EP0843559A2 - Systeme d'administration de medicaments a base de chitosan - Google Patents

Systeme d'administration de medicaments a base de chitosan

Info

Publication number
EP0843559A2
EP0843559A2 EP97931091A EP97931091A EP0843559A2 EP 0843559 A2 EP0843559 A2 EP 0843559A2 EP 97931091 A EP97931091 A EP 97931091A EP 97931091 A EP97931091 A EP 97931091A EP 0843559 A2 EP0843559 A2 EP 0843559A2
Authority
EP
European Patent Office
Prior art keywords
chitosan
drug
composition
oral
progesterone
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.)
Withdrawn
Application number
EP97931091A
Other languages
German (de)
English (en)
Inventor
Joseph S. Podolski
Kuang T. Hsu
Gurpreet Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Repros Therapeutics Inc
Original Assignee
Zonagen Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zonagen Inc filed Critical Zonagen Inc
Publication of EP0843559A2 publication Critical patent/EP0843559A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates generally to a novel drug delivery system. Specifically, the invention relates to a drug delivery system comprising a modified iron/chitosan particles and chitosan-formulated compounds which provide enhanced drug delivery via oral administration. In another aspect, the present invention relates to a chitosan matrix for oral delivery of therapeutic or prophylactic substances.
  • Chitin poly-/3-(l ⁇ 4) linked N-acetyl-D-glucosamine
  • the deacetylated form of chitin, chitosan has structural characteristics similar to glycosaminoglycans and shows particular promise as a exogenous matrix in reparative connective-tissue rebuilding [Muzzarelli, etal.
  • chitosan In addition, the ability of chitosan to stimulate macrophages for tumoricidal activity and for interleukin-1 production suggests it possible use as a drug carrier for tumor patients with depressed immune systems. Id. These properties have led investigators to test various chitosan formulations with hopes of providing a potential drug delivery vehicle which can itself survive the gastric environment while protecting an associated drug, and which permits release of the drug over extended periods of time. Past efforts have been directed to chitosan formulations which have been tested in limited in vitro assays to examine the formulations ability to maintain integrity and provide sustained drug release.
  • chitosan beads, or gels were prepared in combination with, for example, glutaraldehyde crosslinking [Thacharodi and Ro, Biomaterials 16: 145-148 (1995); Chandy and Sharma, Biomaterials 14:939-944 (1993)]; alginate [Alexakis, et al , Appl. Biochem. Biotechnol. 50:93-106 (1995); Polk, et al. , J. Pharm. Sci.
  • Chitosan fo ⁇ nulations which incorporate iron appear to be limited to one instance where iron was entrapped in chitosan beads and which were then coated with either liposomes or albumin in order to modulate the rate of iron release from the beads [Chandy and Sharma, Biomaterials 17:61- 66 (1996)].
  • iron derived from FeCl ⁇
  • entrapment of iron was effected by spraying solubilized chitosan into a sodium hydroxide/methanol solution which produced chitosan particles with a size on the order of one millimeter in diameter.
  • the present invention relates to a drug delivery composition
  • a drug delivery composition comprising iron/chitosan particles or complex within which a drug can be entrapped.
  • the composition is particularly useful for oral administration of drugs in that the particles or complex provide protection for the entrapped drug against the harsh environment of the digestive tract, and permit drug adsorption by a route that increases the circulatory half-life of the drug.
  • Another advantage offered by the metal/chitosan complex is a high affinity for hydrophobic organic compounds, which permits delivery of normally insoluble drugs to the circulatory system.
  • the iron/chitosan particles are less than ten microns in size. More preferred, however, are particles less than five microns in diameter, and most preferably, all particles are less than 5 nm in diameter, in order to facilitate endocytosis by cells of the intestinal mucosa.
  • the present invention provides a chitosan matrix for oral delivery of therapeutic or prophylactic substances. Substances particularly useful in the chitosan delivery system are those which are largely unable to survive the harsh environment of the digestive tract and are therefore absorbed at levels generally too low to be useful in an oral delivery system.
  • the invention may be utilized in various forms, such as a powder, pill, caplet, capsule, gel, liquid, liquid suspension, emulsion, elixir, syrup, and the like, as long as the manufacturing process does not result in significant changes in bead size or in properties of the beads in the composition which have the preferred size.
  • the form may be such that the particles themselves are released over a period of time or made available all at one time.
  • Oral compositions are preferably designed to release the active compound at the point in the gastrointestinal tract where bioavailability is maximized and substance degradation is minimized.
  • oral administration is the presently preferred method of use, other routes of administration are contemplated, including for example, subcutaneous, transdermal, intramuscular, intravenous, intranasal, intrapulmonary, intrarectal, intravaginal, intraperitoneal, ophthalmic, and the like.
  • Optimal particle size for each mode of administration will vary and is readily determined by one of ordinary skill in the art. For example, a larger particle will be more easily tolerated in an oral system than in an injectable system, which may be constrained by the mechanical injection device and/ or constraints due to capillary size.
  • the presently preferred method for producing the drug delivery particles involves dissolving chitosan powder in an acidic solution, preferably containing acetic acid, and sonicating the resultant mixture with concurrent addition of a metal salt, preferably ferric ammonium citrate.
  • a metal salt preferably ferric ammonium citrate.
  • an acid stable drug formulation is added initially to the chitosan in the acidic solution prior to sonication.
  • Preparation of the particles may be effected by numerous alternative methods. For example, any of a number of commercially available grades of chitosan may be utilized to produce the drug delivery system, as well as chitosan at various degrees of deacetylation.
  • Chitosan may also be produced from chitin by deacetylation with alkali treatment well known in the art. Presently preferred is chitosan which is deacetylated between approximately 50-80% . More preferred is chitosan deacetylated to 60-75 % .
  • any of a number of acidic buffers may be utilized to dissolve the chitosan powder.
  • concentration of the acid solution in which chitosan is initially dissolved may vary in the range of 0.1 % to 15 % . Most preferred, however, is 2% acid solution.
  • pH of the acid solution may vary within a pH range of 1.0 to 6.8, however to most preferred buffer is in a pH range of 2 to 3.
  • iron salts may be used as an iron source to effect particle formation during sonication including, for example, ferric chloride.
  • Other metal ions for example, zinc, copper, or nickel, may also be useful in forming chitosan particles. Any physiologically acceptable acid or metal salt is contemplated by the invention.
  • a drug may be administered orally in a composition comprising chitosan, a sugar, such as, but not limited to maltose, hexose, mannose, or glucose and the drug.
  • the invention is also directed to a method for producing an oral drug delivery system, the method comprising the steps: (a) preparing a chitosan/ sugar solution, (b) dissolving the drug in an organic solvent, such as, but not limited to acetone, methanol, ethanol, or acetonitrile) (c) mixing the results of steps (a) and (b), (d) lyophilizing the mixture of step (c), and (e) reconstituting the lyophilized mixture in a suitable oral excipient for administration to a subject.
  • an organic solvent such as, but not limited to acetone, methanol, ethanol, or acetonitrile
  • the resulting lyophilized mixture may also be ground to produce a fine powder.
  • the invention may be utilized in various forms, such as a powder, pill, caplet, capsule, gel, liquid, liquid suspension, emulsion, elixir, syrup, and the like.
  • a method for oral drug administration comprising administering to a patient an oral composition comprising chitosan in combination with a sugar and a drug.
  • oils such as, but not limited to canola oil, corn oil, peanut oil, olive oil, vegetable oil, mineral oil and the like or lipid compositions may be included in the chitosan/drug matrix, either prior to, during, or after the sonication step. Addition of lipids may necessitate addition of any of a number of physiologically acceptable surfactants, depending on the physical characteristics of the drug to be incorporated. Oils or lipids may provide additional protection for the entrapped drug as it traverses the gastro-intestinal tract, slow the release of the therapeutic or prophylactic substance from the chitosan matrix, or improve absorption in the intestines.
  • Oils or lipids as described above may also be included to form emulsions which can then be sprayed onto a surface, dried, collected and compressed into a capsule or tablet.
  • gelatin may be included as an agent to fix the chitosan matrix with the entrapped substance; the fixed therapeutic or prophylactic substance- containing particles can then be collected for delivery in a capsule form.
  • Sonication is performed to the extent that the resulting chitosan particles are less than ten microns in diameter, and preferably less than five microns in diameter. Most preferably sonication is continued until particles - 7 - are less than about five nanometers in diameter.
  • the duration and power of sonication can vary as long as particles of a preferred size are obtained.
  • any type and model of sonicator can be utilized to produce the chitosan particles, again, provided that the resultant particles are of a preferred size.
  • either probe style or water bath types of sonicator are adaptable to producing the drug delivery system.
  • the duration of sonication may vary from one to ten minutes.
  • a currently preferred sonicator is a Branson Sonifier Model 250 used at approximately 60% full strength for one to three minutes in duration.
  • the drug delivery system may also be produced using various types of homogenizer, emulsifier, fluidizer and the like.
  • the preferred method for producing the chitosan matrix includes dissolving chitosan in an acidic solution, to which a therapeutic or prophylactic substance is then added. An aliquot of the mixture is withdrawn, mixed with a pharmaceutically acceptable oil, and sonicated.
  • the resulting chitosan matrix is particularly useful for oral delivery of therapeutic or prophylactic substances, for example, hormones (such as but not limited to insulin, progesterone, estrogen, testosterone, glucocorticoids, mineralocorticoids, growth hormone), cytokines (such as, but not limited to interleukins, lymphokines, monokines), chemokines, hematopoietic factors (such as, but not limited to erythropoietin) and other therapeutic or prophylactic substances, polypeptides or proteins which are not ordinarily physiologically active following oral delivery.
  • hormones such as but not limited to insulin, progesterone, estrogen, testosterone, glucocorticoids, mineralocorticoids, growth hormone
  • cytokines such as, but not limited to interleukins, lymphokines, monokines
  • chemokines such as, but not limited to erythropoietin
  • proteins or polypeptides which are useful in the system may be native and purified from naturally occurring sources,
  • chitosan particles can be prepared by the preferred method but in the absence of a drug. Once prepared in this manner, the chitosan particles can then be mixed with a solution of a desired drug, after which the mixture can be delivered as described.
  • chitosan particles can be prepared, again in the absence of a drug, the particles lyophilized, and subsequently rehydrated in a solution containing a drug.
  • FIG. 1 sets forth the in vitro release rates of bromthymol blue (BTB) from iron (Fe), chitosan (Ch), or iron/chitosan particle complexes.
  • BTB bromthymol blue
  • Figure 2. shows the bioavailability of progesterone after oral administration of progesterone/iron/chitosan particles.
  • Figure 3 sets forth the bioavailability of progesterone after oral administration of chitosan-formulated progesterone as compared to micronized progesterone.
  • Figure 4. sets forth data illustrating blood glucose levels in streptozotocin-treated animals after oral administration of either a insulin/chitosan composition or a insulin/PBS composition.
  • Example 1 describes preparation of iron/chitosan particles.
  • Example 2 illustrates in vitro retention and release of a compound in and from iron/chitosan particles.
  • Example 3 shows in vivo delivery of a compound by iron/chitosan particles after a set period of time.
  • Example 4 describes in vivo release of a compound by iron/chitosan particles or release of a chitosan-formulated compound as a function of time.
  • Example 5 describes use of a chitosan matrix to orally administer insulin.
  • Example 1 Preparation of Iron/Chitosan Particles
  • a 1 % SeaSanMer N2000 grade chitosan (CTC Organics, Atlanta, GA) solution was initially prepared by dissolving powdered chitosan in 2 % acetic acid and the solution was autoclaved.
  • CTC Organics Atlanta, GA
  • iron/chitosan particles a 1 to 5 ml chitosan solution was sonicated for one to three minutes while 0.2-0.3 ml of a 4% ferric ammonium citrate stock solution/ml of chitosan solution was added dropwise.
  • the stock ferric ammonium citrate solution was initially prepared in water. The end result of these steps was in a very fine suspension of chitosan particles.
  • the density of the chitosan particles was approximately 0.3 g wet weight per ml chitosan solution, or approximately 18 mg lyophilized solid per reconstituting ml buffer. Particles in the suspension were measured on a periodic basis using a micrometer and found to range from about 2 to about 10 microns in diameter. In order to incorporate small molecules in the iron/chitosan particles, the above procedure was modified as described below.
  • the iron/chitosan particles containing bromthymol blue prepared as described above were placed individually in dialysis bags having a molecular weight cutoff of 12 kD and each bag immersed in 45 ml phosphate buffered saline (PBS) in a 50 ml conical tube. The tube was placed on an end to end shaker and release rate of the bromthymol blue into the buffer was measured over time by absorption at 595 nm with a Spectronic-20.
  • PBS phosphate buffered saline
  • nystatin Sigma
  • distilled water 100 ⁇ l was mixed thoroughly with 200 ⁇ l of the chitosan solution prepared as described in Example 1.
  • the resulting mixture was sonicated for two to three minutes while 4 % ferric ammonium citrate in water was added (100 ⁇ l/ml chitosan: nystatin mixture) producing yellowish particles.
  • the suspension was centrifuged, the supernatant removed by aspiration, and the particles resuspended in 200 ⁇ l phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • nystatin is generally insoluble in water and gives a fine particulate appearance in aqueous solution.
  • Drug incorporation in the chitosan particles was determined by HPLC (Waters) on a C-18 column and by extracting entrapped nystatin from the particles with cold methanol.
  • a test group of adult female mice were orally administered iron/chitosan particles containing nystatin with a feeding needle fitted on 1 ml syringe.
  • a first control group of mice was fed nystatin suspended in PBS and a second control group was fed a chitosan suspension mixed with nystatin to which 5 ⁇ l glutaraldehyde was added to obtain a gel.
  • Each mouse received an equivalent of approximately 4 mg nystatin in a volume of 200-400 ⁇ l.
  • mice were bled at 0, 1 and 5 hr interval through retro-orbital puncture.
  • the blood was allowed to clot and serum was separated. After extracting the serum with cold methanol, the serum levels of nystatin were measured using HPLC as described above
  • mice that received nystatin entrapped in iron/chitosan particles produced higher serum nystatin levels after five hours as compared to mice that received nystatin alone or merely mixed with chitosan.
  • comparison of serum nystatin levels between groups in which mice received either oral or intraperitoneal administration of nystatin in iron/chitosan particles it was observed that mice receiving oral administration had greater than 150% more serum nystatin than the intraperitoneal group. This result suggests that association with chitosan provided a higher level of available drug.
  • Progesterone (Sigma Chemical Co. , St. Louis, MO) was dissolved in dimethyl sulfoxide (DMSO; Sigma) to a final concentration of 10 mg/ml and 1 ml of the solution was mixed with an equal volume of 1 % iron/chitosan containing 0.1 % Tween 20 and 1 ml mineral oil. The resulting emulsion was sonicated one to three minutes while 50 ⁇ l ferric ammonium citrate stock solution was added dropwise. Particles in the resulting solution were measured under the microscope and were determined to range in size from two to ten microns. Rats receiving administered this preparation were designated Group 1.
  • DMSO dimethyl sulfoxide
  • Control preparations included: progesterone suspended in PBS and the resulting was suspension sonicated (administered to Group 2); progesterone suspended in PBS to which ferric ammonium citrate was added during sonication (administered to Group 3); and a suspension of progesterone without ferric ammonium citrate (administered to Group 4).
  • the second preparation comprising water soluble progesterone was prepared similar to the first except that 50 ⁇ l 4% ferric ammonium citrate was added during sonication to obtain iron/chitosan particles with entrapped steroid. This preparation was orally administered to rats in Group 6.
  • Serum progesterone levels were found to be highest in the Group 1 rats which were administered insoluble progesterone in iron/chitosan particles, with the highest levels detected four hours after administration. Similarly high levels (particularly four hours after administration) were also detected in animals from Group 6 which were administered water soluble progesterone entrapped in iron/chitosan. While rats which received progesterone in several of the other formulations showed highest serum progesterone levels 2 hours after administration, the level of detectable progesterone reduced to near control levels at four hours.
  • progesterone Sigma Chemical Co. , St. Louis MO
  • acetone reagent grade; Fisher Scientific, Pittsburgh, PA
  • maltose a maltose
  • 5 ml of the progesterone/acetone solution were mixed with 5 ml of the chitosan/maltose solution. The resulting mixture was rapidly frozen in liquid nitrogen and lyophilized.
  • the resulting sponge-like dried chitosan-formulated progesterone may also be ground into a fine powder.
  • the resulting lyophilized mixture was reconstituted in deionized water for oral administration to test animals.
  • the invention may also be utilized in various forms, such as a powder, pill, caplet, capsule, gel, liquid, liquid suspension, emulsion, elixir, syrup, and the like.
  • the rats were bled via tail at 0, 1 , 5, 24, and 48 hrs after administration and serum progesterone levels were measured by radioimmunoassay (RIA) using a Coat-A-Count Progesterone solid phase radioimmunoassay kit (Diagnostic Product Corporation, Los Angeles, CA).
  • RIA radioimmunoassay
  • Example 5 In Vivo Protein Drug Release
  • the ability of chitosan to deliver proteins via the same oral administration route was investigated.
  • a 1 % chitosan solution was prepared in 2% acetic acid (pH 3.9) as described in Example 1 , above, except that no ferric ammonium citrate was added to the mixture.
  • a 1 ml aliquot of the chitosan solution was combined with 12 mg bovine pancreatic insulin (Sigma, approximately 300 units) and the resulting solution was mixed well.
  • a second 1 ml aliquot of the chitosan/acetic acid solution containing 0.1 % polyoxyethylenesorbitan monolaurate (Tween 20) (Sigma) was added and the mixture vortexed.
  • a 1 ml aliquot of this final solution was removed and added to 1.5 ml Canola oil
  • the final insulin concentration in the resulting cloudy mixture was 60 units/ml.
  • each rat was fed 0.3 ml of a 0.625 g/ml glucose solution. Five minutes later each rat was fed 0.3 ml of either the insulin/chitosan mixture or the insulin control mixture. Blood was drawn from the tail vein of each rat at 0, 30, 60, and 120 minutes after administration of insulin, and blood glucose levels were determined using an
  • diabetes was induced in rats by intravenous administration of streptozotocin dissolved in normal saline buffered with anticoagulant acid citrate dextrose (ACD) solution (1 :50 dilution of ACD with 0.9% NaCl).
  • ACD anticoagulant acid citrate dextrose
  • the final streptozotocin concentration of the solution was 20 mg/ml, pH 5.0.
  • the diluted solution was sterilized by filtration through a 0.22 micron filter and used within 10 to 15 minutes of preparation. Rats were anesthetized with halothane and administered a single intravenous injection via the tail vein at a dosage of approximately 50 mg/kg body weight.
  • blood glucose levels were in the range of 80 to 110 mg/dl blood.
  • Rats were administered bovine insulin in the oral drug delivery system described in (A) and resultant changes in bloo ⁇ glucose was determined. As controls in various experiments, rats from each group were also orally administered: (i) insulin in PBS, (ii) insulin prepared as in (A) above without addition of chitosan; and (iii) the preparation described in (A) above except that no insulin was added. As an additional positive control, bovine insulin in PBS was administered intramuscularly.
  • Insulin prepared as described in (A) above was administered to a group of rats and blood glucose levels were measured and compared to the levels in a group administered insulin in PBS. In each group, 18.4 units of insulin were provided. In rats fed only insulin in PBS, no change in blood glucose levels were detected. In rats fed insulin in chitosan, however, blood glucose levels were suppressed over the course of the first three hours which the rats were monitored. These data indicate that the oral delivery of insulin in a chitosan matrix is useful for treating diabetes in an animal model, suggesting usefulness of the same drug delivery system for treating diabetes in humans. Finally, the above described methods and formulations may be used with other drugs and therapeutic or prophylactic substances.
  • Such drugs or substances may be (but are not limited to) those that are difficult to place in solution such as many psychoactive drugs (e.g. clozapine) or hormones (e.g. insulin, progesterone, estrogen, testosterone, glucocorticoids, mineralocorticoids, growth hormone), cytokines (e.g. , interleukins, lymphokines, monokines), chemokines, hematopoietic factors (e.g. , erythropoietin) or other therapeutic or prophylactic substances.
  • psychoactive drugs e.g. clozapine
  • hormones e.g. insulin, progesterone, estrogen, testosterone, glucocorticoids, mineralocorticoids, growth hormone
  • cytokines e.g. , interleukins, lymphokines, monokines
  • chemokines e.g. , hematopoietic factors (e.g. , erythropoietin) or other therapeutic or pro

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte d'une manière générale sur une nouvelle composition pour l'administration de médicaments et plus spécifiquement sur une composition pour l'administration de médicaments consistant en particules de fer/chitosan combinées au médicament désiré, à un composé du médicament préparé avec du chitosan, ou à une composition de chitosan/huile-tensioactif et de la substance désirée. Elle porte en outre sur un système d'administration de médicaments recourant à ces compositions et sur des procédés d'élaboration de ces compositions.
EP97931091A 1996-06-11 1997-06-11 Systeme d'administration de medicaments a base de chitosan Withdrawn EP0843559A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1954396P 1996-06-11 1996-06-11
US19543P 1996-06-11
PCT/US1997/010028 WO1997047323A2 (fr) 1996-06-11 1997-06-11 Systeme d'administration de medicaments a base de chitosan

Publications (1)

Publication Number Publication Date
EP0843559A2 true EP0843559A2 (fr) 1998-05-27

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Country Status (6)

Country Link
EP (1) EP0843559A2 (fr)
JP (1) JPH10513202A (fr)
CN (1) CN1198100A (fr)
AU (1) AU3481497A (fr)
CA (1) CA2228251A1 (fr)
WO (1) WO1997047323A2 (fr)

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US9161901B2 (en) 2008-02-21 2015-10-20 University Of South Florida Nanoparticle targeted drug delivery to the lungs using extra-testicular Sertoli cells
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Also Published As

Publication number Publication date
WO1997047323A3 (fr) 1998-04-23
WO1997047323A2 (fr) 1997-12-18
CA2228251A1 (fr) 1997-12-18
CN1198100A (zh) 1998-11-04
AU3481497A (en) 1998-01-07
JPH10513202A (ja) 1998-12-15

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