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WO2008067573A2 - Drug delivery system - Google Patents

Drug delivery system 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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WO
WIPO (PCT)
Prior art keywords
chitosan
drug
polycarbophil
solution
cross
Prior art date
Application number
PCT/ZA2007/000083
Other languages
French (fr)
Other versions
WO2008067573A3 (en
Inventor
Josias Hendrik Hamman
Zhilei Lu
Original Assignee
Tshwane University Of Technology
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Publication of WO2008067573A2 publication Critical patent/WO2008067573A2/en
Publication of WO2008067573A3 publication Critical patent/WO2008067573A3/en

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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

The invention provides a polymeric complex including an interpolyelectrolyte complex of chitosan and polycarbophil. Then invention further provides a drug dosage form including said complex.

Description

Drug Delivery System
Field of the Invention
The invention relates to a drug delivery system.
Background to the Invention
The inventor is aware that drug delivery systems are critical to effective treatment of many diseases.
Advances in polymer science have contributed towards the development of a new generation of drug delivery systems that are capable of providing drug delivery according to the therapeutic needs of the patient.
There is an ongoing need to improve the properties of existing polymers or to discover new polymers that can be used in matrix type controlled release dosage forms. Summary of the Invention
According to the invention, there is provided 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.
Complexation of the two polymers to form a new compound was confirmed with differential scanning calorimetry as well as infared spectroscopy.
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.
Description of the Invention
A prerequisite for progress in the design of novel drug delivery systems is the development of excipients that are capable of fulfilling multifunctional roles such as controlling the release of the drug according to the therapeutic needs of the body.
Although several polymers have been utilised in the development of specialised drug delivery systems, their scope in dosage form design can possibly be enlarged through the use of combinations (Hamman and Tarirai, 2006). When a polymer is cross-linked or complexed with an oppositely charged polyelectrolyte (e.g. chitosan cross-linked with polycarbophil), a three-dimensional polymeric network is formed in which the drug can be incorporated into a dosage form to control its release. The swelling properties and release kinetics of monolithic matrix tablets consisting of an interpolyelectrolyte complex (IPEC) between chitosan and polycarbophil loaded with different model drugs (i.e. highly water-soluble diltiazem and poorly water-soluble ibuprofen) and a macromolecular model drug (i.e. insulin) were investigated in this study.
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 results further indicated that 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. 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.
Interpolyelectrolyte complexes (IPECs) 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. These 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 effect of the different IPECs on the TEER of Caco-2 cells and the IR analysis of the IPEC between chitosan and polycarbophil shows that ionic bonding is probably the primary binding force for complex formation between the oppositely charged polymers.
The results obtained from the DSC analysis confirmed the formation of IPECs between chitosan as well as TMC and Eudragit® L100-55, Eudragit® L100, Eudragit® S100, TPP, polycarbophil and PVAP as distinct chemical entities, but could not clearly indicate the formation of a complex with PLGA.
Furthermore, a slight decrease in TEER values of the Caco-2 cell monolayers when IPECs between TMC and Eudragit® L100-55, Eudragit® L100, Eudragit® S100 were applied to the apical surface of the cells indicated that the intensity and number of the bonds between TMC and the Eudragit® polymers are generally lower than the bonds between chitosan and the Eudragit® polymers. This can possibly be explained by the steric effects of the methyl groups present in the TMC molecule that may shield the charge on the amino acid, which may hinder strong bond formation. Decrease of the TEER value with the application of the IPEC between chitosan and PVAP also possibly indicate that the bonds between chitosan and PVAP are weaker at pH 5.8 (TEER value only 67.17 % of the initial value), but the bonds in this IPEC are more stable at pH 7.4 (TEER value 96.65 % of the initial value). Relatively high decreases of the TEER values were observed for the IPEC between TMC and TPP at both pH 5.8 and 7.4 (TEER values were 58.84 % and 43.67 % of the initial values, respectively). This indicates most probably that the bonds between TMC and TPP are very weak and some quaternised amino groups on the TMC molecules are available for interactions with the cell surface and are therefore not involved in interactions with the TPP molecules. Very high decreases in the TEER values of Caco-2 cell monolayers when administered with the IPEC between TMC and PLGA at both pH values (TEER values were 76.75 % and 56.35 % of the initial values, respectively) probably indicate poor bond formation between these two polymers. A similar effect was observed for the IPEC between chitosan and PLGA at pH 5.8 (TEER value was 61.18 % of initial value).
Furthermore, the IPEC between chitosan and polycarbophil showed excellent properties as an excipient for use in swellable controlled release matrix systems. When 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. Furthermore, 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.
Drug release from all matrix tablet formulations containing the highly water- soluble model drug, diltiazem, presented zero-order release kinetics (n > 0.66) at pH 7.4. The results from the swelling studies, dissolution experiments and kinetic analysis of the release profiles indicated that in some of the formulations, swelling predominate while in other formulations there may be some erosion combined with swelling. The IPEC between chitosan and polycarbophil were successful in controlling the release of this highly soluble model drug, which may further be controlled by the composition of excipients in the matrix systems.
Drug release from all formulation matrix tablet formulations containing the poorly- soluble model drug, ibuprofen, presented zero-order release kinetics (n ranges between 0.8 and 1.16) at pH 7.4. Once again, in some of the formulations swelling pre-dominated while in other formulations erosion occurred with swelling.
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. 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.
The 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.
Description of Embodiments of the Invention
The entire contents, including the description, of the provisional patent application from which this application claims priority, being ZA 2006/10076, is to be considered an integral part of the disclosure in this application as if specifically reproduced here.
The description which follows is an excerpt of said ZA 2006/10076 reproduced here for the convenience of the reader.
MATERIALS AND METHODS
1 INTRODUCTION
The revolution in the development of novel oral drug delivery systems has been made possible by an increase In the knowledge of pharmacokinetics and advances in the area of drug delivery system technology. Innovative therapeutic systems, such as controlled release dosage forms, offer many advantages over traditional dosage forms in the treatment of diseases, which require constant drug blood levels over the entire duration of therapy (Aϊnaoui and Vergnaud, 2000:383).
The development of effective formulations for non-invasive peptide delivery represents one of the major challenges in modern pharmaceutical technology. It was therefore aimed in this study to design a controlled release drug delivery system for different types of drugs including the polypeptide, insulin.
To produce polymeric matrix systems, the natural polysaccharide chitosan and its derivative, N - trimethyl chitosan chloride (TMC), were each cross-linked by forming complexes with polyanionic substances such as Eudragit® L100-55, Eudragit® L100, Eudragit® S100, tripolyphosphate (TPP), polycarbophil, polyvinyl acetate phthalate (PVAP) and ρoly(lactide-co-giycolic acid) (PLGA). The formation of a complex between the materials was confirmed by differential scanning calorimetric (DSC) analysis. The effect of complexatioπ was further investigated on the transepthelial electrical resistance (TEER) of Caco-2 cell monolayers. It was hypothesised that a complex, which occupy all the amino groups of chitosan (or TMC) and thereby neutralise the positive charge on these groups as a result of electrostatic interactions between oppositely charged macromolecules, would not be able to open the tight junctions between adjacent cells. The absence of a drop in TEER would therefore be an indirect indication of how well the chitosan (or TMC) molecules cross-linked with the other polymer. 2 SYNTHESIS AND CHARACTERIZATION OF /V-TRIMETHYL CHITOSAN CHLORIDE (TMC)
2.1 Chemical synthesis of TMC
A method based on the reductive methylation of chitosan as previously described by Domared et al., (1986:105) and Sieval βt al., (1998:157) was used to synthesise TMC. The chemical reaction between chitosan and methyl iodide in the presence of sodium hydroxide is schematically presented in Figure 4-1. The chemical reaction was repeated three times (i.e. a three step reaction) under the same conditions with the product obtained from each reaction step to increase the degree of quaternisation of the resultant TMC polymer.
Figure imgf000011_0001
N -trim ethy l ch itos an iod ide
Chitosan
Figure imgf000011_0002
N -trim ethy l chitos an c h lo ride
Figure 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 Λ/-trimethyl chitosan chloride (TMC).
First reaction step: A mixture of 4 g chitosan (Warren Chem Specialities, South Africa, Deacetylation Degree = 91.25%), 160 ml N-methylpyrrolidone was stirred on a water bath at a temperature 600C over night to dissolve. A quantity of 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 while it was kept in the mixture by using a reflux condenser.
The product that formed during the chemical reaction was precipitated with ethanol and isolated by cβntrifugation. 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 Λ/-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 600C.
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.
Third reaction step: 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 6O0C.
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.
The final product was dried by means of freeze-drying (Jouan LP3, France) at -490C for a total period of 48 h and then stored in an airtight container from which samples were taken to characterise it by means of nuclear resonance spectrometry and differential scanning calorimetry. 2.2 Characterization of TMC
2.2.1 Nuclear magnetic resonance spectrometry (NMR)
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 1H-NMR spectrum obtained with a 500 MHz BRUKER DAX500 spectrometer (Karlsruhe, 76189 Germany) in D2O at 800C 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 = ([(CH3WH] x 1/9) x 100 Equation [4.1]
Where: % DQ = degree of quaternisation as a percentage,
[(CH3)3] = integral of the trimethyl amino group peak at 3.1 ppm and [H] = integral of the 1H peaks between 4.7 and 5.7 ppm
2.2.2 Differential scanning calorimetry (DSC)
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. The calorimeter was calibrated with 2 mg indium (melting point = 156.40C) at a heating rate of 10 °C/min. 3 FORMATION OF INTERPOLY-ELECTROLYTE COMPLEXES (IPEC) OF CHITOSAN AND TMC WITH DIFFERENT POLYANIONIC COMPOUNDS
Different polyanionic polymers/compounds were used to form IPECs with chitosan and TMC, respectively, which include Eudragit® L100-55, Eudragit® L100, Eudragit® S 100 (Rϋhm 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) (PLGA1 Sigma-Aldrich, inc., USA).
3.1 Preparation of interpoly-electrolytβ complexes
3.1.1 Preparation of IPECs between chitosan and Eudragit® L100-55, Eudragit® MOO1 Eudragit® S100
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.
Each IPEC was finally freeze-dried at -490C for 48 h (Jouan LP3, France) followed by screening the powder through a 25 μm sieve.
3.1.2 Preparation of IPECs between TMC and Eudragit® L100-55, Eudragit® L100, Eudragit® S100
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 usiπgiM 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.
The same method as described before was used to prepare IPECs between TMC and Eudragit® L100 and Eudragit® S100, respectively.
Each IPEC was finally freeze-dried at -490C for 48 hours (Jouan LP3 France) followed by screening the powder through a 25 μm sieve.
3.1.3 Preparation of a cross-linked chitosan hydrogel with tripolyphosphate (TPP)
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 -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve.
3.1.4 Preparation of a cross-linked TMC hydrogel with tripolyphosphate (TPP)
A quantity of 1.0 g TMC was dissolved in 50.0 ml distilled water under mechanical stirring at 800 rpm for 10 min and 50.0 ml ethanol was added to this TMC solution. 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 hydrogβl was freezβ-dried at -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve.
3.1.5 Preparation of an IPEC between chitosan and polycarbophil
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 μm sieve.
3.1.6 Preparation of an IPEC between TMC and polycarbophil
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.
The hydrogel was freeze-dried at -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve. 3.1.7 Preparation of an IPEC between chitosaπ and polyvinyl acetate phthalate (PVAP)
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 -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve.
3.1.8 Preparation of an IPEC between TMC and PVAP
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 μm sieve.
3.1.9 Preparation of an IPEC between chitosan and poly(lactide-co-glycolic acid) (PLGA)
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.
The product was finally freeze-dried at -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve. 3.1.10 Preparation of an IPEC between TMC and PLGA
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 -490C for 48 h (Jouan LP3 France) followed by screening the powder through a 25 μm sieve.
4. DESIGN OF A CONTROLLED RELEASE DOSAGE FORM FOR THE WATER SOLUBLE DRUG DILTIAZEM
It is well known that the formation of cross-links between the functional groups on hydrophilic polymer chains lead to decreased hydrophilicity, which slows down the diffusion of biological fluids into the polymer complex and consequently also decreases the diffusion of an incorporated drug from the matrix system. A problem related to the design of multiple unit cross-linked matrix systems for water soluble drugs is the low drug loading efficiency due to loss of the drug during the manufacturing process. A unique combination of polymers in an IPEC (i.e. chitosan and polycarbophil) as well as an innovative cross-linking method of suspended rather than dissolved polymer were used to overcome this problem. 4.1 Preparation of microparticles using conventional method
4.1.1 Preparation of IPEC microparticles between chitosan and polycarbophil loaded with diltiazem
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 solution and 15 g diltiazem (3% w/v, Fabbrica Italiaπa 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 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.
The 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 (Jouaπ LP3 France) for 48 h.
4.1.2 Preparation of microparticles by cross-linking chitosan with tripolyphosphate (TPP)
In order to determine the effectiveness of the chitosan-polycarbophil formulation as a controlled release dosage form for water soluble drugs, it was compared with a conventional cross-linked chitosan hydrogel formulated into microparticles.
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 Italiaπa 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.
4.2 Preparation of microparticles using polymer dispersion method
4.2.1 Preparation of microparticles by cross-linking a chitosan dispersion with polycarbophil
An 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 4O0C for 24 h.
4.2.2 Preparation of microparticles by cross-linking a chitosan dispersion with TPP
An 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.
The particles were recovered by vacuum filtration and were dried in a conventional hot air oven at 4O0C for 24 h. 4.4 Manufacturing of matrix type tablets
The 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) showed very low drug loading efficiencies and were therefore excluded from further investigation. 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
Formulation Ingredients Quantity (%)
Chitosan microparticles (cross-linked with TPP) 89.5
5 1 Avicel® 5 Magnesium stearate 0.5 Explotab® 5
Chitosan microparticles (cross-linked with polycarbophil) 89.5
5 2 Avicel® 5 Magnesium stearate 0.5 Explotab® 5
Chitosan microparticles (cross-linked with Eudragit 81SIOO) 89.5
S-3 Avicβi® 5
Magnesium stearate 0.5
Explotab® 5
Mixing procedure: The different chitosan microparticles and other excipients as indicated in Table 4-2 for each formulation were premixed by manual stirring in a 1000 ml glass beaker for 30 min. 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 min at 200 rpm.
Compression procedure: The tablets were compressed using a multi-station tablet compression machine (Cadmach CM 03-16, India) fitted with round, flat punches, which are 6 mm in diameter. DRE = --- ^x 100% Equation [4.10]
Where: MDTad is amendable Mean dissolution time; t-ιoo% is the time at 100% drug released
4.5 Preparation of cross-linked mlcroparticles using a novel method
4.5.1 Chitosan cross-linked with tripolyphosphate (TPP)
A 3% w/v solution of chitosan (Warren Chem Specialities, South Africa, Deacetylation Degree = 91.25%, 500 ml) was prepared in 2% v/v acetic acid and 3% w/v diltiazem ( 15 g) (Fabbrica ltaliana Sintetici, Italy) was added to this solution and stirred with an overhead mechanical stirrer at 1000 rpm for 15 minutes to dissolve the diltiazem.
A quantity of 15 g of TPP (Sigma-Aldrich, USA) powder was added to 500 ml of the chitosan and diltiazem mixture under homogenisation at 5000 rpm for 30 min. The resultant cross-linked chitosan hydrogel was freeze-dried (Jouan LP3 France) for 48 h. One halve of the dry product was screened through a 150 μm sieve and the other halve through a 300 μm sieve to investigate the influence of particle size on drug release.
4.5.2 Chitosan cross-linked with polycarbophil
A 3% w/v solution of chitosan (Warren Chem Specialities, South Africa, Deacetylation Degree = 91.25%, 500 ml) was prepared in 2% v/v acetic acid and 3% w/v diltiazem (15 g) (Fabbrica ltaliana Sintetici, Italy) was added to this solution and the mixture was stirred with an overhead mechanical stirrer at 1000 rpm for 15 minutes to dissolve the diltiazem.
A quantity of 15 g of polycarbophil (Noveon, USA) powder was added to 500 ml of the chitosan and diltiazem mixture under homogenisation at 5000 rpm for 30 min. The resultant cross-linked chitosan hydrogel was freeze-dried (Jouan LP3 France) for 48 h. One halve of the dry product was screened through a 150 μm sieve and the other halve through a 300 μm sieve to investigate the influence of particle size on drug release. 4.5.3 Yield of particles
The product obtained after freβze-drying of the hydrogel was weighed and the percentage yield of the microparticles was then calculated by means of the following equation [4.11]:
W Yield (%w/w) = -ua*-**. x 100% Equation [4.11]
Where: Wmicroparticies = weight of the microparticels obtained after freeze-drying,
Wπrodei drug = weight of model drug that was included,
Wchitosan = weight of chitosan ,
WTPP = weight of TPP for cross-linking,
Wpoiycarbophii = weight of polycarbophil for cross-linking.
4.5.4. Drug content of the microparticles
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 μm 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].
4.5.5 Preparation of matrix type tablets
4.5.5.1 Direct compression of microparticles with size ≤ 150 μm
These tablets were made by direct compression of a mixture of ingredients as indicated in Table 4-5.
Table 4-5: Tablet formulations for chitosan microparticles with size ≤ 150 μm
Formulation Ingredient Quantity (%)
Chitosan cross-liking TPP Microparticles 89.5
Avicel 5
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking TPP Microparticles 74.5
Avicel 20
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking TPP Microparticles 49.5
Avicel 45
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil Microparticles 89.5
Avicel 5 n
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil Microparticles 74.5 p Avicel 20
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil Microparticles 49.5
Avicel 45
Magnesium stearate 0.5
Explotab 5
Mixing procedure: The different drug loaded chitosan microparticles (i.e. cross-linked with TPP or polycarbophil) and different excipients as indicated in Table 4-5 were premixed by manual stirring in a 1000 ml glass beaker for 30 min. 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 min at 200 rpm. Compression procedure: The tablets were compressed using a multi-station tablet compression machine (Cadmach CM 03-16, India) fitted with round, flat punches, which are 6 mm in diameter.
4.5.5.2 Direct compression of microparticles with size ≤300 μm
These tablets were made by direct compression of a mixture of ingredients as indicated in Table 4-6.
Table 4-6: Tablet formulations for chitosan microparticles with size < 300 μm
Formulation Ingredient Quantity (%)
Chitosan cross-liking TPP granules 89.5
/^ Avicel 5
Magnesium stβarate 0.5
Explotab 5
Chitosan cross-liking TPP granules 74.5
Avicel 20
Magnesium stearate 0.5
Explotab ■ 5
Chitosan cross-liking TPP granules 49.5
Avicel 45
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil granules 89.5
■ Avicel 5
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil granules 74.5
K Avicel 20
Magnesium stearate 0.5
Explotab 5
Chitosan cross-liking polycarbophil granules 49.5
Avicel 45
Magnesium stearate 0.5
Explotab 5 Mixing procedure: The different drug loaded chitosan microparticles (i.e. cross-linked with TPP or polycarbophil) and different βxcipients 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.
5. PREPARATION OF SUSTAINED RELEASE MONOLITHIC MATRIX SYSTEMS CONTAINING DIFFERENT DRUG LOADED CROSS-LINKED POLYMERIC MICROPARTICLES
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.
5.1 Preparation of cross-linked polymeric filler material
The bulk filler for the matrix systems was prepared by cross-linking chitosan with polycarbophil as described before. Briefly, the method entails preparation of a 3% w/v chitosan (Warren Chem Specialities, South Africa, Deacetylation Degree = 91.25%, 1000 ml) solution in a 2% v/v acetic acid solution. 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.
The 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 μm sieve to obtain microparticles with a more homogenous size distribution. 5.2 Swelling properties of cross-linked polymeric filler material
Swelling studies were carried out for the tablets containing only cross-linked polymeric filler as well as for the different monolithic matrix type tablets. Three tablets were weighed and each tablet was transferred into a metallic basket and placed in 900 ml phosphate buffer with a pH of 5.8 and 7.4, respectively at 37.0 ± 0.50C. The medium was stirred with a paddle at a rotation speed of 50 rpm. At time intervals of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 and 48 h, the tablets were removed from the baskets and gently wiped with a tissue to remove surface water after which they were weighed and then placed back into the baskets. The baskets were then placed back into the phosphate buffer as quickly as possible. The average weight was calculated for the three tablets of each type at every time interval and the data obtained were used to calculate the swelling index.
5.2.1 Swelling index
Swelling index (or the degree of swelling) was calculated according to equation [4.12).
5.2.2 Swelling profile
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. W4βh - Wd) were used as reference point for 100% swelling. The percentage swelling of each tablet was calculated according to equation [4.13].
5.2.3 Mean swelling time (MST)
MST is a statistical moment for the swelling process and provides an accurate tablets swelling rate. It is calculated by the equation [4 14].
5.3 Preparation of dlltiazem-loaded chitosan spray-dried microspheres
Diltiazem-loaded chitosan microspheres were prepared by spray-drying a 1 :1 mixture of diltiazem and chitosan in 2% v/v acetic acid in a mini spray-dryer (Bϋchi 190, Flawil Switzerland). A quantity of 15 g chitosan was dissolved in 500 ml of a 2% v/v acetic acid solution under mechanical stirring at 800 rpm for 15 minutes and 15 g diltiazem were then added to this solution, which was stirred until dissolved. The resultant mixture was spray-dried using the following process parameters: feed rate = 2 ml/min; aspirator setting = 15; spray-flow = 600 Nl/h; inlet temperature = 8O0C and spray-nozzle = 0.5 mm.
5.4 Preparation of dlltiazem-loaded chitosan freeze-dried microparticles
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 μm sieve to obtain microparticles with a more homogenous size distribution.
5.5 Preparation of ibuprofen microparticles using freeze-dry method
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 μm sieve to obtain microparticles with a more homogenous size distribution.
5.6 Drug content of the different chitosan microparticles
5.6.1 Dru9 content of diltiazem-loaded chitosan microparticles
Approximately 50 mg of the microparticles obtained from each of the freeze-dry and spray-dry methods were weighed accurately and quantitatively transferred into a 100 ml volumetric flask, which was made up to volume with distilled water. This mixture was stirred for 24 h to allow total release of the drug. After filtration through a 0.45 μm filter membrane, the solution was assayed using a UV spectrophotometer at the wavelength of 265 nm. This assay was performed in triplicate. The percentage drug content of the microspheres was calculated by means of equation [4.4]. .6.2 Drug content of ibuprofen-loaded chitosan microparticles
Approximately 100 mg of the 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 μm 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
Figure imgf000029_0001
Where: ABS88111PIe= absorbance of the sample at 264 nm Wsampiβ = weight of the particle sam pie K = slope of standard curve (1.6448) a = y-intercept (0.0145).
5.7 Preparation of monolithic matrix type tablets
Monolithic matrix tablets were made by direct compression of a mixture of ingredients as indicated in Table 4-8. In these tablets, the drug-loaded chitosan microparticles were uniformly distributed throughout a matrix formed by cross-linked polymeric filler material as well as other excipients.
Mixing procedure: The cross-linked polymeric filler material and different excipients were pre-mixed with either diltiazem-loaded microspheres or diltiazem-loaded microparticles or ibuprofen microparticles in the ratios indicated in Table 4-7 by manual stirring in a 1000 ml glass beaker for 30 mln. 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 min at 200 rpm.
Compression procedure: The monolithic matrix 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. Table 4-8: The formulations of the monolithic matrix type tablets
Concentration (% w/w)
Ingredient
Formula Formula Formula Formula Formula Formula 1 2 3 4 5 6
Diltiazem
29.8 24.8 — — — — microspheres
Diltiazem
— — 29.8 24.8 — — microparticles lbuprofen
— — — — 29.8 24.8 microparticles
Cross-linked
59.7 49.7 59.7 49.7 59.7 49.7 polymer filler
Avicel 5 20 5 20 5 20
Explotab 5 5 5 5 5 5
Mg-stearate 0.5 0.5 0.5 0.5 0.5 0.5
6. PREPARATION OF SUSTAINED RELEASE MONOLITHIC MATRIX SYSTEMS CONTAINING DIFFERENT DRUGS IN POWDER FORM
Pure drug in powder form was 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.
6.1 Preparation of 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 centrifugatioπ 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 -490C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 μm sieve.
6.1.2 IPEC between chitosan and polycarbophil
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 uπreacted material. The IPEC was finally freeze-dried at -490C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 μm sieve.
Table 4-12: Formulation of monolithic matrix type tablets containing an IPEC between chitosan and polycarbophil and ibuprofen as the model drug.
Concentration (% w/w)
Ingredient
Formula M Formula I-2 Formula 1-3 Formula I-4
Ibuprofen 17.9 14.9 14.9 14.9
Chitosan polycarbophil
71.6 59.6 44.7 14.9 IPEC
Chitosan — — 14.9 37.3
Polycarbophil — — — 7.5
Avicel® 5 20 20 20
Explotab® 5 5 5 5
Mg-stearate 0.5 0.5 0.5 0.5
Table 4-11 : Formulations of monolithic matrix type tablets containing an IPEC between chitosan and polycarboph.il and diltiazβm as the model drug.
Concentration (% w/w) Ingredient
Formula I Formula Il Formula III Formula IV Formula V Formula Vl Formula VII Formula VIII Formula IX Formula X Formula Xl
Diltiazem 17.9 14.9 17.9 14.9 17.9 14.9 17.9 14.9 14.9 14.9 14.9
PCC 71.6 59.6 53.7 44.7 53.7 44.7 35.8 29.8 29.8 22.4 14.9
Chitosan — — 17.9 14.9 — — 17.9 14.9 22.4 29.8 37.3
Polycarbophil — — — — 17.9 14.9 17.9 14.9 7.5 7.5 7.5
Avicel 5 20 5 20 5 20 5 20 20 20 20
Explotab 5 5 5 5 5 5 5 5 5 5 5
Mg-stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
. PREPARATION OF A SUSTAINED RELEASE MONOLITHIC MATRIX SYSTEM CONTAINING A MACROMOLECULAR DRUG AND AN ABSORPTION ENHANCER
7.1 IPEC between chitosan and polycarbophil
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 -490C for 48 h (Jouan LP3, France) followed by screening the powder through a 297 μm sieve.
A mixture of insulin and the absorption enhancer, TMC1 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 0C for 48 h and the resultant powder was screened through a 297 μm 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.
Table 4-14: The formulations of insulin monolithic matrix tablets
Concentration (% w/w)
Ingredient
F 1 F 2 F 3 F 4 F 5 F 6 F 7
Insulin — 2.5 2.5 2.5 2.5 2 5
TMC and insulin
17.9 — 14.9 — microparticlβs
Chitosan and polycarbophil 71.6 57.1 44.7 42.2 42.2 34.8 27.3
IPEC
Chitosan — — 14.9 14.9 22.4 29.8 37.3
Polycarbophil — 14.9 — 14.9 7.5 7.5 7.5
Avicel 5 20 20 20 20 20 20
Explotab 5 5 5 5 5 5 5
Mg-stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Mixing procedure: The ingredients as outlined in Table 4-14 were premixed by manual stirring in a 1000 ml glass beaker for 30 min. 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 min 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.

Claims

Claims
1. A polymeric complex including an interpolyelectrolyte complex of chitosan and polycarbophil.
2. A complex as claimed in claim 1 , which is used as an excipient in swellable matrix drug delivery systems, including chitosan and polycarbophil
3. A complex as claimed in claim 1 , which exhibits swelling properties when formulated into a compressed matrix system.
4. A complex as claimed in any one of the preceding claims, wherein the polymeric complex exhibits controlled drug release.
5. A complex as claimed in any one of the preceding claims, which exhibits zero order drug release.
6. A drug dosage form including a polymeric complex as claimed in any one of claims 1 to 5.
7. A drug dosage form as claimed in claim 6, which form is a solid dosage form.
8. A drug dosage form as claimed in claim 6 or claim 7, which form is a tablet, a capsule, or a caplet, whether coated or uncoated.
9. A sustained release drug delivery system including a polymer complex as claimed in any one of claims 1 to 5.
10.An insulin dosage system, said system including a drug dosage form as claimed in any one of claims 6 to 8.
11. A polymeric complex as claimed in claim 1 , substantially as herein described and illustrated.
12. A drug dosage form as claimed in claim 6, substantially as herein described and illustrated.
13. A sustained release drug delivery system as claimed in claim 10, substantially as herein described and illustrated.
14. A new polymeric complex, a new drug dosage form, or a new sustained release drug delivery system substantially as herein described.
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