acid solution and was added drop-wise (over a period of 10 min) to the chitosan and diltiazem mixture under mechanical stirring at 1000 rpm for 1 h to allow for cross-linking between the two polymer's chains.
  • microparticles that formed during the cross-linking process were separated by centrifugation for 5 min at 2000 rpm, washed one time with 200 ml distilled water to remove any un-reacted materials and were then freeze-dried (Joua ⁇ LP3 France) for 48 h.
  • a 3% w/v solution of chitosan (Warren Chem Specialities, South Africa, Deacetylation Degree: 91.25%) was prepared in 500 ml of a 2% v/v acetic acid and 15 g diltiazem (3% w/v) (Fabbrica Italia ⁇ a Sintetici, Italy) was added to this solution and stirred with an overhead mechanical stirrer at 1000 rpm for 15 minutes to dissolve the diltiazem in the chitosan solution.
  • a 10% w/v aqueous solution of TPP (Sigma-Aldrich, inc., USA, 500 ml) was added drop-wise (over a period of 10 min) to the chitosan and diltiazem mixture under mechanical stirring at 1000 rpm for 1 h to allow for cross-linking between the chitosan chains.
  • the chitosan microparticles that formed during the cross-linking process were separated by centrifugation for 5 min at 2000 rpm, washed once with 200 ml distilled water to remove any un-reacted material and were then freeze-dried (Jouan LP3 France) for 48 h.
  • aqueous suspension of chitosan was prepared by dispersing 4.5 g finely divided chitosan in 150 ml distilled water. A quantity of 9 g of diltiazem was added to the chitosan suspension under magnetic stirring to dissolve the drug. Microparticles were formed by dropping the chitosan and diltiazem mixture with a syringe into a polycarbophil solution (10% w/v in 90 ml glacial acetic acid) at an average rate of 90 drops/min under magnetic stirring for 30 min.
  • the particles were recovered by vacuum filtration and were dried in a conventional hot air oven at 4O 0 C for 24 h.
  • aqueous suspension of chitosan was prepared by dispersing 4.5 g finely divided chitosan in 150 ml distilled water. A quantity of 9 g of diltiazem was added to the chitosan suspension under magnetic stirring to dissolve the drug. Microparticles were formed by dropping the chitosan and diltiazem mixture with a syringe into 90 ml of a 10% w/v TPP aqueous solution at an average rate of 90 drops/min under magnetic stirring for 30 min.
  • microparticles that were prepared by cross-linking suspended chitosan by means of different cross-linking agents were selected to be formulated into compressed mini-matrix type dosage forms.
  • the microparticles that were produced by the conventional cross-linking method i.e. chitosan in solution
  • the formulations of the different tablets that were composed of the cross-linked microparticles and other excipients are shown in Table 4-2 (i.e. formulations S-1, S-2 and S-3).
  • Table 4-2 The formulations of tablets made of cross-linked chitosan microparticles
  • MDT ad is amendable Mean dissolution time
  • t- ⁇ oo % is the time at 100% drug released
  • Wmicro p articies weight of the microparticels obtained after freeze-drying
  • W ⁇ ro d ei d rug weight of model drug that was included
  • Wc h itosan weight of chitosan
  • WTPP weight of TPP for cross-linking
  • W po iycar b op h ii weight of polycarbophil for cross-linking.
  • the drug content of the microparticles was determined by weighing approximately 50 mg samples of the microparticles accurately (in triplicate) and transfer them into 100 ml volumetric flasks, which were made up to volume with distilled water. These mixtures were stirred with a magnetic stirrer for 24 h to allow total breakdown of the microparticles or total release of the drug. After filtration through a 0.45 ⁇ m filter membrane, the solutions were diluted 10 times with distilled water and assayed using a UV spectrophotometer at a wavelength of 265 nm. The percentage drug content of the particles was then calculated by using equation [4.4].
  • Table 4-5 Tablet formulations for chitosan microparticles with size ⁇ 150 ⁇ m
  • Table 4-6 Tablet formulations for chitosan microparticles with size ⁇ 300 ⁇ m
  • Explotab 5 Mixing procedure The different drug loaded chitosan microparticles (i.e. cross-linked with TPP or polycarbophil) and different ⁇ xcipients as indicated in Table 4-6 were premixed by manual stirring in a 1000 ml glass beaker for 30 minutes. After the addition of 0.05 g magnesium stearate (0.5% w/w), the powder mass was mixed thoroughly by an overhead mechanical stirrer for a further 10 minutes at 200 rpm.
  • Table 4-6 The different drug loaded chitosan microparticles (i.e. cross-linked with TPP or polycarbophil) and different ⁇ xcipients as indicated in Table 4-6 were premixed by manual stirring in a 1000 ml glass beaker for 30 minutes. After the addition of 0.05 g magnesium stearate (0.5% w/w), the powder mass was mixed thoroughly by an overhead mechanical stirrer for a further 10 minutes at 200 rpm.
  • Compression procedure The tablets were compressed using a multi-station tablet compression machine (Cadmach ® CM 03-16 India) fitted with a round, flat punches, which are 6 mm in diameter.
  • Drug loaded chitosan microparticles prepared by spray-drying or freeze-drying were mixed with cross-linked polymer material before compressed into monolithic matrix systems. These drug delivery systems were characterised in terms of their swelling characteristics as well as drug release behaviour.
  • a polycarbophil solution was obtained by dissolving 30 g polycarbophil (Noveon, USA) in 3000 ml of a 2% v/v acetic acid solution under mechanical stirring at 1000 rpm for 20 min.
  • the chitosan solution was added to the polycarbophil solution under homogenisation at 5000 rpm for 60 min to obtain cross-linked polymer hydrogel particles.
  • cross-linked hydrogel particles were separated by centrifugation for 5 min at 3000 rpm and freeze-dried (Jouan LP3 France) for 48 h.
  • the product was screened through a 300 ⁇ m sieve to obtain microparticles with a more homogenous size distribution.
  • the swelling profiles of the different tablets were illustrated by plotting the percentage swelling as a function of time.
  • the weight of the tablets after exposure to the phosphate buffer for a period of 48 h minus the weight of the dry tablets (i.e. W 4 ⁇ h - W d ) were used as reference point for 100% swelling.
  • the percentage swelling of each tablet was calculated according to equation [4.13].
  • MST is a statistical moment for the swelling process and provides an accurate tablets swelling rate. It is calculated by the equation [4 14].
  • a quantity of 15 g chitosan was dissolved in 500 ml of a 2% v/v acetic acid solution and 15 g diltiazem were added under mechanical stirring at 800 rpm for 15 minutes.
  • the chitosan and diltiazem mixture was frozen and then freeze-dried (Jouan LP3 France) for 48 h.
  • the product was screened through a 422 ⁇ m sieve to obtain microparticles with a more homogenous size distribution.
  • lbuprofen was used as a poorly water-soluble model drug as opposed to diltiazem that was included as a water-soluble model drug.
  • a quantity of 15 g chitosan was dissolved in 500 ml of a 2% v/v acetic acid solution and 15 g ibuprofen were added under mechanical stirring at 800 rpm for 15 minutes to form a uniform suspension.
  • the chitosan and ibuprofen mixture was frozen and then freeze-dried (Jouan LP3 France) for 48 h.
  • the product was screened through a 422 ⁇ m sieve to obtain microparticles with a more homogenous size distribution.
  • microparticles were weighed accurately (in triplicate), which were transferred into 100 ml volumetric flasks and made up to volume with 0.1 M NaOH. These mixtures were stirred for 24 h to allow total release of the drug. After filtration through a 0.45 ⁇ m filter membrane, the solutions were assayed using a UV spectrophotometer at the wavelength of maximum absorbance (264 nm). The percentage drug content of the microparticles was then calculated by the following equation
  • ABS 88111PI e absorbance of the sample at 264 nm
  • Wsampi ⁇ weight of the particle sam pie
  • K slope of standard curve (1.6448)
  • a y-intercept (0.0145).
  • Monolithic matrix tablets were made by direct compression of a mixture of ingredients as indicated in Table 4-8.
  • the drug-loaded chitosan microparticles were uniformly distributed throughout a matrix formed by cross-linked polymeric filler material as well as other excipients.
  • IPEC polymeric filler material 6.1.1 IPEC between chitosan and Eudragit ® S100 A quantity of 15.0 g chitosan was dissolved in 500 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 10 min. A solution of Eudragit ® S100 was prepared by dissolving 22.5 g Eudragit ® S100 in 1000 ml ethanol. The chitosan solution was added to the Eudragit ® solution using a syringe under homogenisation for 20 min and the mixture was then mechanically stirred for 1 h at 800 rpm to allow complete cross-linking to occur between the two polyelectrolytes.
  • the formed gel was separated by centrifugatio ⁇ for 5 min at 3000 rpm and was then washed 5 times by using ethanol and 2% v/v acetic acid solution.
  • the IPEC was finally freeze-dried at -49 0 C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 ⁇ m sieve.
  • a quantity of 30 g chitosan was dissolved in 1000 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 10 min.
  • a polycarbophil solution was obtained by dissolving 30 g polycarbophil in 3000 ml of a 2% v/v acetic acid solution.
  • the chitosan solution was added to the polycarbophil solution by using a syringe under homogenisation for 20 min and it was then mechanically stirred for 5 h at 1200 rpm to allow complete cross-linking to occur between the two polyelectrolytes.
  • the formed gel was separated by centrifugation for 5 min at 3000 rpm and then was then washed 20 times by using a 2% v/v acetic acid solution to remove any u ⁇ reacted material.
  • the IPEC was finally freeze-dried at -49 0 C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 ⁇ m sieve.
  • Table 4-12 Formulation of monolithic matrix type tablets containing an IPEC between chitosan and polycarbophil and ibuprofen as the model drug.
  • Table 4-11 Formulations of monolithic matrix type tablets containing an IPEC between chitosan and polycarboph.il and diltiaz ⁇ m as the model drug.
  • a quantity of 30 g chitosan was dissolved in 1000 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 10 min.
  • a polycarbophil solution was obtained by dissolving 30 g polycarbophil In 3000 ml of a 2% v/v acetic acid solution.
  • the chitosan solution was added to the polycarbophil solution by using a syringe under homogenisation for 20 min and it was then mechanically stirred for 5 h at 1200 rpm to allow complete cross-linking to occur between the two polyelectrolytes.
  • the formed gel was separated by centrifugation for 5 min at 3000 rpm and then was then washed 20 times by using a 2% v/v acetic acid solution to remove any unreacted material.
  • the IPEC was finally freeze-dried at -49 0 C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 ⁇ m sieve.
  • TMC 1 A mixture of insulin and the absorption enhancer, TMC 1 was prepared as follows: a quantity of 0.8 g of insulin was dissolved in 100 ml of a 0.1 M HCI solution under magnetic stirring. A quantity of 4 g of TMC was added to the insulin solution and stirred until dissolved. The mixture was freeze-dried (Jouan LP3, France) at -49 0 C for 48 h and the resultant powder was screened through a 297 ⁇ m sieve to produce a more homogenous particle size distribution. 7.2 Preparation of monolithic matrix tablets
  • Monolithic matrix tablets were made by compressing a mixture of ingredients as indicated in Table 4-14.
  • Compression procedure The tablets were compressed using a multi-station tablet compression machine (Cadmach ® CM 03-16 India) fitted with a round, flat punches, which are 6 mm in diameter.

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Abstract

L'invention concerne un complexe polymérique comprenant un complexe interpolyélectrolytique de chitosane et de polycarbophile. L'invention se rapporte en outre à une forme posologique médicamenteuse comprenant ledit complexe.
PCT/ZA2007/000083 2006-12-01 2007-11-30 Système d'administration de médicament Ceased WO2008067573A2 (fr)

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ZA200610076 2006-12-01
ZA2006/10076 2006-12-01

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WO2008067573A2 true WO2008067573A2 (fr) 2008-06-05
WO2008067573A3 WO2008067573A3 (fr) 2009-03-12

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JP2014518289A (ja) * 2011-06-13 2014-07-28 ライバル，ソシエテ エン コマンダイト Ｎ，ｎ，ｎ−トリアルキルポリマー、その調製方法およびその使用
JP2017222869A (ja) * 2011-06-13 2017-12-21 ライバル，ソシエテ エン コマンダイト Ｎ，ｎ，ｎ−トリアルキルポリマー、その調製方法およびその使用

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