WO2015186108A1 - Forme galénique orale de comprimé à deux couches pour la libération de divers médicaments - Google Patents

Forme galénique orale de comprimé à deux couches pour la libération de divers médicaments Download PDF

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Publication number
WO2015186108A1
WO2015186108A1 PCT/IB2015/054270 IB2015054270W WO2015186108A1 WO 2015186108 A1 WO2015186108 A1 WO 2015186108A1 IB 2015054270 W IB2015054270 W IB 2015054270W WO 2015186108 A1 WO2015186108 A1 WO 2015186108A1
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layer
dosage form
api
oral pharmaceutical
pharmaceutical dosage
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English (en)
Inventor
Viness Pillay
Yahya Essop Choonara
Pradeep Kumar
Lisa Claire Du Toit
Famida G. HOOSAIN
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University of the Witwatersrand, Johannesburg
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University of the Witwatersrand, Johannesburg
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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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • This invention relates to oral pharmaceutical dosage form for providing in use uniform and/or pulsatile release of active pharmaceutical ingredients (APIs) in use.
  • APIs active pharmaceutical ingredients
  • Schizophrenia is one of the major psychiatric disorders that greatly impairs the quality of life of patients and their caregivers as well creating an substantial financial burden on society (Peuskens J., et al., 1999).
  • the high cost of second generation antipsychotics as compared to their first generation counterparts has led to a great many debates about the cost benefit ratios, however comparative studies have shown that these agents improve negative symptoms and concomitant depression better than the conventional agents (Leucht S., et al., 2009).
  • first generation agents Furthermore clinical outcomes with first generation agents have shown suboptimal results with a high degree of extrapyramidal side effects and relapse rates compared to second generation agents (Jones P.B, et al., 2006).
  • second generation antipsychotics are sulpiride, one of the many drugs used in the management and treatment of psychiatric disorders. It is an anti-psychotic neuroleptic agent that displays anti-dopminergic activity which is responsible for it efficacy to treat psychotic disorders.
  • Non adherence to therapy is a common cause for relapse and hospitalization among the schizophrenic community and thereby leads to greater costs incurred in treatment programs as well as reduced prognosis; many studies have linked poor therapeutic outcomes with low patient compliance, thus researchers have suggested that the use of long-acting drug delivery systems may significantly improve compliance (Olivares et al., 2009).
  • the hazard and intensity of side-effects related to anti-psychotic drugs increases with a corresponding increase in dosage, furthermore it has been stated that the risk of side -effects also depends on the rate of drug delivery (Barnes et al., 2006).
  • APIs active pharmaceutical ingredients
  • mental disorders preferably antipsychotics such as sulpiride.
  • an oral pharmaceutical dosage form comprising a first layer of porous crosslinked polymers including a polysaccharide, polyethylene oxide (PEO) and/or polyethylene glycol or derivatives of polyethylene glycol, and a crosslinking agent, the first layer to provide uniform release of a first active pharmaceutical ingredient (API) upon oral administration of the dosage form.
  • a first layer of porous crosslinked polymers including a polysaccharide, polyethylene oxide (PEO) and/or polyethylene glycol or derivatives of polyethylene glycol, and a crosslinking agent, the first layer to provide uniform release of a first active pharmaceutical ingredient (API) upon oral administration of the dosage form.
  • PEO polyethylene oxide
  • API active pharmaceutical ingredient
  • Polyethylene glycol may include at least one of the following group: high molecular weight polyethylene derivatives such as, but not limited to, the following group: polyoxyethlene, polyoxyethlene ether, polyglycol, and hydro-omega hydroxy poly (oxy-1, 2- ethanediyl).
  • high molecular weight polyethylene derivatives such as, but not limited to, the following group: polyoxyethlene, polyoxyethlene ether, polyglycol, and hydro-omega hydroxy poly (oxy-1, 2- ethanediyl).
  • the oral pharmaceutical dosage form may further comprise a second layer including a plurality of multilayered devices loaded with a second API and said plurality of multilayered devices embedded within a carrier, the second layer to provide pulsatile release of the multilayered devices and in turn pulsative release of the second active pharmaceutical ingredient (API) upon oral administration of the dosage form. Further inclusion of the second layer provides a dosage form having a dual layered or bi-layered configuration.
  • the carrier may comprise porous crosslinked polymers including the polysaccharide, polyethylene glycol (PEO), and a crosslinking agent. Alternatively, and in a preferred embodiment of the invention, the carrier may comprise carboxymethylcellulose and gellan gum.
  • the first layer may further include a first lipid such that in use after oral administration of the dosage form, the first lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the first API at the blood brain barrier and in so doing improving bioavailability of the first API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • a first lipid such that in use after oral administration of the dosage form, the first lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the first API at the blood brain barrier and in so doing improving bioavailability of the first API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • the carrier may further comprise a second lipid such that in use after oral administration of the dosage form, the second lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the second API at the blood brain barrier and in so doing improving bioavailability of the second API, and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • a second lipid such that in use after oral administration of the dosage form, the second lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the second API at the blood brain barrier and in so doing improving bioavailability of the second API, and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • the first and second API may be the same and/or different.
  • the first and/or second API may be an anti-psychotic agent.
  • the anti-psychotic agent may be a typical and/or atypical anti-psychotic agent.
  • the first and/or second APIs may be sulpiride and/or valproic acid.
  • the first and second lipid may be the same.
  • the first and second lipids may be lectins and/or lecithins.
  • the polysaccharide may be a starch based polysaccharide or a derivative thereof.
  • the polysaccharide may be gellan gum.
  • the crosslinking agent may be phosphorus oxychloride (POCI 3 ), sodium trimethaphosphate, epichlorohydrin and/or a derivatives of the aforementioned.
  • POCI 3 phosphorus oxychloride
  • the crosslinking agent is epichlorohydrin.
  • the first layer of porous crosslinked polymers and/or the carrier may further each comprise at least one inactive polymer agent selected from the group including, but not limited to: substituted or unsubstituted acrylic and methacrylic acids, alkyl celluloses, polyethylene glycol, sodium alginate, polyvinyl alcohol, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, ethylcellulose, hydroxyethylcellulose, a sugar or sugar based group, and mixtures of the aforementioned.
  • the first layer of porous crosslinked polymers and/or the carrier may further each comprise N- acetyl cysteine facilitating bioadhesion of the dosage form to the stomach in use.
  • the first layer of porous crosslinked polymers and/or the carrier may each form a semi- interpenetrating polymer network (IPN) wherein the polysaccharide and the polyethylene oxide (PEO) semi-interpenetrate each other.
  • IPN semi- interpenetrating polymer network
  • a semi- interpenetrating polymer network forms from crosslinked PEO and gellan gum.
  • the first layer of porous crosslinked polymers and/or the carrier may be layered like an onion and/or a sandwich.
  • the first layer of the dosage form may comprise 1 part by weight of a API in predominantly amorphous form, between 0.1-12 parts by weight of an inactive polymer that assists in the dissolution of the API in a ratio of 2 parts by weight of the crosslinked polymer and crosslinked by 0.4-0.8 part by weight of crosslinking agent.
  • the first layer may comprise 1 part by weight of API relative to 1-10 parts by weight of crosslinked polymer.
  • the first layer may comprise 2 parts by weight of API in a predominantly amorphous form and between 1-12.5 part by weight of an inactive polymer that assists in controlling the dissolution of the active agent in ratio of 0.5 parts by weight of crosslinked polymer and crosslinked by 0.3-6% by weight crosslinking agent.
  • the first layer may comprise 2 parts by weight of the API relative to 1.12.5 parts by weight of crosslinked polymer.
  • Each of the plurality of multilayered devices may comprise: a mucus cleaving layer, preferably the mucous cleaving layer may comprise N-acetyl cysteine loaded alginate; a mucoadhesive layer comprising a mucoadhesive polymer, preferably the mucoadhesive layer comprising lectin, hypromellose and chitosan; a second API carrier layer, preferably the second API carrier layer comprising crosslinked Eudragit, sodium alginate and the second API; and a water insoluble layer, preferably the water insoluble layer comprising a water insoluble polymer, further preferably the water insoluble polymer may comprise gellan gum.
  • Each of the plurality of multilayered devices may be layered like an onion and/or a sandwich.
  • FIGURE 1 shows a cross-sectional graphical illustration of an oral dosage form according to the invention
  • FIGURE 2 graphically depicts the formulation processes undertaken during synthesis of a first layer of the dosage form according to the invention
  • FIGURE 3 shows a cross-sectional graphical illustration of multilayered device typically embedded into the a carrier to form a second layer of the oral dosage form according to the invention
  • FIGURE 4 shows a diagrammatic representation of Brinells Hardness Number for Box
  • FIGURE 5 shows an illustration of the difference of Resilience between all statistical Box
  • FIGURE 6 shows SEM Micrographs of (a) Formulation Fl and (b) F7 of the first layer of the dosage form, after swelling test, showing the change in morphological structure such as porosity achieved by crosslinking reactions as compared to the compact structure of the pure polymers;
  • FIGURE 7 shows DSC thermogram of semi IPN-xerogel Formulations Fl, F7, F9 of the first layer of the dosage form, as well as PEO and GG at a heating rate of 10°C/ min from 10- 300°C under nitrogen atmosphere -
  • Spectra (a) and (b) correspond to PEO and GG respectively with (c), (d), and (e) representing Formulations 1, 7 and 9 respectively;
  • FIGURE 8 shows FTIR spectra of crosslinked semi-IPN xerogel Fl, F7, F9 of the first layer of the dosage frorm, as well as pure PEO and GG depicting the change within chemical structure via the identification of specific functional groups within the spectra obtained.
  • FIGURE 9 shows a graphical illustration of the in vitro fractional drug release vs. time of sustained release croslinked semi IPN-xerogel first layer Formulations F1-F15 in comparison to release profiles of PEO-GG blend formulations - (a) shows Formulations F1-F7 and (b) shows Formulations F8-F15 and PEO-GG blend;
  • FIGURE 10 shows a graphical illustration of mucoadhesion for prepared mucoadhesive layer samples 1-20 of the multilayered devices
  • FIGURE 11 shows an illustration of % swelling over 24 hours for the mucoadhesive layer samples 1-20 of the multilayered devices
  • FIGURE 12 shows values of Young's Modulus for mucoadhesive layer samples 1-20 of the multilayered devices.
  • an oral pharmaceutical dosage form comprising a first layer of porous crosslinked polymers including a polysaccharide, polyethylene oxide (PEO) and/or polyethylene glycol (PEG) or a derivative of PEG, and a crosslinking agent, the first layer to provide uniform release of a first active pharmaceutical ingredient (API) upon oral administration of the dosage form.
  • a first layer of porous crosslinked polymers including a polysaccharide, polyethylene oxide (PEO) and/or polyethylene glycol (PEG) or a derivative of PEG, and a crosslinking agent, the first layer to provide uniform release of a first active pharmaceutical ingredient (API) upon oral administration of the dosage form.
  • PEO polyethylene oxide
  • PEG polyethylene glycol
  • API active pharmaceutical ingredient
  • Polyethylene glycol may include at least one of, but not limited to, the following group: high molecular weight polyethylene derivatives such as but not limited to polyoxyethlene, polyoxyethlene ether, polyglycol, and hydro-omega hydroxy poly (oxy-1, 2-ethanediyl).
  • high molecular weight polyethylene derivatives such as but not limited to polyoxyethlene, polyoxyethlene ether, polyglycol, and hydro-omega hydroxy poly (oxy-1, 2-ethanediyl).
  • the oral pharmaceutical dosage form may further comprise a second layer including a plurality of multilayered devices loaded with a second API and said plurality of multilayered devices embedded within a carrier, the second layer to provide pulsatile release of the multilayered devices and in turn pulsative release of the second active pharmaceutical ingredient (API) upon oral administration of the dosage form. Further inclusion of the second layer provides a dosage form having a dual layered or bi-layered configuration.
  • the carrier may be porous crosslinked polymers including the polysaccharide, polyethylene glycol (PEO), and a crosslinking agent. Alternatively, and in a preferred embodiment of the invention, the carrier comprises carboxymethylcellulose and gellan gum.
  • the first layer may further include a first lipid such that in use after oral administration of the dosage form, the first lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the first API at the blood brain barrier and in so doing improving bioavailability of the first API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • a first lipid such that in use after oral administration of the dosage form, the first lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the first API at the blood brain barrier and in so doing improving bioavailability of the first API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • the carrier may further comprise a second lipid such that in use after oral administration of the dosage form, the second lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the second API at the blood brain barrier and in so doing improving bioavailability of the second API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • a second lipid such that in use after oral administration of the dosage form, the second lipid and the polysaccharide form in situ a lipopolysaccharide increasing permeation of the second API at the blood brain barrier and in so doing improving bioavailability of the second API and further facilitating interaction of the dosage form with surface carbohydrates on mucous or epithelial cells of a stomach of a user therein increasing adhesion of the dosage form to the stomach wall to increase gastric retention.
  • the first and second API may be the same and/or different.
  • the first and/or second API may be an anti-psychotic agent.
  • the anti-psychotic agent may be a typical and/or atypical anti-psychotic agent.
  • the first and/or second APIs are generally sulpiride and/or valproic acid.
  • the first and second lipid may be the same.
  • the first and second lipids are generally lectins and/or lecithins.
  • the polysaccharide may be a starch based polysaccharide or a derivative thereof.
  • the polysaccharide may be gellan gum.
  • the crosslinking agent may be phosphorus oxychloride (POCI 3 ), sodium trimethaphosphate, epichlorohydrin and/or a derivatives of the aforementioned.
  • POCI 3 phosphorus oxychloride
  • the crosslinking agent is epichlorohydrin .
  • the first layer of porous crosslinked polymers and/or the carrier typically each further comprises at least one inactive polymer agent selected from the group including, but not limited to: substituted or unsubstituted acrylic and methacrylic acids, alkyl celluloses, polyethylene glycol, sodium alginate, polyvinyl alcohol, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, ethylcellulose, hydroxyethylcellulose, a sugar or sugar based group, and mixtures of the aforementioned.
  • at least one inactive polymer agent selected from the group including, but not limited to: substituted or unsubstituted acrylic and methacrylic acids, alkyl celluloses, polyethylene glycol, sodium alginate, polyvinyl alcohol, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, ethylcellulose, hydroxyethylcellulose, a sugar or sugar based group, and mixtures of the aforementioned.
  • the first layer of porous crosslinked polymers and/or the carrier typically each further comprises N-acetyl cysteine facilitating bioadhesion of the dosage form to the stomach in use. Increased bioadhesion will facilitate more effective release of the API in use.
  • the first layer of porous crosslinked polymers and/or the carrier may each form a semi- interpenetrating polymer network (IPN) wherein the polysaccharide and the polyethylene oxide (PEO) semi-interpenetrate each other.
  • IPN semi- interpenetrating polymer network
  • a semi- interpenetrating polymer network forms from crosslinked PEO and gellan gum.
  • Gellan gum is an extracellular polysaccharide produced by the bacterium Pseudomonas Elodea.
  • the naturally occurring form of gellan gum is a linear anionic heteropolysaccharide grounded on a tetrasaccharide repeat unit of glucose, rhamnose and glucuronic acid with a molar ratio of 2: 1: 1 (14).
  • Gellan gum exists as a half staggered, parallel, double helix that is stabilized by hydrogen bonds linking the hydroxymethyl groups of the one chain and both the carboxylate and glyceryl groups of the other.
  • Polyethylene (oxide) exists as a high viscosity non-ionic linear homopolymer of ethylene oxide, a water soluble resin which affords great biodegradable properties to pharmaceutical formulations.
  • Polyethylene (oxide) swells when in contact with dissolution medium, API release occurs via diffusion through a gel layer and/or erosion of the swollen surface gel.
  • the PEO also increases membrane fluidization via ATPase inhibition increasing API absorption in use.
  • IPN semi-interpenetrating network
  • the gellan gum and/or the PEO may inhibit P-gp efflux transporter proteins, which P-gp efflux transporter proteins would otherwise bind to sulpiride and prevent said sulpiride from entering the bloodstream and/or crossing the blood brain barrier. Consequently, the gellan gum and/or the PEO improve bioavailability of the first and/or second API and may allow for administration of decreased dosages which will lower the negative side effects currently experienced upon administration of sulpiride, and consequently improve patient compliance.
  • the first layer of porous crosslinked polymers and/or the carrier may be layered like an onion and/or a sandwich.
  • the first layer of the dosage form may comprise 1 part by weight of a API in predominantly amorphous form, between 0.1-12 parts by weight of an inactive polymer that assists in the dissolution of the API in a ratio of 2 parts by weight of the crosslinked polymer and crosslinked by 0.4-0.8 part by weight of crosslinking agent.
  • the first layer may comprise 1 part by weight of API relative to 1-10 parts by weight of crosslinked polymer.
  • the first layer may comprise 2 parts by weight of API in a predominantly amorphous form and between 1-12.5 part by weight of an inactive polymer that assists in controlling the dissolution of the active agent in ratio of 0.5 parts by weight of crosslinked polymer and crosslinked by 0.3-6% by weight crosslinking agent.
  • the first layer may comprise 2 parts by weight of the API relative to 1.12.5 parts by weight of crosslinked polymer.
  • Each of the plurality of multilayered devices typically comprises: a mucus cleaving layer, preferably the mucous cleaving layer may comprise N-acetyl cysteine loaded alginate; a mucoadhesive layer comprising a mucoadhesive polymer, preferably the mucoadhesive layer comprising lectin, hypromellose and chitosan; a second API carrier layer, preferably the second API carrier layer comprising crosslinked Eudragit, sodium alginate and the second API; and a water insoluble layer, preferably the water insoluble layer comprising a water insoluble polymer, further preferably the water insoluble polymer may comprise gellan gum.
  • Each of the plurality of multilayered devices may be layered like an onion and/or a sandwich.
  • an oral pharmaceutical dosage form substantially as herein described, illustrated and/or exemplified with reference to any one of the accompanying examples and/or diagrammatic drawings.
  • Figure 1 shows a graphical illustration of a preferred embodiment of an oral dosage form 10 according to the invention.
  • the preferred embodiment of the invention shows a dual- or bi- layered dosage form.
  • the dual- or bi-layered dosage form 10 shows a first layer of crosshnked polymers 12 and a first active pharmaceutical ingredient (API) 14.
  • the first layer of crosshnked polymers 12 may include a polysaccharide, polyethylene oxide (PEO) and/or polyethylene glycol (PEG) or a derivative of PEG, and a crosslinking agent.
  • the first layer of crosshnked polymers 12 comprises gellan gum (as the polysaccharide) and PEO which are crosshnked with epichlorohydrin (as the crosslinking agent).
  • the first layer of crosshnked polymers 12 generally forms a semi-interpenetrating network (s-IPN).
  • the dual- or bi-layered dosage form 10 further comprises a second layer 16 including a plurality of multilayered devices 18 embedded within a carrier 20.
  • Each of the multilayered devices 18 includes a second API such that in use the second layer 16 provides pulsatile release of a second pharmaceutically active ingredient (API) upon oral administration of the dosage form 10.
  • the carrier 20 comprises porous crosshnked polymers comprising carboxymethylcellulose and gellan gum.
  • each of the plurality of multilayered devices 18 typically comprises a mucus cleaving layer of N-acetyl cysteine loaded alginate 22; a mucoadhesive layer 24 comprising lectin hypromellose and chitosan; a second API carrier layer 26 comprising crosshnked Eudragit, sodium alginate and the second API; and a water insoluble layer 28 of gellan gum.
  • each multilayered device is layered like a sandwich.
  • the mucous cleaving layer 22 is substantially proximal a mucous layer of the stomach and/or intestinal wall
  • the water insoluble layer 28 is substantially distal the mucous layer of the stomach and/or intestinal wall.
  • the water insoluble layer 28 ensures unidirectional release of API toward the mucous layer of the stomach and/or intestinal wall in use.
  • Table 1 Box-Behnken design template for the statistically derived 15 semi-IPN xerogel formulations of the first layer of porous crosslinked polymers, and their respective chemical compositions.
  • Methacrylic acid copolymer (Eudragit RS 100) (Degussa, Rohm GMbH, Pharma polymers, Germany). Soybean Lecithin (Schuchardt (Hohenbrunn, Germany). All other reagents were of analytical grade and are used as received.
  • the first layer of porous crosslinked polymers is manufactured to be a semi-interpenetrating network (IPN) xerogel formulation.
  • IPN semi-interpenetrating network
  • Several formulations of the first layer of porous crosslinked polymeris were synthesized in accordance with the Box-Behnken statistical experimental design as shown in Table 1 and as illustrated in Figure 2.
  • the first layer of porous crosslinked polymers comprised gellan gum as the polysaccharide, polyethylene oxide (PEO), and epichlorohydrin as the crosslinking agent.
  • a process 100 for the manufacturing of the first layer is illustrated in Figure 2 wherein gellan gum 112 and poly (ethylene oxide) 114 were crosslinked 116 using epichlorohydrin as follows: % w/v solutions of poly (ethylene oxide) of varying concentrations in distilled water were prepared; thereafter a variation of weights of gellan gum ranging between 0.5-lg was mixed into the already prepared poly (ethylene oxide) solution, once gellan gum was completely dissolved, epichlorohydrin was added within a range of 0.4-0.8mL with further stirring with a magnetic stirrer for 30 minutes. These reactions conferred the formation of a tri-molecular complex 118 that pharmaceutically offers advantages to the functionality of the drug delivery system.
  • the resulting gel is poured into a beaker of 200-500ml acetone, and allowed to precipitate 120 for approximately 3 hours. It is then removed from the acetone and air dried under a fumehood for a further 24 hours. The resultant xerogel is then crushed into a uniform powder for formulation with a first API.
  • the resulting gel was removed and air dried.
  • the dried xerogel was then crushed employing a laboratory electric grinder to form a uniform powder.
  • the crushed xerogel was then mixed with drug (API) and surfactant (1.5mg Magnesium Stearate) which allows for the stabilization of the polymer particles (Bassett and Hamilec, 2009) to form the porous xerogel-polymer drug loaded matrix.
  • the porous xerogel matrix system will then be compressed 122 into the first layer using a Carver Tablet Compressor (model 3851-0).
  • API sulpiride was used.
  • Another suitable APIs include, but are not limited to, the following group: benezenoids, benzamides, salicylamides, methoxybenzenes, benzoyl derivatives, N-alkypyrrolidines, sulfonamides, amino sulfonyl compounds, trialkylamines, secondary carboxylic acid amides, azacyclic compounds, hydrocarbon derivatives, carbonyl compounds, and drugs of poor solubility.
  • the tri-molecular complex 118 is mixed with leptin (preferably lyophilized human leptin) 124 and the first API (for example sulpiride) 126 prior to the precipitation step 120 and tableting step 122.
  • leptin preferably lyophilized human leptin
  • first API for example sulpiride
  • the second layer of the dosage form The carrier:
  • the carrier will be formulated employing an immediate release polymer in addition to tableting excipients.
  • the carrier may include the same polymer combination as that of the first layer but without the first API (drug).
  • the carrier comprises carboxymethylcellulose (a fast disintegrating polymer) in combination with gellan gum.
  • the multilayered device is a multilayered device.
  • the multilayered devices are also referred to herein as intestinal patches.
  • the devices are multilayered films comprising four layers: (1) mucus cleaving layer, (2) a mucoadhesive layer (3) a second API (drug) carrier layer, and (4) a water insoluble layer, wherein the film is layered like a sandwich.
  • the mucus cleaving layer adheres to a mucous layer of the stomach and/or intestinal wall and cleaves the mucus lining
  • the mucoadhesive layer which is layered onto the mucous cleaving layer can then more readily adhere to the intestinal wall
  • the second API (drug) carrier layer is layered onto the mucoadhesive layer carrying with it the second API
  • the water insoluble layer is layered onto the drug carrier layer to ensure unidirectional release of the API toward the intestinal wall and subsequently into the blood stream.
  • the mucus cleaving layer is formulated with the N-acetyl cysteine loaded alginate.
  • the incorporation of N-acetyl cysteine into the formulation enables in vivo interaction with surface mucous of the stomach in use, resulting in depolymerization of mucous glycoproteins, therefore hydrolyzing disulfide bonds, reducing mucous viscosity and allowing for bioadhesion of the drug delivery system to the intestinal wall. Increased bioadhesion increases gastric retention times and also increases the amount of API that can be released and that is ultimately bioavailable.
  • the mucoadhesive layer typically comprises lectin, hypromellose and chitosan. Chitosan at 1-5% w/v will be dissolved in a citric acid 0.3-0.45% solution to aid dissolution, once dissolution is achieved hypromellose at 1-3% will be added to the above mentioned solution and allowed to become homogenous, thereafter, lectin at a concentration of 0.25mg/ml will then added and the conjugation was carried out over a 2 hour incubation period.
  • the second API (drug) carrier layer The drug loaded layer will be formulated via the crosslinking of Eudragit and sodium alginate with the aid of calcium chloride. Generally, the drug loaded release layer will be formulated via the crosslinking of Eudragit RS 100 at 0.2-2% with the use of calcium chloride as crosslinker at 0.02-0.2%.
  • the water insoluble layer also herein referred to as the backing layer (and/or the encapsulating layer) is synthesized via the use of ethycellulose, an insoluble polymeric agent.
  • a preferred embodiment of the invention comprises a first and second layer manufactured using a direct compression method and a tableting press. Textural analysis studies of the first layer
  • Textural analysis data profiles were employed to study the physiochemical properties of the crosslinked PEO-GG semi-IPN-xerogel matrix of the first layer in comparison to the PEO-gellan gum blend tablets alone when a uniaxial compression force was applied to the tablets.
  • the work of deformation energy which is calculated as the area under the force-distance curve points to the deformation and rigidity of the tablets.
  • the force -distance curves obtained is a measure of the resistance force encountered by the probe infiltration as a function of the travelled distance into the tablet.
  • a low resistance is depicted by a low slope which further illustrates that the strength of the tablet is low, while a sharp increase in force, a higher slope as the test probe penetrates deeper into the tablet corresponds to a greater strength (Pillay and Fassihi, 2000).
  • the crosslinked xerogel tablet showed a lower level of deformity whereas the poly (ethylene oxide) - gellan gum blend tablet showed the highest value of deformation due to the high binding properties and loose bonds between polymer molecules.
  • a strain of 10% was applied to the tablets whereby a textural analysis profile was generated of force (N) - time (sec) to the 1:2 and 2:3 ratios. From the results obtained it can be seen that the semi IPN-xerogel matrix tablets Fl has the greatest % resilience relative to its comparatives, which may be attributed to the greater mechanical strength of the crosslinked xerogel due to a greater concentration of crosslinker being used.
  • Figure 4 shows Brinells Hardness numbers for Formulations F1-F15 of the first layer prepared samples, and Figure 5 shows the difference of resilience. Theoretically, from the equation of young's modulus (E), (Ruvalcaba et al, 2009);
  • ⁇ is the applied stress
  • A is the deformation
  • R is the indenter radius
  • d is the displacement of the indenter
  • F is the compression force
  • the strain applied as well as the deformation of the xerogel is directly proportional to the compression force applied, in addition the applied stress and deformation is inversely proportional to the radius and diameter of the indenter probe.
  • k is the release constant and n is the release index (Rokhade et al, 2006);
  • the amount of drug released is directly proportional to the extent of swelling. Furthermore the amount of drug released at time t is inversely proportional to the overall swelling; hence with an increase in swelling the drug release at time, t will be reduced. Scanning electron microscopy of the first layer
  • Figures 6 a and b display the scanning electron micrographs of the surface morphology of pure poly (ethylene oxide), gellan gum (GG), and crosshnked semi-IPN Xerogel formulations Fl and F7 after swelling tests.
  • the SEM micrographs show that the semi IPN-Xerogel formulations are highly porous as compared to the pure PEO and GG.
  • the drastic change in surface morphology between the pure polymers and crosshnked semi IPN-xerogels shows that the modification of these polymers was successful.
  • the porous nature of the semi IPN-xerogel furthermore allows for the sustained release of the active from within the interpenetrating network formed. There is also shrinkage of the semi IPN molecules within certain xerogel formulations due to the greater crosslink density and concentration (Kulkarni, 2011).
  • the DSC Thermogram of pure poly (ethylene oxide) WSR 303 shows an endothermic peak at 65.72°C which corresponds to the glass transition temperature, a second endothermic peak at 73.86°C, a broad asymmetric melting point as well as absorption of moisture, as well as an exothermic peak at 190.51°C which depicts crystallization of stable modification.
  • Figure 7 also depicts the Thermogram of gellan gum (GelzanTM CM), shows a glass transition peak at 55.33°C and an endothermic peak at 62.98°C. Glass transition temperature (Tg) if defined as the process by which an amorphous material undergoes melting.
  • Crystallization involves the transition of the polymeric material from a liquid to a crystalline solid, with repeated units forming a rigid structure. It was found that the temperature of crystallization was shifted to higher temperatures with a corresponding increase in crosslinker and polymer concentrations.
  • crosslinking peak is also noted within the crosslinked semi IPN-xerogel formulations, thus proving the crosslinking reaction of Gellan Gum-PEO employing epichlorohydrin. This peak is representative of the crosslinking reaction that occurs upon heating of the sample called Curing. These crosslinking peaks are observed with formulations with a higher degree of crosslinking density, but absent from those with a reduced crosslinking density, most prominent around the temperature of 215°C.
  • Figure 8 shows FTIR results.
  • IR Spectroscopy shows the structure of a new compound by identifying which molecular groups are present or absent from the sample being tested.
  • a specific group of atoms, called functional groups creates characteristic absorption bands within the spectra (Coates, 2000).
  • the FTIR Spectra of poly (ethylene oxide) above depicts the functional groups present within the chemical compound by determining characteristic bands.
  • Modifications in chemical structure of the semi-IPN-xerogel formulations were analyzed employing FTIR spectroscopy, which assists in identifying interactions of parent polymers upon chemical reactions such as crosslinking.
  • the current observation of crosslinking was optically detected by noted change in solution viscosity as well as opacity on completion of the crosslinking reaction.
  • Crosslinked networks of both synthetic and natural polymers have been researched to a great degree.
  • Chemical crosslinking is one method employed among many. Modifications such as crosslinking enhance the mechanical and pharmacokinetic properties of the crosslinked agents, with many uses in the pharmaceutical industry (Syed et al, 2011).
  • Chemical crosslinking entails the use of a crosslinking agent to allow a linkage between two polymer chains. The actual crosslinking reaction of both synthetic and natural polymers is accomplished via the reaction between their functional groups with crosslinkers such as epichlorohydrin. Chemical crosslinking largely implicates the introduction of new functional groups and molecules between the polymeric chains to thereby produce crosslinked chains (Syed et al, 2011).
  • hydrophilic matrices that come into contact with water are known to undergo prompt 'gelification' which is due to the increased size of polymer molecules.
  • drug release occurs within hydrophilic matrix systems; namely, release by 'controlled swelling', whereby drug undergoes the process of diffusion through the gel layer which is formed as stated above by the swelling or increase in size if polymer chains owing to entry of water, and secondly release by 'controlled dissolution' in which the water gains entry into the system thereby causing 'gelification' of the polymer chains that it comes into contact with, on the other hand, in addition to the conversion of polymer chains to a gel it also causes the polymer to be dissolved, this therefore involves dissolution or erosion of the polymer.
  • PEO-GG blends showed drug release behavior with characteristics of both the above mentioned mechanisms, gellan gum was subject to controlled dissolution and thus together with swelling it showed an increase tendency to disintegrate and dissolve thus leading to the initial burst effect in drug release, whereas the following controlled release behavior was mainly based on the properties of poly (ethylene) oxide which follows controlled swelling mechanisms of drug release, in that polymer chains undergo swelling on contact with aqueous phase due to the vitreous-elastic transition of the polymer been activated, thus the gel layer becomes thicker therefore making the drug release slower, because the drug molecule has to now pass through the thickened gel layer formed by swelling of polymer chains, which is at a greater distance from the surface of the dosage form, which creates a greater resistance to the diffusion of drug out of the gel layer (Maderuelo et al, 2011).
  • drug release from the PEO-GG blend indicated an initial burst effect followed by a rhythmic sustained release above the desired study period of 24 hours.
  • Crosslinked PEO-GG semi IPN- xerogel formulations F1-F15 displayed constant sustained release during the 24 hour period with 100% drug being released by the end of 24 hours, with slight variations in release rate due to the fact that the swelling and erosion properties of both polyethylene oxide and gellan gum where modified via the crosslinking reaction, thus these formulations showed a combined mechanism of drug release in terms of 'controlled erosion' and 'controlled dissolution'.
  • D is the diffusion coefficient of the drug
  • ⁇ is the tortuosity of the diffusion matrix
  • D ' is the effective diffusion coefficient
  • the boundary layer thickness is directly proportional to the diffusion of the drug, in addition the tortuosity of the matrix is inversely proportional to the boundary layer thickness.
  • Bio-adhesion can be defined as the process by which a natural or synthetic polymer is able to adhere to a biological tissue.
  • the biological tissue in question is a mucosal layer then it is referred to as mucoadhesion.
  • the material having bioadhesive properties can assist in allowing a delivery system (such as the dosage form according to the invention) to deliver a bioactive over a prolonged period of time site specifically.
  • the current drug delivery system allows for intial mucoadhesion of the multilayered device via the mucoadhesive layer (lectin fused hypromellose- chitosan blend), then followed by bioadhesion of the mucus cleaving layer once the N-acetyl cysteine cleaves the mucous.
  • the mucus cleaving layer attaches to the intestinal wall it cleaves off the excess mucus lining, thereby allowing for the following mucoadhesive layer to attach directly to the intestinal wall with minimal mucus interference. Since it is attached to the intestinal wall itself it is considered bioadhesion as it is attached to biological tissue. Mucoadhesion studies were performed on all Box-Behnken design formulations of the mucoadhesive layer to evaluate the effect of the change in concentration of the respective polymers on the degree of mucoadhesion. The mucoadhesive layer samples were prepared according to Table 2 above. For this study a 1% (w/v) mucin solution was prepared in USP intestinal fluid (pH 6.8).
  • the formulated mucoadhesive layers were incubated in USP intestinal fluid in an orbital shaker maintained at 37°C and 50rpm. Concentration of free mucin in solution, after a 6 hour test period, was determined via a UV spectrophotometer, at an absorption wavelength of 201nm (IMPLEN NanophotometerTM, Implen GmbH, Munchen Germany), using a 10 times dilution factor and a pathlenght of 0.1mm. The difference in mucin concentration in solution before and after incubation, provided an indication to the amount crosslinked with the lectin fused hypromellose-chitosan layer as seen in equation 13, showing the interaction between the mucoadhesive layer and the mucin;
  • FIG. 10 summarizes the mucoadhesion results of all 20 formulations, depicting the average percentage crosslinking values of the formulation to the mucin solution.
  • the dynamic swelling of the mucoadhesive layer of the multilayered device was evaluated in simulated intestinal fluid (pH 6.8), lxl.5mm strips of the formulated films were cut, weighed and placed in 50ml simulated intestinal fluid, and incubated in an orbital shaker maintained at 37°C and 50rpm, film samples were removed from the intestinal fluid and predetermined time intervals, dried on blotting paper and weighed to evaluate the change in weight via fluid uptake and hence swelling.
  • FIG. 11 depicts graphically the % swelling of all design formulations over a 24 hour test period.
  • % swelling was relatively high, this may be attributed to the presence of chitosan and hypromellose which are both hydrophilic polymers and tend to swell in aqueous medium.
  • Formulations 6, 7, 13, 14, 19 and 20 did not undergo swelling, they disintegrated on contact with the intestinal medium, and these formulations consisted of a reduced concentration of polymer and thus underwent dissolution faster.
  • Formulations with a higher concentration of polymer were shown to swell greatly and maintain their shape over the 24 hour test period, as compare to those with an intermediate ratio of polymer, which did undergo swelling with an alteration in their shape.
  • the tensile properties of the mucoadhesive layer of the multilayered device were determined employing the (TA.XT.plus Texture Analyser, Stable Microsystems®, Surrey, UK). The texture analyzer was calibrated before samples were tested to ensure accuracy. Samples of approximately 2x15mm strips, were mounted on the specially designed tensile testing brackets. Samples were fastened on to either end of the bracket, accurate measurements of the sample widths, thickness and length were recorded using a digital caliper. The parameters employed were tension, a pre-test and test speed of 0.5 and a post test speed of 5mm/s, and a force of 0.05N. Young's Modulus (E) of all 20 design formulations were determined by equation 14;
  • Lo is the length before tensile testing
  • Ao is the area of the sample before testing
  • AL is the change length after tensile testing.
  • F is the force exerted on an object under tension
  • NanoTensile® 5000 Hysitron Inc. Nanomechanical Test Instrument, Minneapolis, MN
  • NanoTensile (NT) system was calibrated prior to sample testing to ensure accurate analysis. Samples cut into approximately 0.55x 2.55 mm2 strips were mounted on the specially designed mounting brackets. Brackets were held together with a rigid cardboard frame, enabling ease of sample alignment, samples were attached to the brackets using double sided adhesive tape, thus keeping the sample in place during evaluation. Accurate measurements of the sample width, thickness and length were recorded utilizing a digital caliper. Thereafter, the upper sample bracket was attached to the upper sample holder of the NT head and the mass recorded.
  • the observed Young's Modulus values were relatively low indicating that the film demonstrated good elasticity.
  • the Youngs Modulus values for the mucus cleaving layer were low and thus indicate higher elasticity. This ideal characteristics for the multilayered device and thus is satisfactory.
  • Mucoadhesive properties of the mucus cleaving layer were evaluated to determine the ability to adhere to the intestinal lining, to allow for sufficient retention for mucus cleaving to occur. Mucoadhesion results for the mucus cleaving layer via mucin cleavage, yielding the average percentage crosslinking values over 6 hours of the mucus solution was 98%. This shows that the mucus cleaving layer possesses sufficient mucoadhesive strength so as to adhere to the intestinal wall for an appropriate period to allow for satisfactory mucus cleaving to occur. The incorporation of N-acetyl-cysteine displays a significant increase in mucoadhesion.

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Abstract

L'invention concerne une forme galénique pharmaceutique orale qui comporte une première couche de polymères réticulés poreux comportant un polysaccharide, de l'oxyde de polyéthylène (PEO) et/ou du polyéthylène glycol ou un dérivé de polyéthylène glycol, un agent de réticulation et un premier principe pharmaceutique actif (API), la première couche fournissant une libération uniforme du premier API lors de l'administration orale de la forme galénique. En outre, la forme galénique comporte de préférence une seconde couche, la seconde couche comportant une pluralité de dispositifs multicouches incorporés dans un support, la seconde couche fournissant la libération pulsatile d'un second principe pharmaceutiquement actif (API) lors de l'administration orale de la forme galénique.
PCT/IB2015/054270 2014-06-05 2015-06-05 Forme galénique orale de comprimé à deux couches pour la libération de divers médicaments Ceased WO2015186108A1 (fr)

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WO2019126215A1 (fr) * 2017-12-18 2019-06-27 Tris Pharma, Inc. Compositions pharmaceutiques de ghb comprenant un système de formation de réseau polymère interpénétrant flottant
US11337919B2 (en) 2017-12-18 2022-05-24 Tris Pharma, Inc. Modified release drug powder composition comprising gastro-retentive RAFT forming systems having trigger pulse drug release
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