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WO1997004747A1 - Systemes d'administration de medicaments pour medicaments macromoleculaires - Google Patents

Systemes d'administration de medicaments pour medicaments macromoleculaires Download PDF

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Publication number
WO1997004747A1
WO1997004747A1 PCT/US1996/012203 US9612203W WO9704747A1 WO 1997004747 A1 WO1997004747 A1 WO 1997004747A1 US 9612203 W US9612203 W US 9612203W WO 9704747 A1 WO9704747 A1 WO 9704747A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled release
pharmaceutical formulation
release pharmaceutical
poly
acid
Prior art date
Application number
PCT/US1996/012203
Other languages
English (en)
Inventor
James M. Dunn
Original Assignee
Dunn James M
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 Dunn James M filed Critical Dunn James M
Publication of WO1997004747A1 publication Critical patent/WO1997004747A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to improved pharmaceutical formulations for administration of macromolecules or drugs that are not bioavailable using standard pharmaceutical methods. More specifically, the invention relates to pharmaceutical formulations of controlled release rate dosages of the drugs that may be administered orally, parenterally, or by inhalation.
  • Oral delivery of drugs or long acting parenteral dosage forms of drugs is preferred by the patient and physician because of compliance and the inherent beneficial effect of constant pharmacodynamic action.
  • a drug to be absorbed by the intestine it must first become soluble in the aqueous media of the gut. Products that are rapidly dissolved in water are usually rapidly absorbed into the body.
  • these drugs when given parenterally may have short half lives or may not have effective injection delivery systems. This problem arises from the fact that the drugs are destroyed before being absorbed or they are of such a size and nature that the body cannot absorb the medication. Similarly, their injectable forms have short durations of action, requiring frequent injections, making the products unsuitable for use in the non hospitalized patient.
  • the driving force for passive drug diffusion is the difference between the concentration gradient of the diffusing drug in the intestinal tract and the concentration gradient on the other side of the plasma membrane.
  • the rate of drug penetration-diffusion corresponds to the concentration gradient as is characterized by
  • the present invention obviates the problems of solvation as well as the need for classic abso ⁇ tion for delivery of those drugs where the molecular size is too large to be absorbed when the product is formulated and administered, or because of the deleterious effects of gastrointestinal enzymes, and other factors.
  • the invention is directed to pharmaceutical formulations for effective controlled release of many drugs not now orally or parenterally available. These formulations, properly adjusted, also may be administered by inhalation and achieve the same kinetic characteristics.
  • the pharmaceutical formulations of this invention are made by entrapping the drug of choice in either an organic or water phase biodegradable hydrogel polymer system to produce nanoparticles.
  • the advantage of the nanoparticle system is that its absorption by the body is by the lymphatic or lacteal system. Because of the resistant hydrogel coating it is not affected by the enzymes or degradative influences present in the gastrointestinal tract. Using bioadhesive hydrogel polymers ensures a more prolonged duration of time in which the nanoparticles are in contact with the intestinal mucosa, obfuscating the deleterious action of heightened gastrointestinal peristalsis. All of these compounds work in harmony to produce viable products that have demonstrated favorable and reproducible effects in animals.
  • the invention thus describes simple and predictable methods for the preparation of oral, parenteral, or inhalation dosage forms of a drug or drugs entrapped in biodegradable hydrogel polymers.
  • the following combinations may be used to formulate a controlled release pharmaceutical product:
  • a controlled release pharmaceutical formulation with a biologically active molecule which is encapsulated with a cyclodextrin, entrapped with liposomes and formed into nanoparticles then with water-soluble hydrogel polymers, and then coated with one or more bioadhesive adjuvants.
  • the sphere size in the nanoparticle will typically be in the range of 500 to 1500 nm, so that the drug(s) so entrapped may be administered orally, parenterally, or by inhalation.
  • the exact diameter of the nanoparticles is not critical, provided that is sufficiently small for cell diffusion by the lymphatic or lacteal system.
  • the rate of active drug release from the entrapped spheres is dependent upon the basic kinetics of the drug administered, the amount of hydrogel polymer, the cyclodextrin used, the phospholipid coating and, in the case of parenteral administration, the method of administration, the area of deposition, and the vascularity of the body region.
  • inhalation dosing it is not necessary to use the bioadhesive adjuvants, although the adjuvants may be included in these formulations.
  • Heparin is a well-established drug that is a complex polysaccharide that is highly charged (electronegative). It has a molecular weight of 20,000-60,000 daltons, which are covalently attached to a core protein found in most secretory cells. Heparin is a multifaceted drug with primary actions as an anticoagulant. When venous or arterial thrombi occur and the patient survives, heparin is given at doses of 10,000-20,000 units every 4-6 hours to maintain blood levels at 0.5-1.5 anti-factor Xa units/mL, which should prevent further thromboembolic phenomena. After this, the heparin dose is usually maintained at 10,000 units every 4-6 hours to prevent further thromboembolic events.
  • heparin has the ability to bind to the arterial wall following angioplasty and ameliorate the proliferation of smooth muscle cells and ameliorate the restenosis that so often occurs with this procedure. Also, heparin is used as a preventive agent for those patients that are at close risk of stroke or heart attack as well as the patients recovering from a heart attack.
  • Heparin also has a clearing effect in the blood by activating lipoprotein lipase on the cell surface. This action clears hyperlipoproteinmia and lowers the low density lipoprotein. In animals, it has reversed the athrogenic deposits on the arterial walls, which is a phenomenon of arteriosclerosis in humans.
  • Insulin is a polypeptide with two peptide chains linked by a disulfide bridge.
  • the A chain of insulin contains 21 amino acids and the B peptide chain contains 30 amino acids. This structural integrity is important for its biologic activity. If the amino acid sequences are disrupted or the disulfide bridge broken, the hormone becomes inactivated.
  • biodegradable polymers poly (lactic acid), poly (glycolic acid), (poly (e-caprolactone), poly (p-hydrohybutyrate), poly (b-hydroxyvalerate).
  • methacrylate polymers can be used specifically in water soluble systems. These include, but are not limited to acrylic acid, methacrylacetic cyanoethyl methocrylitic aminoakyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, polymethacrylic acid, methacrylate acid alkylamide copolymer, polymethacrylic acid, polyacrylic acid, methacryic acid alkylamide copolymer, polymethacrylic acid (anhydride), and polymethyl methacrylate.
  • the advantage of the acrylate series is that when properly compounded they are water soluble or can be supplied as a 30% aqueous solution with varying degrees of solubility.
  • polymers known to the art can be used in either the water or organic phase, if properly prepared.
  • An example of this is alginic acid in intimate admixture with the drug, then cross-linking the alginic acid with a known inorganic element such as zinc, magnesium, calcium, or sodium salts.
  • pectin, zein, and guar gum can be used and cross-linked with a metallic ion.
  • Ethyl cellulose can also be used as a polymer to entrap the molecule and can be used in an aqueous or organic solvent system.
  • Cyclodextrins are a new class of compounds derived from corn. They are cyclic, non-reducing oligosaccharides built up from six, seven, and eight glucopyranose rings known respectively as alpha, beta, and gamma cyclodextrins. In addition, hydroxypropyl and other groups have been and are added to the molecule giving each series its own specific characteristics and pharmacological behavior. These molecules have a unique shape as shown in Figure 1.
  • the cyclodextrins act as a biodegradable trapping agent, inco ⁇ orating the active medication into its core and forming a unique molecular inclusion complex. These complexes provide an anchoring compound with the formation of covalent bonds. This guest-host complex protects the active drug, while not forming tight chemical bonds.
  • Cyclodextrins can be used to entrap the drug, providing a guest-host interaction.
  • Cyclodextrins are usually used in amounts that range from 0.25%-2% W/W, depending upon the bioactive molecule and the degree of protection required. The type of cyclodextrins used will again depend upon the molecule and the degree of protection required. These parameters can easily be determined by routine experimentation by one of skill in the art.
  • Liposomes were first characterized in 1965. They are single or combinations of lipids formed into spherical shapes with drugs or other active medicaments. Lipids or liposomes, primarily phospholipids, are, in general, readily absorbed intact by the intestinal cells, degraded as they pass through the interstitial space and slowly reconstituted by the body where they are then excreted by active transport in the ileum and colon in a newly reconfigured formulation. About 30-40% of the fecal dry weight is fat or lipid. Most importantly, essentially all the fat or lipids ingested are absorbed directly into the portal blood and lymphatic system or by transcell migration. Liposomes, like their parent lipids, can enter the system in a number of ways:
  • Intermembrane transfer which occurs when liposomes are in close contact with the cell they are exchanged with certain lipids in the cell wall, where they are transported intact into the cell.
  • Fusion which occurs when there is a close approach of the lipids in the cell wall and those of the liposomal lipids. Fusion results in complete mixing of the plasma membrane and release of the liposomal contents into the cytoplasm of the cell.
  • liposomes have been used for some drug delivery, there are problems with manufacturing, stability, and assurance of release. Their advantage is that drugs encapsulated into a lipid sphere can carry an electrostatic charge, allowing them to interact with cells of the opposite charge. By such a process of fusion and constant release, they efficiently can deliver the active drug moiety to the body.
  • the preferred agents are cholesterol, lecithin, glycerol monostearate, phospholipon 90H (Natterman) maleated soybean oil, sphingomylein, phosphatidyl entanolamine, dipamitoyl phoisphophatidykaline, phophosinositol, phophatidic acid, triglycerides. Since lipids tend to undergo oxidative degeneration, alpha tocopherol is usually added as an ancillary agent along with other antioxidants when the drug and or the liposomes.
  • the preferred bioadhesive adjuvant(s) that is added only to the total formulation are hydroxypropyl methyl cellulose, methyl cellulose, pectin, guar gum, xantham gums, gum acacia, gum dragon, hydroxypropyl alginate, sodium carboxymethyl cellulose, carbomer 934-P, acrylic acid derivatives and those of similar pharmaceutical characteristics and behavior.
  • These adjuvants are pharmacopeial items and are blended in with the nanoparticle granulate at the final stage of production.
  • the preferred dose is a single or combination of these adjuvants at a 50/50 W/W ratio and a percentage weight of the total granulate of 0.1-3% preferably in the range of 0.3-1.5% and most preferably 0.2-1.2 weight percentage.
  • the invention describes the formulation of a range of products with a variety of process steps and combinations. Embodiments in addition to those illustrated will be readily understood by those skilled in the art.
  • the present invention includes within its scope novel processes and products derived from the invention whether as individual features or in combination with each other to produce novel combinations.
  • the invention is illustrated further by the following examples, which are not to be taken as limiting in any way.
  • gastrointestinal absorption of oral formulations of water soluble dyes entrapped into nanoparticles, prepared according to the present invention, were studied by light microscopy.
  • Nanoparticles containing fluorescent stains were prepared and administered orally with concomitant bioadhesive adjuvants, as a single dose to anesthetized rabbits, via a gastric tube.
  • the rabbits were sacrificed 7 and 14 days after oral administration of the manufactured spheres. Both ultraviolet light microscopy and direct vision revealed dye-containing spheres widely distributed throughout the animal's bodies.
  • the yield was 742 mg out of a theoretical yield of 1,400 mg.
  • the resultant powder/granulate was weighed and titrated against protamine in normal saline to ensure that heparin was in fact entrapped in the spheres. To do this, the beads were suspended in normal saline and agitated by vortex. Protamine was then added to the solution and no precipitate was observed. The nanoparticles were assayed before l o degradation and found to have 0.75 U/ mg of heparin.
  • Electron microscopy demonstrated an average diameter of 850 nm, with a range of 650 to 1250 nm.
  • nanoparticles were coated with bioadhesive adjuvant. Nanoparticles were coated by dispersion in 20-mL of an aqueous
  • Vancomycin hydrochloride (3,000 mg) was added to 300 mL of KH2PO4 at pH 6.8
  • Heparin nanoparticles prepared according to Example 1, were orally administered to rabbits in an animal study. These preliminary results showed that heparin, a large molecular weight drug, can be formulated for oral absorption in a controlled, sustained-release fashion.
  • the rabbits were sedated with xyalazine for administration of the drugs and control.
  • a soft #10 rubber French catheter was then placed into the animals' stomach and the material was delivered by pressure to simulate a controlled oral administration.
  • the tube was rinsed with deionized water to make sure all the particles were expelled from the tube into the rabbits' stomach. In all, this process was repeated five times over a six month period with three different animals treated each time, for a total of 15 animals.
  • the animals were housed and fed rabbit chow and were given water ad lib. Blood samples were taken from the marginal ear vein at the following times, 6 hours post dose, 24, 48, 96, 120 and 144 hours after drug administration. The blood samples were placed in a citrate Eppendorf test tube immediately after blood was obtained and spun down using 3,000 Xg for 23 minutes. All samples were then assayed for antifactor Xa by Dr. Richard Malar at the University Of Colorado-Veterans Administration Hospital coagulation lab. The test was blinded as to the specimen, its timing and the specific animal. Following the centrifugation, the plasma was removed and frozen immediately at -20"C until assay.
  • thromboplastin 100 mL/mouse
  • a blood clotting activating agent a blood clotting activating agent
  • the model measures the level of protection given by the various drugs.
  • the intravenous injection of thromboplastin with the dose of 100 ⁇ L/mice (0.2 ng) provokes a thromboembolism involving 80% mortality in 24 hours.
  • the intravenous heparin standard protects 50% of animals treated when administered in the range of 0.09 mg/kg.
  • the heparin nanoparticles were given by oral route in suspension in a carboxymethyl cellulose solution (0.06%) in doses of 50, 150, and 300 mg/kg.
  • heparin nanoparticles In addition to the three dosage levels of the heparin nanoparticles tested, a blank and two heparin standards were run.
  • the blank was the bioadhesive adjuvant, carboxymethyl cellulose, at 0.6%.
  • the first heparin standard was intravenous heparin at 0.3 mg/kg.
  • the second heparin standard was 85 mg/kg administered orally.
  • the fluid was then placed on a preheated stirring plate and at very low temperature ⁇ 40°C and stirred 1700 Rpm's for 30 minutes. After stirring was complete, the fluid was placed into a modified Pyrex® dish and allowed to air dry for 24 hours. At the end of this time there was a very fine granulated powder that was removed by a sharp razor blade edge and weighed. The theoretical yield was 2.80 grams, while the actual yield was 2.75 grams.

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Abstract

La présente invention permet d'administrer de grosses macromolécules par voie orale, par voie parentérale ou par inhalation. Des médicaments biologiquement actifs sont emprisonnés dans des polymères sous forme d'hydrogel biodégradable dans des systèmes organiques ou à phase aqueuse. Grâce à des cyclodextrines, les molécules sensibles peuvent être protégées au cours de la phase de production de granulations de nanoparticules.
PCT/US1996/012203 1995-07-27 1996-07-25 Systemes d'administration de medicaments pour medicaments macromoleculaires WO1997004747A1 (fr)

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US50824795A 1995-07-27 1995-07-27
US08/508,247 1995-07-27

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WO2006128937A2 (fr) 2005-06-02 2006-12-07 Universidade De Santiago De Compostela Nanoparticules qui contiennent du chitosane et de la cyclodextrine
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US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
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