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WO1994028881A1 - Formulation de retention a liberation retardee pour adsorbant d'acides biliaires - Google Patents

Formulation de retention a liberation retardee pour adsorbant d'acides biliaires Download PDF

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Publication number
WO1994028881A1
WO1994028881A1 PCT/US1994/006550 US9406550W WO9428881A1 WO 1994028881 A1 WO1994028881 A1 WO 1994028881A1 US 9406550 W US9406550 W US 9406550W WO 9428881 A1 WO9428881 A1 WO 9428881A1
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WO
WIPO (PCT)
Prior art keywords
vehicle
resin
layer
bile acid
selected region
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1994/006550
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English (en)
Inventor
Thomas W. Mix
Martin C. Corey
Terence C. Mcdonald
Liem T. Vu
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Merix Corp
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Merix Corp
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Filing date
Publication date
Application filed by Merix Corp filed Critical Merix Corp
Publication of WO1994028881A1 publication Critical patent/WO1994028881A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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

Definitions

  • This invention relates to a composition for complexing bile acids and eliminating them from the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • FIG. 1 illustrates schematically a human small intestine, detailing the pyloric canal 1 which is separated from the duodenum 2 by the pyloric valve; jejunum 3; ileum 4; ileocecal valve 5; and common bile duct 6, as well as the approximate regions of fatty acid (FA) and bile acid (BA) absorption.
  • Fatty acids, as well as monoglycerides and cholesterol, are present in the proximal portions of the small bowel, i.e., the duodenum and jejunum. They are solubilized in micelles and transported by bile acids to the intestinal enterocytes for absorption.
  • the fats are assembled into emulsion particles (chylomicrons) and delivered into the lymphatics.
  • chylomicrons emulsion particles
  • the bile acids themselves are not immediately absorbed to a large extent in the upper small intestine, but rather remain in the chyme to repeat their micellization and transport functions.
  • the bile acids are absorbed principally from the distal ileum via active transport.
  • Bile acid adsorbing resins such as cholestyramine
  • anionic exchange resins that adsorb bile acids onto their surfaces.
  • these resins When introduced into the gastrointestinal tract, these resins combine with bile acids to form an insoluble complex that is excreted with the feces.
  • the concentration of bile acids returning to the liver in the enterohepatic circulation is therefore lowered by preventing their reabsorption through the intestinal wall. This causes a greater demand for new bile acid synthesis, which utilizes low-density lipoprotein (LDL) as the preferred substrate.
  • LDL low-density lipoprotein
  • Cholestyramine is typically administered to patients in the form of a powder, or in the form of an edible bar.
  • CHOLYBARTM Parke-Davis, Morris Plains NJ
  • QUESTRANTM or QUESTRAN LIGHTTM is cholestyramine provided as an anhydrous powder (Bristol Laboratories, Princeton NJ) to be consumed dispersed in an aqueous beverage.
  • QUESTRANTM OR QUESTRAN LIGHTTM contain the inactive ingredients acacia, citric acid, coloring, flavor, polysorbate 80, propylene glycol alginate, colloidal silicon dioxide, xanthan gum, and a sweetener, such as sucrose or aspartame (Physicians Desk Reference, 46th ed. 1992. Medical Economics Co. Montvale NJ. pp. 710-711,1705).
  • Bile acids can also be removed from the gastrointestinal tract by being encapsulated by a clathrating compound such as beta-cyclodextrin (Riottot et al. Lipids 28:181-186, 1993; hereby incorporated by reference) or by its short chain acyl derivatives (De Caprio et al., J. of Lipid Research 33:441-443, 1992).
  • a clathrating compound such as beta-cyclodextrin (Riottot et al. Lipids 28:181-186, 1993; hereby incorporated by reference) or by its short chain acyl derivatives (De Caprio et al., J. of Lipid Research 33:441-443, 1992).
  • this invention features a delivery vehicle for a bile acid adsorbing resin that is designed to increase the efficiency by which the resin binds and retains bile acids from the intestinal chyme, thereby facilitating fecal elimination of bile acids.
  • the vehicle contains, in addition to the resin itself, either 1) a material to delay the exposure of the resin until the resin has entered a selected portion of the gastrointestinal tract, the material being either a pH- sensitive material or a timed release material or these two materials used jointly; or 2) a mechanism to prevent resin-bound bile acids from desorbing from the resin and being actively transported back across the intestinal wall in the distal region; or 3) these mechanisms in combination.
  • a “delayed release mechanism” is a mechanism for controlling the exposure of the resin, i.e., a mechanism that controls when the resin is initially exposed to, and when it will be sealed off from further contact with, the intestinal chyme.
  • a “delayed release material,” as used herein, is a material that is functionally relied on to facilitate such a mechanism, e.g., one that facilitates retarded delivery of the resin.
  • the invention generally features an orally-administered vehicle for delivering a bile acid adsorbing resin to a selected internal region of the body to adsorb bile acids present in that region.
  • the vehicle includes a layer of material that surrounds the resin, the material delaying the exposure of the resin within the body until the vehicle has entered, or is proximate to, the selected region.
  • the selected region is the region where the vehicle is to be exposed to the contents of the gastrointestinal tract, e.g., the small intestine, more preferably the region distal to the duodenum and proximal jejunum of the small intestine, most preferably the region of the intestine distal to the bulk of fatty acid absorption, but proximal to the bulk of bile acid absorption.
  • the gastrointestinal tract e.g., the small intestine
  • the region distal to the duodenum and proximal jejunum of the small intestine most preferably the region of the intestine distal to the bulk of fatty acid absorption, but proximal to the bulk of bile acid absorption.
  • the material includes an opening that permits exposure of the resin when the vehicle has entered, or is proximate to, a selected region of the body in which bile acids are present, and a mechanism for closing the opening when the vehicle has passed the selected region.
  • the material includes one or more openings, e.g., two, three, or four openings.
  • the term "resin” encompasses an anionic exchange resin, or a clathrating compound.
  • anionic exchange resins useful herein include cholestyramine, colestipol, or MCI-196, a methylimidazoline-epichlorohydrin derived resin.
  • a clathrating compound such as a cyclic sugar (e.g., beta- cyclodextrin) , has a hydrophilic exterior surface and a hydrophobic interior inner surface, the latter encapsulating bile acids and cholesterol.
  • the resin is in the form of small particles or beads. Alternatively, the resin can be encapsulated within a membrane to form a larger aggregate within the vehicle.
  • the resin can either adsorb (e.g., as in ion exchange adsorption) or absorb (e.g., as would happen with a clathrating compound) the bile acids to be useful in a vehicle of the invention.
  • a study of the pH profile of the gastrointestinal tract has provided pH profiles and transit times for the gastrointestinal tract of normal ambulant human subjects. Seventy-two individuals (51 male and 21 female, ranging in age from 20 to 83 years old) participated in the program. The study showed that the average pH of the proximal jejunum (see Fig. 1) in the small intestine for 55 individuals was 6.6 ⁇ 0.5, meaning that, for two thirds of the individuals, the pH for the first hour of transit varied between 6.1 and 7.1. In contrast, the mid small bowel, i.e., the mid jejunum, had a mean pH of 7.4 ⁇ 0.4, appreciably higher than the mean for the duodenum and proximal jejunum (Evans et al.
  • the layer of delayed release material is a pH-sensitive material
  • the material is relatively insoluble at pH levels below that range, and relatively soluble at pH levels above that range, so that the pH- sensitive material dissolves, decomposes, or breaks apart to expose the resin to bile acid when the vehicle reaches the selected region.
  • the selected region is the distal small intestine
  • the material is relatively insoluble at a pH equal to or below 6.6
  • the material is relatively soluble or breaks apart at a pH equal to or above 6.6, e.g., 6.6., 6.8, 7.0, 7.2, 7.4, 7.6, or 7.8.
  • the delayed release material can further include the quality of dissolving in the body over a predetermined time interval so as to further ensure the non-exposure of the resin until the vehicle reaches the selected region.
  • the timed release material is an intervening layer between the resin and the pH- sensitive material.
  • the pH-sensitive material would be formulated to be relatively insoluble at a pH equal to or below 6.0, and the material is relatively soluble at a pH equal to or above 6.0.
  • the timed release layer would expose the timed release layer more proximally in the intestine than a pH-sensitive material which is relatively insoluble at a pH equal to or below 6.6, and the material is relatively soluble or breaks apart at a pH equal to or above 6.6, but the timed release layer would delay resin exposure until the vehicle is further down the intestine.
  • the delayed release material is a timed release material
  • the material dissolves in the body after a predetermined time interval in the gastrointestinal tract, or has a controlled permeability, allowing water to pass through it at a specific rate. Effectively, the timed release material, after it has been exposed to the content of the gastrointestinal tract, delays contact of the resin with bile acids for a selected time interval following that exposure, independent of gastrointestinal pH.
  • the predetermined time interval can be two hours to eight hours in total, or one hour to three hours after the material has passed the pyloric valve.
  • the timed release material can be a hydrophilic (including a cellulosic) gel.
  • the vehicle further comprises a void between the resin and the layer of material, the void being in the form of a continuous void, or of void pockets within the material or within the resin. If the resin swells, e.g., due to permeation of water through the coating, the void will allow room for the resin to swell within the layer during transit of the vehicle through the body, thereby minimizing the risk that the resin will burst through the material of the vehicle. This avoids premature exposure of the resin to the gastrointestinal contents.
  • the vehicle includes more than one type of delayed release material.
  • the vehicle includes a first layer of pH-sensitive material, wherein a first selected region of the body has a pH within a predetermined pH range, the layer of pH-sensitive material being relatively insoluble at pH levels below the first selected internal range and relatively soluble at pH levels within the first selected internal range, and a second layer of timed release material, the timed release material dissolving in the body over a predetermined time interval, thereby to dissolve and expose the resin to the bile acids when the vehicle reaches the second selected region in which bile acid adsorption is to take place.
  • This embodiment is particularly useful when it is desired to increase the precision of delivery of the region to the second selected region.
  • the pH-sensitive material targets the resin generally to the duodenum, and then the timed release material targets the resin to a more distal region within the small bowel.
  • the timed release material is an intervening layer between the resin and the pH-sensitive material; the layer of timed release material is spaced from the resin to allow room for the resin to swell within the layer during transit of the vehicle through the body.
  • a “vehicle” as used herein, is a medium in which a medicinally active agent is administered to a mammal, e.g. , a human patient.
  • the vehicle can be in the form of a tablet, i.e., a small mass of material, e.g., in the shape of a disk or a slab; a pill, i.e., a small rounded mass to be swallowed whole; or a capsule, i.e., a shell and its contents.
  • the resin within any of these types of vehicles can further be contained within a membrane, e.g., a porous membrane. The membrane is intended to prevent dispersal of the resin particles once the overlying materials have become solubilized.
  • the invention features an orally administered vehicle for preventing the desorption of bile acid from a bile acid-adsorbing resin.
  • the vehicle includes a layer of material, e.g., an impermeable material, preferably a material impermeable to anions only after activation, e.g., bile acids or chloride ions, that surrounds the resin.
  • the impermeable material includes an opening that permits exposure of the resin when the vehicle is proximate to or has entered a selected region of the body in which bile acid is present, and a mechanism for closing the opening when the vehicle has passed the selected region.
  • the resin is further enclosed in a porous, i.e., permeable, membrane.
  • a vehicle in an "open configuration”, as used herein, has openings through which bile acids diffuse.
  • the openings In a vehicle in a “closed configuration", as used herein, the openings have been closed, sealed, or blocked off so that bile acids can not diffuse into or out of the vehicle.
  • the mechanism includes a timed release material that is in or around the opening, which initially keeps the opening open to allow gastrointestinal material to pass through it and, after a specified time, swells when exposed to water to close and block the opening when the vehicle has passed the selected region.
  • the timed release material initially blocks the opening, the material dissolving or decomposing when exposed to water to expose the opening.
  • the timed release material is encapsulated in a cylinder, the cylinder expanding to close the opening.
  • the timed release material is, for example, hydrophilic (e.g., cellulosic) .
  • a flap is attached to the opening and covers the opening when, or after, the vehicle has passed the selected region and entered the region where activated transport of bile acids across the gastrointestinal wall is taking place.
  • the flap can be covered with a lubricous coating.
  • the flap is initially folded with its center portion curled away from the vehicle opening to leave free access for bile acids entering the opening to reach the resin.
  • the mechanism for closing the flap includes a timed release material located on the inside of the curl of the flap that swells at a predetermined time interval to push the flap closed.
  • the timed release material is a sodium bicarbonate mixture, e.g., Alka-SeltzerTM, that effuses carbon dioxide when in contact with water, or is a water swellable material, e.g., a cellulosic material.
  • a sodium bicarbonate mixture e.g., Alka-SeltzerTM
  • a water swellable material e.g., a cellulosic material.
  • the vehicle includes: 1) a first layer of pH-sensitive material, and a second layer of bile acid impermeable material incorporating one or more closable openings; 2) a first layer of timed release material, and a second layer of bile acid impermeable material incorporating one or more closable openings; or 3) a first layer of pH-sensitive material, a second layer of timed release material, and a third layer of bile acid impermeable material incorporating one or more closable openings.
  • Different combinations of delayed release materials can effect the optimal pH at which the pH- sensitive material is soluble or insoluble.
  • the pH-sensitive material is relatively soluble at a pH equal to or above 6.6, as stated above, for release of the resin.
  • the pH-sensitive material is solely relied on to prevent exposure of the resin until it reaches the mid- jejunum.
  • the pH-sensitive material can be relatively soluble at a pH below 7.0, e.g., 6.5, or 6.0, because the timed release material extends the period of delay beyond the point at which the pH-sensitive material becomes soluble.
  • the pH-sensitive material can be at a pH of 7.2 for closure of the holes in the polymeric film.
  • the main criterion is that the pH sensitive material is insoluble at a pH below that of the desired selected region, e.g., the stomach and proximal small intestine, but soluble within the desired selected region, e.g., the distal small intestine, of a mammal, e.g. a human.
  • the pH at which the resin is exposed is sufficiently lower than the pH at which the openings in the polymeric film are closed to give the resin adequate time and exposure to adsorb bile acids through the film openings.
  • the invention features an orally administered vehicle for impeding, i.e., decreasing or preventing, the desorption of bile acid from a bile acid adsorbing resin.
  • the vehicle includes the bile adsorbing resin, a layer of bile acid impermeable material, e.g., a polymeric film, spaced from the resin to provide an opening that permits exposure of the resin to the bile acid when the vehicle is proximate to a selected region of the body in which bile acids are present, and a mechanism for closing the opening with a layer of impermeable material when the vehicle has passed the selected region.
  • the mechanism includes an agent, e.g., a water or intestinal fluid swellable agent, which is initiated by exposure to fluid in the body for pressing the layer of impermeable material against the resin, thereby to close the opening.
  • agent e.g., a water or intestinal fluid swellable agent
  • initiated is meant that the water causes the agent to begin swelling, thereby triggering the mechanism to close the opening.
  • the vehicle further includes a delayed release material for shielding the agent from the fluid until the vehicle has passed the selected region and entered another region of the body.
  • the delayed release material is a pH-sensitive material selected to dissolve when exposed to pH levels that exist in another region of the body, i.e., further down the intestinal tract than the selected region, thereby to expose the agent to the fluid.
  • the vehicle further includes a first permeable membrane at least a portion of which is spaced by the agent from the layer of impermeable material.
  • the layer of impermeable material includes a second section of permeable membrane bonded to the impermeable material, the second section being attached to a region of the first permeable membrane so as to support the layer of impermeable material and provide the spacing between the layer of impermeable material and the resin.
  • the vehicle can further optionally include a water soluble polymer coating between the outer permeable membrane and the pH- sensitive material.
  • the vehicle can also further include a water soluble spacer disposed in the opening to maintain the spacing until the vehicle has passed the selected region.
  • the vehicle further includes a layer of material delaying the exposure of the resin to the bile acids until the vehicle is proximate to the selected region.
  • the vehicle further includes a water soluble spacer between the resin and the layer of impermeable material to define the opening and to maintain the spacing until the vehicle has passed the selected region.
  • the water soluble spacer is coated with a delayed release material, i.e., a pH-sensitive material, for shielding the agent from the fluid until the vehicle has passed the selected region.
  • the delayed release material is a pH-sensitive material selected to dissolve when exposed to pH levels that exist in the another region of the body, thereby to expose the agent to the fluid.
  • the mechanism includes a water swellable agent disposed between the permeable membrane and the layer of impermeable material, and the water soluble spacer dissolving to press the impermeable material onto the resin when the vehicle has passed the selected region.
  • the vehicle further includes a layer of material delaying the exposure of the resin to the bile acids until the vehicle is proximate to the selected region.
  • the invention also features a method of decreasing the level of bile acid in the gastrointestinal tract of a mammal, e.g., a human, the method involving administering any of the various vehicles of the invention to the patient.
  • the method can further include dietary therapy, and is preferably used to treat ailments that are related to retention in the blood of bile acids, triglycerides, or cholesterol, including, but not limited to, hypercholesteremia, hypertriglyceridemia, pruritus, or some forms of arteriosclerosis, e.g., atherosclerosis.
  • the method can also be used preventively, e.g., to prevent coronary heart disease.
  • Fig. 1 shows a schematic of regions of a human small intestine.
  • Fig. 2 illustrates a vehicle in which resin is coated with a pH-sensitive material.
  • Fig. 3 illustrates a vehicle in which resin is coated with a timed release material with a void between the resin and timed release material.
  • Fig. 4 illustrates a vehicle in which resin is enclosed by a void, a timed release material, and a pH-sensitive material.
  • Fig. 5 shows resin enclosed by a capsule of delayed release material.
  • Fig. 6 shows resin covered with a void and delayed release material, this in turn enclosed by an outer shell.
  • Fig. 7 shows a vehicle in which resin is covered with a permeable membrane which is in turn covered with a polymeric film, the polymeric film being permeated with openings.
  • Figs. 8A and 8B show resin enclosed in a permeable membrane that is in turn covered with a polymeric film containing flap-covered openings.
  • Figs. 9A and 9B show a tablet with resin on either side of a central swellable material, all enclosed by a permeable membrane and polymeric film, the polymeric film including openings.
  • Figs. 10A and 10B show a vehicle in which a water- swellable material expands to close off a lengthwise opening in the polymeric film, thereby blocking the diffusion of fluid through the periphery of the vehicle.
  • the fluid path (shown by an arrow) is directed first through the central portion and then through the lateral portion of the vehicle.
  • Figs. 11A and 11B show a vehicle as in Figs. 10A and 10B with the exception that the fluid flows first through the lateral portion of the vehicle, and then through the center of the vehicle.
  • Figs. 12A and 12B show a vehicle with cylinders containing water swellable material in layers above and below the resin.
  • Figs. 13A and 13B show a vehicle with cylinders that, when expanded, pull a permeable membrane sideways in order to convert an open configuration (A) to a
  • Figs. 14A and 14B show a vehicle as in Figs. 13A and 13B, but with smaller strips of permeable membrane.
  • Fig. 15 illustrates a process for making the vehicle of Example 7 and Figs. 8A and 8B.
  • Figs. 16A and 16B show a vehicle with heat seals on the sides that close the end walls of the vehicle, leaving the side-walls of the vehicle open to intestinal chyme in the open configuration (A) , which is converted to the closed configuration (B) when a water soluble material dissolves, and a water swellable agent compresses an impermeable membrane against the resin.
  • Figs. 17A, 17B, 17C, and 17D show a vehicle in which an impermeable polymeric film is held up by attaching it the outer permeable membrane, creating an opening through which intestinal fluid can flow (A: center section; B: polymeric film with attached permeable membrane before assembly; C: end section; D: side view) .
  • Anionic exchange resins are highly efficient at adsorbing bile acids from simulated chyme in vitro, but are an order of magnitude less efficient at binding and eliminating bile acids in vivo .
  • the second reason is that bile acid retention by the resin is reduced in the distal ileum, where active reabsorption of bile acids from the ileum back into the blood stream naturally takes place, and in the colon, where deconjugation and dissociation from the resin may occur.
  • bile acid bonded to the resin is displaced by other anions present in the gastrointestinal tract (e.g., chloride anions) and is transported across the gastrointestinal wall, which is another major factor causing the relatively poor in vivo efficiency of bile acid adsorbing resins.
  • the invention described herein provides two sets of mechanisms for enhancing the in vivo efficiency of bile acid adsorbents.
  • the first set of mechanisms delays the exposure of a bile acid resin for a time sufficient to allow it to pass beyond the region of high fatty acid concentration into the region of the small intestine where fatty acid concentrations are greatly reduced.
  • These mechanisms are embodied in an orally-administered vehicle that includes a delayed release material(s), e.g., either or both of a pH-sensitive material or a timed release material, designed to delay the exposure of the resin until it passes through the duodenum into the jejunum.
  • the embodiments of a vehicle of the invention are designed to allow the binding sites of the resin to remain relatively unoccluded by fatty acid micelles, and thus available to bile acids.
  • the invention also provides a set of mechanisms for sealing off resin from further exposure to the intestinal chyme after bile acid adsorption, but before significant desorption of the bile acids from the resin can occur where active transport of bile acids across the intestinal wall is present.
  • the vehicle possesses openings that remain open when the resin is adsorbing bile acids, but that close when the resin is in the region of active bile acid reabsorption. This occurs primarily in the distal region of the small intestine
  • Closing of the vehicle openings also prevents desorption of bile acids from the resin and passage of them through the gastrointestinal tract, including in the colon.
  • Fig. 2 shows one example of a vehicle for the delayed exposure of bile acid resin to the intestinal environment according to the invention.
  • the vehicle shown is intended for oral administration.
  • a resin bead 7 is covered with a pH-sensitive material 8.
  • a first mechanism for the delayed exposure of the resin is accomplished by overlaying the resin with a material 8 that does not dissolve until a sufficiently high pH is reached.
  • the pH-sensitive material 8 protects the resin from premature exposure in the highly acidic stomach environment, as well as in the higher pH of the proximal bowel. The pH-sensitive material thereby delays exposure of the resin until it has migrated beyond the point where most fatty acid dispersions have been absorbed by the gut.
  • the total volume within the vehicle is as small as 0.04 to 0.07 cm 3 , corresponding to a particle with an inner diameter of 0.2-0.3 cm.
  • the vehicle may also be a small diameter cylinder.
  • the pH-sensitive material 8 is preferably .02-.05 mm thick, which would be sufficient to protect the encapsulated resin bead 7 from contacting the contents of the gastrointestinal tract until the vehicle has migrated beyond the duodenum.
  • the thickness of the pH-sensitive material 8 is independent of the size of the resin bead 7.
  • the fraction of the vehicle which is the pH-sensitive material 8 increases as the size of the resin bead 7 decreases.
  • the pH-sensitive material 8 is of the order of 10% of the volume within the vehicle, which corresponds to the order of 25% of the resin weight.
  • the vehicles are preferably small to ensure that, once exposed, the contained resin 7 comes into raakedd contact with the gastrointestinal contents. This in turn ensures good contact of the bile acids in the chyme with the resin binding sites.
  • the pH-sensitive material 8 is insoluble at the pH environment of the stomach.
  • the pH-sensitive material is also insoluble in the proximal small intestine (duodenum 2) , but should be soluble in the proximal to mid-jejunum 3.
  • a resin bead 7, covered with pH-sensitive material 8, is delivered intact to the jejunum 3, where it is then exposed, and can initiate bile acid adsorption. This delays exposure of the resin 7 until after the vehicle has bypassed the proximal portion of the small bowel, where the greatest concentration of fatty acid dispersions are absorbed into the lymphatics.
  • a pH-sensitive material useful for any of the various vehicles of the invention is a material that is insoluble at the pH level of the stomach and proximal small intestine (duodenum 2) , but which is increasingly soluble, or tends to break apart, as the vehicle progresses toward the elevated pH levels of the jejunum 3.
  • suitable materials are EUDRAGIT LTM, which dissolves above pH 6, and EUDRAGIT STM, which dissolves above pH 7 (Rohm Pharma, Rothstadt, FRG and their distributor, Rohm Tech. Inc., Maiden, MA) . Below these pH values the EUDRAGIT materials are insoluble, and impermeable to water or gastric juice (pH «l.5-2.5) (EUDRAGIT brochures, hereby incorporated by reference) .
  • the pH-sensitive material dissolves at a pH of 6.0-7.0, inclusive, but most preferably dissolves at a pH closer to, or greater than, 7.0 or 7.2.
  • the EUDRAGIT LTM and STM preparations can be mixed together, the ratio of LTM to STM determining the pH at which the pH sensitive material becomes soluble, e.g., EUDRAGIT LTM and STM can be combined in a 2:1, 1:1, or 1:2 ratio, or any continuously varying ratio.
  • the pH at which various mixtures of EUDRAGIT LTM and STM become soluble has been previously titrated by the manufacturer ("EUDRAGIT L and S: Application in the Production of Pharmaceutical Preparations"; Rohm Pharma, Rothstadt, FRG and their distributor, Rohm Tech. Inc.
  • the surface of the resin bead 7 comprises anionic exchange sites that preferentially bind acidic molecular species.
  • suitable resins include cholestyramine (a styrene- divinylbenzene copolymer with quaternary ammonium groups to bind the anions; produced by Dow Chemical Co., and sold by Bristol-Myers) ; colestipol (a copolymer of diethylenetriamine and l-chloro-2,3-epoxypropane (hydrochloride); Upjohn Co.); or MCI-196 (a 2-methylimidazole-epichlorohydrin resin (Mitsubishi Kasei Corp.) (Toda et al.
  • a bile acid-adsorbing resin can also be a clathrating compound, e.g., a cyclic sugar (e.g., beta-cyclodextrin) , which has a hydrophilic exterior surface and a hydrophobic interior inner surface, the latter encapsulating both bile acids and cholesterol.
  • a clathrating compound e.g., a cyclic sugar (e.g., beta-cyclodextrin) , which has a hydrophilic exterior surface and a hydrophobic interior inner surface, the latter encapsulating both bile acids and cholesterol.
  • An alternative embodiment is to coat the resin with a timed release material selected for its ability to dissolve slowly, independent of pH, or which has a limited permeability, also independent of pH, in the largely aqueous environment of the gastrointestinal tract.
  • Fig. 3 shows an inner resin bead 9 covered with a timed release material 10.
  • Timed release materials are hydrophilic gels that either will first swell with water and then dissolve over time or are hydrophilic gels that transport water at a controlled rate.
  • a timed release material 10 may also be an insoluble coating which has a particular aqueous permeability. Water that penetrates the timed release material 10 and reaches the resin bead 9 will also cause the resin itself to swell.
  • the swelling resin bead 9 would cause a tight coating of timed release material 10 to crack, thus prematurely exposing the resin and terminating the timed release.
  • This problem is avoided by providing voids 11 around the resin to prevent the swelling resin from rupturing the coating.
  • the void 11 can be in the form of small void pockets interspersed within the resin itself, or can be in the form of discrete void pockets on the surface of the resin.
  • the resin may be placed in a capsule and the capsule coated with the timed release material. The capsule and voids inside the capsule will keep the resin from rupturing the coating.
  • the time release material covering the capsule may pass water at a controlled rate, which will dissolve the capsule over a specific time determined by the water permeability of the time release material.
  • Characteristics of a Timed Release Material If the timed release material is one which dissolves with time, it will be chosen for its ability to dissolve slowly enough in the gastrointestinal tract so as not to expose the resin until it reaches the proximal to mid intestine.
  • the timed release materials of this nature that are proposed for use in any of the various vehicles of the invention are:
  • polyanhydrides (Domb, et al., Macromolecules 2_2:3200-3204, 1989; hereby incorporated by reference).
  • the polyanhydrides degrade by hydrolysis into nontoxic acid derivatives and show favorable biocompatibility in tissue response and toxicological studies.
  • Aliphatic polyanhydrides degrade in a few days but can be mixed with a faster eroding material such as a copolymer of acrylic acid and methacrylic acid.
  • the different types of polyanhydrides and other water-soluble polymers can be combined in differing proportions to allow a variation in the time scale of degradation.
  • Polyanhydrides undergo surface erosion in aqueous media.
  • the timed release materials may also be insoluble materials which pass hydrophilic fluids, such as water, at a controlled rate.
  • examples of such materials are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the permeability of the copolymers of acrylic and methacrylic acid can be controlled by the ammonium group concentration as well as the copolymer composition.
  • EUDRAGIT RLTM is a water-insoluble but permeable film coating.
  • EUDRAGIT RSTM which has a lower content of quaternary ammonium groups than does RLTM, is water insoluble and relatively less permeable than EUDRAGIT RLTM.
  • RLTM and RSTM can be combined in continuously varying ratios to obtain the desired permeability
  • Timed release materials of this nature may be used to pass water at a controlled rate to dissolve a water soluble capsule covering the resin.
  • the resin may be encapsulated to ensure that the thin film of the delayed release material covering it will be patent (void free) and effective.
  • a capsule or capsule-like coating may be applied, again to ensure that the thin film of the second release material is patent, void-free and effective.
  • Potato starches, polysaccharides, and gelatin are examples of appropriate water-soluble capsule materials.
  • the vehicle of Fig. 4 combines the advantages of a pH-sensitive material and a timed release material in one orally-administered tablet.
  • Interior resin beads 12 are surrounded by a void 13 which is in turn surrounded by a layer of timed-release material 14, which is in turn surrounded by a layer of pH-sensitive material 15.
  • the pH-sensitive material 15 is shown to be external to the timed release material 14, other arrangements of the materials are embodied within the scope of the invention.
  • the timed release material 14 can be external to or surrounding the pH-sensitive material 15; or the pH-sensitive material 15 and the timed release material 14 can be combined as a single substance.
  • the pH-sensitive material 15 should be soluble in the duodenum, where there is a sudden increase in pH after the vehicle traverses the pyloric valve to enter the duodenum.
  • the timed release material 14 covering the resin bead 12 further delays exposure of the resin to the gastrointestinal contents until the vehicle reaches the proximal to mid-jejunum.
  • a pH-sensitive material suitable for use in this example would be insoluble at the pH level of the stomach, but soluble at the pH level of the duodenum.
  • An example of such a resin is EUDRAGIT LTM, which dissolves at a pH above 6.0.
  • Fig. 5 shows a capsule for oral administration.
  • the outer shell 16 comprises a delayed release material, the delayed release material being either a timed release material or a pH-sensitive material.
  • the interior of the capsule contains multiple resin beads 17.
  • the outer shell 16 naturally encloses enough void between the resin beads 17 to allow room for the resin beads 17 to swell.
  • bile acid resins as currently administered is that they are fine particles dispersed in the stomach, and, as a result, are discharged with the liquid and finely divided solids of the stomach contents.
  • the vehicle of Fig. 5 has the advantage of incorporating the resin into a larger capsule, or of incorporating the resin into a range of different size capsules. Since larger particles are held in the stomach for a longer period of time (Meyer, in Physiology of the Gastrointestinal Tract. Vol. 1, 2nd ed. , Chap. 9, Raven Press, 1987) , the vehicle provided herein makes it possible to accomplish a more general distribution of resin within the chyme.
  • the outer shell 18 comprises a delayed release material (not shown) , the delayed release material again being either the timed release material or the pH-sensitive material.
  • a second delayed release material 19 covers each individual resin bead 20, with intervening void 21.
  • the shell can comprise one material, either the pH-sensitive material or the timed release material, while the resin bead itself can be covered with a second material.
  • the outer shell 18 is preferably solid, but can also be a gel.
  • the outer shell 18 can comprise both delayed release materials, e.g., in layers, or as another alternative embodiment, both materials can coat the bead while the outer shell 18 is comprised of an extraneous material, e.g., gelatin or a polysaccharide.
  • the vehicle it is desirable for the vehicle to include a mechanism for automatically sealing the resin after it has adsorbed bile acids so that the bile acids do not desorb from the resin, both where active transport of bile acids through the gastrointestinal tract occurs in the distal ileum and also in the colon, causing bile acids to re-enter the enterohepatic circulation.
  • the ileal bile acid active transport receptors have a high capacity, but a very low affinity for bile acid adsorption (Hoffman, Bile Acids: 1993 and the Future, Abstract, March 11-14, 1993).
  • Embodiments of vehicles designed to accomplish the sealing of the resin in the distal ileum and colon are shown in Figures 7-14, and described in the following examples. Should a composition of matter be produced which has a high affinity for the bile acid active transport receptors in the distal ileum, this composition could be included in a delayed release material and released once bile acid adsorption on the resin sites has been completed.
  • any of the following embodiments can include one or more of the mechanisms described above for delaying the release, or the exposure, of the resin to the intestinal tract.
  • any of the following vehicles can optionally further include an outermost layer comprising a delayed release material, either a pH-sensitive material that dissolves in the proximal portion of the small intestine, but distal to the region of high fatty acid concentration, or a timed release material chosen to dissolve in this same proximal portion of the small intestine. Once this outer-most layer dissolves, the resin is exposed to the gastrointestinal contents.
  • resin beads 26 are surrounded with a permeable membrane 22 that keeps the resin intact inside the vehicle.
  • an impermeable polymeric film 24 External to the permeable membrane 22 is an impermeable polymeric film 24.
  • Embedded in the polymeric film 24 are one or more openings 23 (e.g., slits) which serve as portals for the bile acid to enter the vehicle and gain access to the resin bead 26.
  • Each opening 23 is surrounded by one or more delayed release materials 25.
  • a delayed release material can perform either of two purposes. In the first purpose, the delayed release material 25 is a pH-sensitive material covering the openings, thereby initially preventing access of fatty acids to the resin.
  • the delayed release material 25 eventually degrades because of the increase in pH during passage down the intestinal tract thereby exposing the resin to bile acids.
  • the delayed release material 25 is a timed release material configured so as to initially hold the slits open and exposed to bile acids. Subsequently, it dissolves or swells so that, in the appropriate distal portion of the small bowel, the opening 23 in the polymeric film 24 is thereby closed. Closure of the opening 23 eliminates or at least greatly decreases mass transfer of bile acid between the resin bead 26 and the intestinal wall.
  • a viscous solution 53 enclosed by a delayed release coating in the space between the permeable membrane 22 and the polymeric film 24, is released between the polymeric film 24 and the resin bead 26.
  • the viscous solution 53 decreases the convection and eddy diffusion of molecules within the vehicle. This further ensures low mass transfer of bile acid after the closure of the openings 23.
  • the viscous solution 53 is, e.g., pectin, carrageenan, or gum.
  • Characteristics of the permeable membrane 22 should be one which meets the following criteria: a) it is fine enough that it will retain the resin bead 26; b) it is porous enough that it will pose minimal interference with bile acid diffusion across it; c) it is biocompatible; d) it is stable under the intended use; and e) it is hydrophilic. Cellulosic or polyester nettings or cellulosic acetate membranes are examples of appropriate materials for the permeable membrane 22.
  • Characteristics of the Polymeric Film Materials suitable for the polymeric film 24 should be flexible, biocompatible, and essentially impermeable to water and to diffusion of chloride and other anions normally present in the gastrointestinal tract and bile acid ions. An example would be a lacto glycolic acids, polycaprolactams, or a polyurethane film (JPS Elastomerics Corp. , 395 Pleasant Street, Northampton, MA) .
  • Figs. 8A and 8B provide a layered vehicle in which resin beads 29 are surrounded with a permeable membrane layer 27, which is fine enough to retain the particulate matter of the resin bead 29, but porous enough to allow free diffusion of bile acids through the membrane so as to contact the resin.
  • the permeable membrane layer 27 is in turn covered with a polymeric film 28, which, as in Example 6, precludes or substantially reduces the diffusion of chloride ion or bile acids.
  • Fig. 8A shows the open configuration of the vehicle, Fig. 8B the closed configuration.
  • the polymeric film 28 has at least two central openings 33 on either side of the vehicle.
  • one opening 33 is shown, the other opening is on the opposing side of the vehicle (not shown) .
  • the openings 33 provide the intestinal contents with free access to the resin beads 29.
  • the openings 33 are optionally covered with additional permeable membrane 31.
  • the openings 33 in the polymeric film 28 each have at least one flap 30, but can also have two flaps 30, adjacent to them, each flap 30 also being composed of polymeric film.
  • the flaps 30 are curled under the sides of the polymeric film 28, and covered with a lubricous coating. When curled, the flaps enclose an agent 32 for pushing the flaps closed.
  • the agent 32 is either a water swellable polymer such as Anidall 1440 from Chemdal Corp (Palatine, IL 60067) or a water swellable material, e.g., a cellulosic sponge, or a bicarbonate reagent, such as an Alka-SeltzerTM mix.
  • Agent 32 is coated with a timed release material 52. When the timed release material 52 allows water to contact agent 32, the agent becomes wet, and the flaps 30 are pushed forward by the generated gas, or by the expanding foam, respectively. When pushed forward, the flaps 30 cover the opening 33 and seal the adsorbed bile acids within the vehicle (Fig. 8B) .
  • Method of Production The following method of manufacturing the vehicle of Example 7 and Figs. 8A and 8B is offered as an example of how to produce a vehicle of the invention. Other vehicles within the scope of this invention are produced in a similar manner.
  • An opening 33 in the outer polymeric film 28 is first cut.
  • a membrane 31 is then sealed over the holes in the outer polymeric film 28.
  • Flaps 30, in an uncurled configuration, are then placed under the polymeric film and the outer edges of the flaps 170 are sealed to the outer polymeric films 28.
  • the vehicle layers are then aligned with two outer polymeric films 28 covering two inner permeable membrane layers 27 and the outer edges are then sealed, leaving one edge, perpendicular to the flaps 30, open.
  • the flaps are slightly shorter than the sealed components and are not sealed in this operation.
  • Resin 29 is then loaded between the permeable membrane layers 27.
  • the flaps are then curled backwards and the swellable agent 32, previously coated with timed release material 52, is loaded into the flap enclosures.
  • the last side of the membrane is then sealed.
  • the sealed vehicle is then loaded into a water soluble capsule which is coated with a pH sensitive material which dissolves at pH 6, using a bottom coated Wurster fluid bed process (K. Lehmann and D. Dreher, "Coating of tablets and small particles with acrylic resins by fluid bed technology," In. J. Phar . Tech. Se Prod. Mfr. 2(4) 31-43 (1981); hereby incorporated by reference) .
  • Membrane roll 100 is cut in a slitting unit 101 to make membrane layer 102.
  • Polymeric film roll 110 is cut in a hole puncher unit 111 to make polymeric film layer 112 with openings 113.
  • Membrane layer 101 and polymeric film layer 112 are aligned and sealed along the outer edges in heat sealing unit 103 to form double layer 104.
  • Polymeric film roll 120 is cut in a hole puncher unit 121 to make polymeric film layer 122 with flaps 123 to later cover openings 113.
  • Membrane roll 114 is cut in a slitting unit 115 to from membrane layer 116.
  • Membrane layer 116 and polymeric film layer 122 are aligned and sealed in heat sealing unit 117 along only one edge 118 with the position of flaps 123 curled back, away from opening 119 to form double layer 125.
  • Double layer 104 and double layer 125 are aligned with openings 113 and openings 119 precisely on top of each other. Indexing guides are employed throughout the continuous process to ensure proper alignment.
  • the four layers 126 are then sealed together on 3 sides in heat sealing unit 127 to form one-half of completed vehicle 128a. One side 131 is not sealed.
  • Filling unit 130 then fills swellable agent 129 into area behind flaps in the compartment formed between layer 122 and flap 123.
  • Half vehicle 128a is then sealed by heat sealing unit 127a sealing the last opened side 131 giving a half vehicle with four sides sealed as in 128.
  • Two halves of vehicle 128 are aligned with seals 147 and openings 148 matching and sealed in heat sealing unit 140 to form complete vehicles 141. Only three sides are sealed leaving the one side 132 unsealed.
  • Filling unit 145 then fills compartment 133 of the vehicles 141 with adsorbing resin 144, the compartment 133 being created by the two halves of vehicles 141.
  • Heat sealing and trimming unit 150 then seal along side 132 and trim off excess sealing frays to form individual vehicles 160. Each vehicle is then loaded into a water soluble capsule 165 and coated with delayed release material 166, as described above.
  • EXAMPLE 8 EXAMPLE 8:
  • Figures 9A and 9B show a vehicle in the shape of, e.g., a tablet, in open and closed configurations, respectively.
  • the interior of the vehicle is surrounded with a permeable membrane 37.
  • Resin 35 occupies two sides of the interior.
  • the center of the interior contains a water-swellable material 34, e.g., guar gum, carrageenan, or Klucel (TM) (ICI, Wilmington, Delaware).
  • the remainder of the interior is empty space 39 (Fig. 9A, open configuration only) .
  • a polymeric film 38 e.g., polyurethane film, that is impermeable to bile acids or chloride ions.
  • the polymeric film 38 is interrupted on either or both sides by an opening 36.
  • the water swellable material 34 is dry and non-swollen and is covered by a pH sensitive material. Initially, the pH sensitive material keeps water from reaching the water- swellable material.
  • the opening 36 permits access of bile acids to the resin bead 35. This opening stays open long enough for bile acid adsorption by the resin to approach equilibrium conditions. Finally a sufficiently high pH is reached for the pH sensitive material to dissolve which enables water to reach the water-swellable material, causing it to expand, and closing the opening.
  • a polymeric film 39A covers the top and bottom of the water swellable material so that, when the water- swellable material presses against the permeable membrane 37, the resin is effectively sealed from fluid contact with the material outside the vehicle.
  • the water- swellable material 34 expands approximately 3-10 times, preferably 5 times, in size.
  • Fig. 10A and 10B includes four layers of material surrounding the resin beads 42, two layers on either side.
  • Fig. 10A shows a cutaway of the vehicle before swelling (the open configuration) ;
  • Fig. 10B shows a cutaway of the vehicle after swelling (closed swelling) .
  • a top layer and a bottom layer of polymeric film 43 are interrupted by sections of permeable membrane 44.
  • the inner layers of permeable membrane 45 are blocked off at the center by a section of polymeric film 40.
  • the polymeric film 40 and the timed release material 46 encapsulate a water-swellable material 47.
  • the pathway for fluid passage through the vehicle is shown by arrows 41.
  • the fluid chyme diffuses through the permeable membrane 44 and then diffuses through the second permeable membrane 45. Bile acids in the fluid adsorb to the resin 42.
  • the timed-release material 46 dissolves gradually during passage through the early ileum the water-swellable material 47 expands, pressing the polymeric film 40 against the top layer of permeable membrane 44, thereby closing off the fluid path 41 between the top permeable membrane 44 and the resin bead 42 (Fig. 10B) .
  • Figs. 11A and 11B shows an alternative to the embodiment shown in Figs. 10A and 10B.
  • the layers are reversed relative to the embodiment shown in Figs. 10A and 10B.
  • Water-swellable material 48 is encased by the top and bottom permeable membranes 49 on the outside, and by a smaller section of polymeric film 50 on the inside.
  • the strip of permeable membrane 49 opposite the strip of polymeric film 50 is coated with delayed release material 90.
  • the layers immediately enclosing the resin bead 51 are composed of polymeric film 50 interrupted in the center by a section of permeable membrane 53. The edges 91 of the vehicle are heat sealed.
  • fluid chyme diffuses through the permeable membrane 49, and then through the smaller section of permeable membrane 53 (see fluid path 54) .
  • Bile acids in the fluid bind to the resin bead 51.
  • the delayed release material 90 releases during passage down the early ileum, the water swellable material 48 expands, pressing the polymeric film 50 against the permeable membrane 53, thereby closing off the fluid path 54.
  • the layers include a top layer and a bottom layer of a polymeric film 55, with openings 56 cut out of the polymeric film 55.
  • the middle two layers are each composed of a permeable membrane 57, which encloses a resin bead(s) 58.
  • the intervening space between layers 55 and 57, both top and bottom, contains cylindrical tube(s) 59.
  • the sides of the tube(s) 59 on the exterior side of the vehicle are made of the same material as the polymeric film 55.
  • the sides of the tube(s) 59 on the interior side of the vehicle are made of permeable membrane, and coated with a timed release material.
  • the perforations of the permeable membrane of the interior side of tube(s) 59 permits water to enter the tube(s) 59.
  • the tube(s) 59 contain compressed water- swellable material 60. All edges are heat sealed.
  • the timed release material covering the cylindrical tube(s) 59 dissolves, allowing water to contact the water-swellable material 60 inside the tube(s) 59 so that the water swellable material 60 gradually expands. This causes the tubes 59 to swell up and block the openings 56, preventing intestinal fluid from reaching the resin bead 58.
  • EXAMPLE 12 The vehicle of Figs. 13A and 13B is constructed with four layers. Each layer is comprised of strips of polymeric film and permeable membrane joined in lengthwise seams. In the center of each layer the polymeric film 70 meets the permeable membrane 62 along a lengthwise seam. Along one outer side of the vehicle the polymeric film 70 is loosely configured with folds 61 of the flexible polymeric film. Along a lengthwise section of the other outer edge of the layer, the permeable membrane 62 is double thickness so as to form a cylinder 71. The outer side of the cylinder 71 is coated with a timed release material 63. Encapsulated within the cylinder 71 is a water-swellable material 64.
  • the folds 61 are optionally coated with timed release material as well (not shown) .
  • Each layer of the four layers 65-68 is configured in this manner.
  • the top layer 65 and bottom layer 68 are oriented so that the timed release material 63 is on the outer side of the vehicle, e.g., on the right-most side.
  • the inner layers 66 and 67 are oriented so that the coating of timed release material 63 faces toward the outer layers 65 and 68, and so that it is on the opposite side of the vehicle from the timed release material 63 of layers 65 and 68, i.e., so that the timed release material 63 is on the, e.g., left-most side of the vehicle.
  • Bile acid adsorbing resin bead(s) 69 are present between the inner layers, i.e., between layers 66 and 67. All corner and joining edges are heat sealed.
  • the intestinal fluid diffuses through the center of the vehicle to reach the resin 69 within. More specifically, the fluid travels through the central portion of the permeable membrane 62 of outer layers 65 and 68 (i.e., the portion of permeable membrane 62 not covered with timed release material) , then diffuses through the corresponding portion of the permeable membrane of inner layers 66 and 67, and finally contacts the resin bead(s) 69. Bile acid in the intestinal fluid binds to the resin bead(s) 69.
  • the open fluid path 72 through the open configuration of the vehicle (Fig. 13A) is shown by arrows.
  • the closed configuration of the vehicle is shown in Fig. 13B.
  • the timed release material 63 dissolves, exposing the water-swellable material 64 to the fluid.
  • the water-swellable material 64 expands, causing the cylinders 71 to expand, increasing the circumference of the cylinders 71.
  • the expanded circumference causes the permeable membrane 62, in total, to be pulled toward the cylinder-side of the vehicle, and the folds 61 in the polymeric film to become stretched.
  • Figs. 14A and 14B show the open and closed configurations, respectively, of an alternative embodiment of Figs. 13A and 13B.
  • Figs. 14A and 14B differ from Fig. 13A and 13B in the following ways: a) Although Figs. 14A and 14B show only the top two layers 73 and 74 of the vehicle, the vehicle includes four layers, as in Example 12; b) Instead of a central region where the permeable membranes of the layers are aligned, Figs. 14A and 14B show thinner lengthwise strips of permeable membrane 76. In the open configuration (Fig. 14A) the strips of permeable membrane 76 are aligned so that the fluid can diffuse through all layers to reach the resin bead(s) 78.
  • Figs. 16A and 16B two opposing sides of the vehicle, i.e., the end walls, are closed by heat seals 210.
  • This vehicle is designed to enhance the diffusion of bile acids onto the resin bead 200. It is also relatively easy to produce.
  • Fig. 16A The open configuration of the vehicle is shown in Fig. 16A.
  • Resin beads 200 are surrounded in the center of the vehicle by a permeable membrane 220.
  • spacers 230 On two sides of the permeable membrane 220 are spacers 230, which are coated with a layer of pH-sensitive material 235.
  • the spacers 230 are in turn encapsulated by an impermeable polymeric film 240, which is preferably a urethane film or a biodegradable impermeable film, both being easily heat sealable.
  • Spacers 230 define longitudinally extended openings between film 240 and resin beads 200.
  • On the outer side of the polymeric film 240 is a water swellable agent 250.
  • the agent 250 is enclosed by another layer of permeable membrane 260, which is in turn covered on the exterior surface by a layer of pH- sensitive material 270.
  • the permeable membrane 220, polymeric film 240, and permeable membrane 260 are attached by heat sealing the edges of the respective films and membranes to each other at the ends of the vehicle 210.
  • the heat seals 210 close the ends of the vehicle, so that the end walls of the vehicle are impermeable.
  • the pH-sensitive material 270 and the pH-sensitive material 235 are of the types described in Examples l and 2. They are preferably each of the same pH-sensitive material, but can also be different materials. Choosing materials of slightly different pH release points can be used to further focus the point at which the vehicle assumes the closed configuration shown in Fig. 16B.
  • the vehicles are preferably small, e.g., 1/8" x 1/8" in cross section. This permits the vehicles to pass through the pyloric valve without difficulty, and to avoid delay of the vehicle in pockets of the gastrointestinal tract such as the diverticula.
  • the thickness of the layer of resin bead 200 is approximately 500 micrometers.
  • the thicknesses of the layers of spacer 230 and agent 250 are each approximately 200 microns.
  • the entire vehicle can also be housed in a gel capsule, as described above.
  • the vehicle is ingested, and where enclosed in a gel capsule the vehicle is released from that gel capsule, in the stomach.
  • the vehicle is then transported through the pyloric valve into the small bowel.
  • the resin beads 200 are in contact with the intestinal chyme, which can freely diffuse across the spacers 230 along the length of the vehicle, and contact the resin bead 200 through the permeable membrane 220.
  • Bile acids bind to the resin beads 200, until the pH- sensitive materials 235 and 270 gradually dissolves.
  • the pH-sensitive materials 235 and 270 dissolve when the pH of the intestinal tract reaches the appropriate value
  • the resin bead 200 is any of the resins provided in Example 1.
  • the resin bead 200 can range from 75-150 microns in diameter.
  • the inner permeable membrane 220 which encloses the resin beads 200 is a hydrophilic membrane.
  • appropriate hydrophilic membranes include those provided in Example 6, as well as polyester or nylon filter materials, which have a 35 micron pore size (Spectrum Medical) . They are an appropriate support for the resin bead 200 that ranges from 75-150 microns.
  • the resin bead 200 can be of a smaller size, e.g., cholestyramine of a 5 micron bead size, placed between two permeable membranes 220 of two micron pore-sized nylon or polyester membrane sheets.
  • the resin bead 200 can also be placed between two permeable membranes 220 of one half micron-sized polyethylene or polypropylene membrane sheets (e.g., Celgard membranes made by Celanese, or KPF and EHF membranes made by Mitsubishi Rayon Co. Ltd.). Since these polyethylene and polypropylene sheets are hydrophobic, they are water-wet with an alcohol solution, which is then displaced with water and stored, water-wet, in a soluble outer capsule which is ready to be swallowed by the patient.
  • polyethylene or polypropylene membrane sheets e.g., Celgard membranes made by Celanese, or KPF and EHF membranes made by Mitsubishi Rayon Co. Ltd.
  • the diffusibility in each of the five micron sized resin bead 200 particles is of the order of 3.7 x IO -7 cm 2 /sec, whereas the diffusibility in the spaces between them will be of the order of 2 x 10 ⁇ 6 cm 2 /sec.
  • a smaller resin size leads to a more rapid approach to equilibrium between the adsorbed and the free bile acid in the intestinal chyme.
  • the resin beads 200 can be mixed with an aqueous solution of polyvinylpyrrolidone (PVP) , in a ratio of resin bead 200 to PVP of approximately 20:1 to 1:1, preferably 10:1 on a weight basis.
  • PVP polyvinylpyrrolidone
  • the resin bead 200, or resin bead 200/PVP mixture is deployed as a thin film, roughly 200 microns thick, on the permeable membrane 220 support.
  • a second identical permeable membrane 220 is placed over the layered resin bead 200 and first permeable membrane 220.
  • a sufficient fringe of permeable membrane 220 is left uncovered to permit the two permeable membranes 220 to be heat sealed at 210.
  • the four side edges of the two permeable membranes 220 are heat sealed.
  • PVP aids the adherence of the resin beads 200 on the membrane, and is subsequently removed by aqueous washing followed by drying.
  • the time for the center of the sheet to reach a concentration equal to 90% of the bulk bile acid concentration will be the square of the diffusion length, l d , divided by the diffusibility.
  • the diffusion time for a film of resin bead 200, e.g., a cholestyramine film with a 21 d thickness of 200 microns, will be 250 seconds.
  • the spacer 230 is prepared from a water soluble material.
  • the spacer 230 can be prepared in triangular shaped units from water soluble material.
  • the spacer units 230 are coated with pH-sensitive material 235 before inserting the spacers 230 into the vehicle.
  • the base of the triangle is preferably adjacent to the impermeable film 240.
  • the opposite peak of the triangular spacer 230 is preferably adjacent to the permeable membrane 220, because this configuration provides the greatest flow of chyme across the resin bead 200 surface, only minimally interfering with bile acid adsorption.
  • the pressure created by the layers of the vehicle is sufficient to prevent the spacers 230 from slipping out of the vehicle while it is in its open configuration.
  • Water soluble materials that are suitable for making the spacers 230 include, but are not limited to, polyvinylpyrrolidone (PVP) , methyl cellulose, or ethyl cellulose.
  • PVP polyvinylpyrrolidone
  • methyl cellulose methyl cellulose
  • ethyl cellulose ethyl cellulose.
  • One advantage of PVP is that it adheres to urethane, and thus can be applied to the polymeric film 240. In this case, the PVP should first be applied to the polymeric film 240, and then covered with the pH- sensitive material 235.
  • the spacers 230 can be applied to the vehicle using a screen printer to deposit a regular array of raised dots of the spacers 230, coated with pH-sensitive material 235.
  • the pH-sensitive material 235 can be any of the pH-sensitive materials provided in Example 1. Since the pH of the small bowel increases from the duodenum to the ileum, the pH-sensitive material 235 selected will be one which has a pH high enough to allow sufficient time for adsorption, but low enough to dissolve before the terminal ileum is reached.
  • Characteristics of the water swellable agents 250 The agent 250 is any of the water swellable polymers or water swellable materials provided in Example 7, e.g., Anidall polymers from Che dal. When agent 250 is contacted by the intestinal fluids, it swells. Agent 250 is prevented from expanding beyond the vehicle by the outer permeable membrane 260. This keeps the swelling inwardly directed.
  • Characteristics of the outer permeable membrane 260 Disposed over the exterior surface of one or both of the polymeric films 240 is an outer permeable membrane 260.
  • the outer permeable membrane 260 can be, but is not of necessity, composed of any of the materials used for the inner permeable membrane 220, and is attached along its entire circumference to the top of the polymeric film 240.
  • the outer permeable membrane 260 has a pore size smaller than the agents 250, and serves the purpose of containing them. After assembly of the vehicle, the outer permeable membrane 260 is selectively coated with a coating of pH-sensitive material 270 to protect the agent 250, being water swellable, from contact with the intestinal fluids until the pH-sensitive material 270 dissolves.
  • the vehicle of Fig. 16A is produced in separate layers, which are then bonded together, preferably by heat sealing.
  • Heat sealing methods are conventional and known to those of ordinary skill in the art (see e.g., Vertrod Corporation, The Ventrod Guide to Thermal Impulse Heat Sealing Machinery, Brooklyn NY) .
  • Multiple units of the vehicles are prepared in one processing step by forming the units on large sheets of membrane or polymeric film, and then cutting the units apart.
  • Screen printing techniques enable a number of vehicles to be made in close proximity. Screen printing techniques are also conventional and known to those skilled in the art (see e.g., de Haart, Inc., Laboratory and Production Equipment for the Thick Film Microelectronic Industry : AOL-15AE-CC Automatic Screen Printer, Burlington MA.).
  • the layers are prepared independently and in any order as follows:
  • the first layer is prepared on a large sheet of the outer permeable membrane 260 material.
  • the water swellable agent 250 material is dispersed in an organic solvent (e.g., cellulose, e.g., methyl or ethyl cellulose) and then deposited in the pattern of vehicle units by a screen printer on the large sheet of outer permeable membrane 260 material. This is then dried.
  • the outer edges of the membrane 260 surface are left uncoated, and available for bonding to other layers.
  • the second layer is prepared on a large sheet of the polymeric film 240 material, e.g., urethane.
  • the spacer 230 material is deposited on one surface of the sheet of polymeric film 240 by first applying a water soluble polymer in the pattern of vehicle units, and forming the water soluble polymer into v-shaped lines leaving the center of the v open. This forms the triangular spacer 230 units described above.
  • the v-shaped units are then coated with a layer of pH- sensitive material 235.
  • the outer edges of the sheet of polymeric film 240 around each vehicle unit are left uncoated, to be available for bonding to the other layers.
  • the triangular spacers 230 can be joined together along the base of each triangle.
  • the entire set of joined spacers 230 are coated with the pH-sensitive material 235, and inserted between the resin beads 200 and the polymeric film 240, again with the base of the triangles adjacent to the polymeric film 240 so as not to interfere with bile acid adsorption.
  • the third layer is the central layer containing resin beads 200 surrounded by permeable membrane 220.
  • the resin beads 200 are cholestyramine particles
  • they are dispersed with PVP in an aqueous solution. They are then deposited by a screen printer onto a sheet of permeable membrane 220 material, in positions desired for vehicle units. A second sheet of permeable membrane 220 is placed on the other, top, side of the resin beads 200. A heat sealer is then used to seal the two membranes together around the outside of each area of resin bead 200 deposition.
  • the PVP helps the resin bead 200 to adhere to the sheet of permeable membrane 220 material, but once deposited the PVP is washed out of the resin beads 200 and the device is dried.
  • the uncoated portion of the inner surface of the permeable membrane 260 layer is laid on top of the inside surface of the polymeric film 240 layer, and layers 240 and 260 are bonded together on two opposing sides, preferably by heat sealing, in the uncoated areas. This seals the outer permeable membrane 260 layer to the polymeric film 240 layer, enclosing the water swellable agent 250, with the spacer 230 layer on the outside. Two of these sheets are prepared separately for each set of vehicles.
  • the layer of permeable membrane 220 which encloses the resin beads 200, is then placed on top of the outer (spacer 230) surface of the coated polymeric film 240, and bonded to the other layers at the uncoated outer areas of each vehicle unit.
  • a second layer of the coated polymeric film 240 is placed in mirror image on the other side of permeable membrane 220 enclosed resin beads 200. This leaves the permeable membrane 220 enclosed resin beads 200 enclosed in a pouch between the pH-sensitive material 235 -coated spacers 230.
  • the individual vehicle units are cut apart from the sheets.
  • the vehicle of Fig. 16A & 16B can be combined with any of the embodiments provided in Examples 1-5, Figs. 2- 6, to delay exposure of the resin until it reaches the portion of the intestine where bile acids are present, as described above.
  • FIGs. 17A, 17B, 17C, and 17D Another alternative embodiment is shown in Figs. 17A, 17B, 17C, and 17D. All materials used to make the components of this vehicle are the same as those provided for the respective components in prior examples.
  • Fig. 17A shows a center section of the open configuration of the vehicle, the direction of fluid flow being from front to back.
  • Resin beads 300 are surrounded in the center of the vehicle by a permeable membrane 310.
  • Above the permeable membrane 310 is a void 320, which is an opening or space through which the intestinal fluid can flow (into and out of the plane of the paper of Fig. 17A) .
  • the top of the void 320 is formed by the impermeable polymeric film 280.
  • the polymeric film 280 includes a section of permeable membrane 290 attached to the center of the exterior surface (i.e., the side distal to the resin) of the polymeric film 280. Referring to Fig. 17B, this section of permeable membrane 290 is attached, preferably bonded, e.g., by heat sealing, to the center portion of the impermeable polymeric film 280.
  • an outer permeable membrane 330 On the outside of the polymeric film 280 is an outer permeable membrane 330. Between the polymeric film 280 and the outer permeable membrane 330 is a water swellable agent 350, which expands when exposed to intestinal fluid.
  • the outer permeable membrane 330 is coated, preferably saturated, with pH-sensitive material 340.
  • a water soluble polymer coating 370 e.g., of PVP, or methyl or ethyl cellulose, may serve as an undercoat for the pH-sensitive material 340 in order to achieve added rigidity.
  • the outer permeable membrane 330 makes contact with the permeable membrane 290 at the top surface of the vehicle, allowing the pH-sensitive material 340 to percolate down and in turn coat or infuse the permeable membrane 290 as well.
  • This pH-sensitive material 340 fuses together the two permeable membranes 290 and 330, creating a joint which holds the polymeric film in place, thereby shaping the void 320.
  • the side edges of permeable membrane 310 and polymeric film 280 are bonded, preferably by heat sealing, on the side of the vehicle at heat seal 360, as described in Example 14.
  • the side edges of permeable membrane 330 are bonded, preferably by heat sealing, to the polymeric film 280 at heat seal 380.
  • FIG. 17C show ⁇ an end section of the open configuration of the vehicle, the direction of fluid flow being from front to back.
  • the resin beads 300, permeable membrane 310, polymeric film 280, and heat seals 360 are as illustrated in Fig. 17A.
  • Water swellable agent 350 is not visible from the end section because it is covered by the outer permeable membrane 330.
  • the outer permeable membrane 330 extends over the end of the vehicle.
  • the folded ends of the permeable membrane 330 are pinched together to form folds 390.
  • Fig. 17D is a side view of the vehicle.
  • the permeable membrane 330 is held in place by the pH-sensitive material 340, which saturates the membrane 330, acting as a glue.
  • a water soluble coating 370 may optionally serve as an undercoat for the pH-sensitive material 340.
  • An additional optional embodiment of the vehicle shown in Fig. 17A and 17C is to incorporate a water soluble spacer into the space of the void 320, to further enhance retention of the shape of the opening.
  • a water soluble spacer is described in further detail in Example 14, above, and is shown in Fig. 16A.
  • bile acid is adsorbed in the proximal portion of the small bowel.
  • the pH-sensitive material 340 dissolves, so that the outer permeable membrane 330 becomes porous, allowing the water swellable agent 350 to be contacted by the intestinal fluids.
  • an optional water soluble polymer 370 undercoat is included, it too dissolves.
  • the agent 350 expands, i.e., swells.
  • the coating of pH- sensitive material 340 that holds the folded ends of the outer permeable membrane 330 together also dissolves, so that the membrane 330 is free to unfold.
  • the vehicle of Figs. 17A-D is assembled as follows:
  • the polymeric film 280 is attached to the two opposite sides of the inner permeable membrane 310 and heat sealed in place.
  • a removable triangular device 350 e.g., a triangular metal bar, is placed inside the space between the polymeric film 280 and the inner permeable membrane 310, so that the permeable membrane 290, located in the center portion of the polymeric film 280, fits over the triangular device.
  • a screen printer releases water swellable agent 350 over the portion of the polymeric film 280 between the center of the bar and the outer edge, being careful to leave uncoated space where the outer permeable membrane 330 will be heat sealed to the polymeric film 280.
  • the center of the polymeric film 280 is also not coated.
  • the outer permeable membrane 330 is smaller than the polymeric film 280.
  • the outer permeable membrane 330 is placed on top of the polymeric film 280, and is heat sealed at the two outer edges on all four sides of the device.
  • the outer permeable membrane 330 extends beyond the vehicle on the two ends where water can enter.
  • the outer permeable membrane 330 is coated with pH-sensitive material 340, which optionally has a water soluble polymer 370 undercoat. In the center portion, where the outer permeable membrane 330 is in close contact with the permeable membrane 290 that was heat sealed to the polymeric film 280, the pH-sensitive material 340 bonds the two membranes together.
  • the ends of the outer permeable membrane 330 are folded over while the pH- sensitive material is still wet and can thus glue the folds 390 of the outer permeable membrane 330 together at the center of the vehicle.
  • This helps maintain the triangular configuration of the void 320 while bile acid is being adsorbed.
  • the removable triangular device is removed prior to the final assembly step.
  • the vehicle of Fig. 17A-D can be combined with any of the embodiments provided in Examples 1-5, Figs. 2-6, to delay exposure of the resin until it reaches the portion of the intestine where bile acids are present, as described above.
  • any of the various vehicles of the present invention are intended to be used for the treatment or prevention of conditions that are related to an elevated level of bile acids, triglycerides, or cholesterol in a region of the body of a mammal, i.e., conditions where it is necessary to reduce serum cholesterol levels or serum triglycerides.
  • These conditions can include, but are not limited to, hypercholesteremia, hypertriglyceridemia, and pruritus associated with partial biliary obstruction.
  • Treatments can be used to lower the risk of related disorders, including atherosclerosis, e.g., coronary heart disease. This will in turn lead to fewer deaths due to coronary heart disease.
  • Preferred materials also have the advantage of reduced irritability to the digestive tract.
  • An appropriate therapeutic dose is an amount of the vehicle containing sufficient resin to effect a reduction in, or postpone progression of, one of the conditions listed herein.
  • the dosage can be adjusted for different people, in recognition of the fact that the effectiveness of the resin, migration time, and pH of the gastrointestinal tract may vary according to the individual.
  • the dosage can be, but is not necessarily, in the range of 0.01-100 grams/day/adult, preferably 0.01-50 grams/day/adult, more preferably 0.1-40 gr/day/adult or 1-25 gr/day/adult, or most preferably a dosage range that is determined in clinical trials to be appropriate by those skilled in the art of conducting a clinical trial for a pharmaceutical formulation (for appropriate clinical study parameters see, e.g., Steinberg, in Lipids, Lipoproteins, and Drugs , Kritchevsky et al. eds. Plenum Press, NY, p. 417, 1975; hereby incorporated by reference) .
  • the effectiveness of a vehicle of the invention for reducing the level of bile acid, or in reducing the level of blood cholesterol can be assayed in an animal model, e.g., according to the methods of Kuron et al. supra (hereby incorporated by reference) , Parkinson et al. (J " . Lipid Res . 8:24, 1967, hereby incorporated by reference; Atherosclerosis 11:531, 1970, hereby incorporated by reference; Atherosclerosis 17:167, 1973, hereby incorporated by reference) , Beher et al. (Atherosclerosis 16:169, 1972, hereby incorporated by reference) , or according to an alternate animal model of at least comparative predictive utility. Kuron et al.
  • a vehicle of the invention has previously administered CAT-FLOCTM or cholestyramine to normo-cholesterolemic dogs and assayed the hypocholesterolemic effect.
  • the effect of a vehicle of the invention on plasma cholesterol levels can be measured according to the method of Abell et al. (J. Biol. Chem. 197:357, 1952, hereby incorporated by reference) .
  • the effectiveness of a vehicle of the invention for a method of treatment in humans can be determined in human trials according to the methods of Gustafson et al. (Europ . J . Clin . Pharmacol . 7:65, 1974, hereby incorporated by reference) , and/or Grundy (Arch . Int . Med . 130:638, 1972, hereby incorporated by reference) .
  • Other Embodiments Other embodiments are included within the claims set forth below. Examples are the following.
  • the vehicle can be administered in accordance with the condition to be treated.
  • the vehicle is intended preferably for oral ingestion as a hard tablet, a soft gel tablet, pill, or capsule.
  • the vehicle can also be administered as a food additive, and can be combined with any ingredients that increase the palatability of the vehicle, e.g., ingredients that affect the flavor or texture of the vehicle. What is claimed is:

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Abstract

L'invention concerne un véhicule pharmaceutique administré par voie buccale conçu pour libérer une résine adsorbant les acides biliaires, les sites de liaison de résine étant fermés jusqu'à ce qu'une région sélectionnée dans laquelle des acides biliaires sont présents soit atteinte, les absorbants utilisés ayant été largement éliminés. Le véhicule ferme ensuite les sites de liaison de résine avant que la section de l'intestin dans laquelle la réadsorption active des acides biliaires a lieu soit atteinte. Ainsi, ce véhicule administé par voie buccale de manière à empêcher la désorption des acides biliaires par une résine adsorbant les acides biliaires (35) comporte une couche de matière entourant la résine (38) présentant une ouverture (36) permettant l'exposition de la résine lorsque le véhicule est près d'une région sélectionnée du corps dans lequel les acides biliaires sont présents, le véhicule étant doté d'un mécanisme servant à fermer l'ouverture lorsque le véhicule a contourné la région sélectionnée (34).
PCT/US1994/006550 1993-06-11 1994-06-10 Formulation de retention a liberation retardee pour adsorbant d'acides biliaires Ceased WO1994028881A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7636093A 1993-06-11 1993-06-11
US08/076,360 1993-06-11
US25783294A 1994-06-09 1994-06-09
US08/257,832 1994-06-09

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WO1994028881A1 true WO1994028881A1 (fr) 1994-12-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065291A3 (fr) * 2003-12-31 2006-02-09 Genzyme Corp Agents sequestrants des acides biliaires a base de polymeres d'amine aliphatique a revetement gastro-resistant
EP4094753A1 (fr) * 2021-05-27 2022-11-30 Manfred Stangl Capsule de cholestyramine perforée
WO2024013649A3 (fr) * 2022-07-11 2024-03-28 Glycemic Shield Article gonflable relatif à la nutrition

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4814354A (en) * 1986-09-26 1989-03-21 Warner-Lambert Company Lipid regulating agents
US5026555A (en) * 1988-10-28 1991-06-25 Warner-Lambert Co. Method for preparing an anion exchange resin delivery system
US5091175A (en) * 1990-05-14 1992-02-25 Erbamont Inc. Pharmaceutical composition containing bile acid sequestrant enclosed in a size-exclusion membrane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4814354A (en) * 1986-09-26 1989-03-21 Warner-Lambert Company Lipid regulating agents
US5026555A (en) * 1988-10-28 1991-06-25 Warner-Lambert Co. Method for preparing an anion exchange resin delivery system
US5091175A (en) * 1990-05-14 1992-02-25 Erbamont Inc. Pharmaceutical composition containing bile acid sequestrant enclosed in a size-exclusion membrane

Non-Patent Citations (1)

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Title
INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol. 37, July 1987, (HARDY et al.), "Evaluation of an Enteric Coated Naproxen Tablet Using Gamma Scintigraphy and pH Monitoring", pages 863-867. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065291A3 (fr) * 2003-12-31 2006-02-09 Genzyme Corp Agents sequestrants des acides biliaires a base de polymeres d'amine aliphatique a revetement gastro-resistant
AU2004311849B2 (en) * 2003-12-31 2009-04-02 Genzyme Corporation Enteric coated aliphatic amine polymer bile acid sequestrants
EP4094753A1 (fr) * 2021-05-27 2022-11-30 Manfred Stangl Capsule de cholestyramine perforée
WO2024013649A3 (fr) * 2022-07-11 2024-03-28 Glycemic Shield Article gonflable relatif à la nutrition

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