WO2000022909A2 - Systemes d'administration orale - Google Patents

Systemes d'administration orale Download PDF

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Publication number
WO2000022909A2
WO2000022909A2 PCT/IB1999/001872 IB9901872W WO0022909A2 WO 2000022909 A2 WO2000022909 A2 WO 2000022909A2 IB 9901872 W IB9901872 W IB 9901872W WO 0022909 A2 WO0022909 A2 WO 0022909A2
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acid
interleukin
growth factor
factor
agents
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WO2000022909A3 (fr
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Gregory John Russell-Jones
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Biotech Australia Pty Ltd
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Biotech Australia Pty Ltd
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Priority to AU10712/00A priority Critical patent/AU1071200A/en
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Publication of WO2000022909A3 publication Critical patent/WO2000022909A3/fr
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to carboxylic acid encapsulation systems useful for pharmaceutical delivery.
  • the invention relates to improved methods of protecting pharmaceuticals from intestinal degradation, for enhancing the oral uptake of the pharmaceutical agent within a vertebrate host and for the delivery of insoluble and moderately soluble pharmaceutical agents, and biologically active pharmaceutical agents.
  • a pharmaceutical agent to its site of action and controlling the rate of release of pharmaceutical agents are enduring problems in developing and improving pharmaceutical therapies. This is particularly a problem when the pharmaceutical to be delivered is administered orally to the target animal.
  • the gastro- intestinal tract of vertebrate animals provides a number of physical and chemical barriers against the successful administration of therapeutic agents.
  • a therapeutic agent must be able to withstand the attack of endogenous enzymes such as trypsin, pepsin and chymotrypsin, as well as gastric acidity without losing activity.
  • endogenous enzymes such as trypsin, pepsin and chymotrypsin, as well as gastric acidity without losing activity.
  • Once the pharmaceutical has survived these conditions it must still cross the gastrointestinal mucosa, enter the blood stream and move to the site where activity is required. Moreover, all of this must take place at an appropriate rate to ensure the correct therapeutic dosage is delivered.
  • many compounds are ineffective or exhibit low or variable potency when administered orally. Despite these problems it is still preferable
  • Microparticulate systems which can encapsulate pharmaceutical agents in order to provide protection in the intestine and regulate their rate of release were described in United States Patent No. 5,352,461.
  • This patent relates to drug delivery systems formed from 2,5-diketo-3.6-di(4-succinylaminobutyl)piperazine, which form particles that are pH sensitive so that at low pH they are stable and protect the encapsulated material from proteolysis, while at high pH they disassemble and release the entrapped pharmaceutical agent.
  • Proteinoid micro-particles are also described, which are claimed to be able to encapsulate agents such as insulin and heparin and protect these molecules from gastric acidity and stomach enzymes.
  • the drug may be included within an enteric coating, whereby the drug is released once it reaches the small intestine.
  • solid dispersions of the drug are milled to produce sub-micron particles with a high surface area for more rapid dissolution.
  • Both the enteric coating and the drug milling processes require complicated, high technology machinery and as such add considerable cost to the delivery of the drug.
  • Another problem has been the delivery of insoluble and moderately soluble pharmaceutical compounds. Many insoluble and moderately water soluble biologically active agents are readily absorbed in the intestine. But the amount of orally administered biologically active agent that is actually absorbed may be much less than the amount administered.
  • One embodiment of the present invention is a pharmaceutical composition for biologically active agent delivery comprising a complex, between a carboxylic acid and a biologically active agent, that is stable at acidic pH in solution and unstable at basic pH in solution, with the proviso that the carboxylic acid does not have an amide bond or a non-aromatic nitrogen.
  • the biologically active agent to be delivered is an organic moiety or a biologically active agent that has a solubility of less than 0.05 moles per liter of water.
  • the carboxylic acid serves as a biologically active agent transport and delivery system.
  • Another embodiment of the present invention is a method of producing a carboxylic acid complex for biologically active agent encapsulation.
  • a method for controlled release, in a patient, of a pharmaceutical agent comprises administering to the patient an effective amount of a composition comprising a pharmaceutical agent entrapped within an acid complex.
  • a method for formulating a pharmaceutical composition that will deliver insoluble or moderately soluble biologically active agents by dissolving such biologically active agents in a alcohol before encapsulating them with a carboxylic acid.
  • a further embodiment of the present invention is a method of delivering biologically active carboxylic acids.
  • FIGURE 1 is a graph of the area under the curve (AUC) reduction in serum glucose levels in mg/dl from animals which have received an oral administration of insulin formulated with a carboxylic acid complex.
  • FIGURE 2 is a graph of the AUC reduction in serum glucose levels in mg/dl from animals which have received an oral administration of insulin formulated with an acid complex.
  • a pharmaceutical or another, biologically active substance, for oral administration can be "coated” or “encapsulated” with a carboxylic acid, such that the substance is protected from proteolvsis in the stomach and is taken up from the intestine.
  • the present inventor observed that when animals were fed insulin that had been precipitated with a carboxylic acid complex by a decrease in pH, there was a significant modification of serum glucose levels. This result is most likely due to the carboxylic acids coating and protecting the insulin from the proteolytic environment of the stomach, allowing the insulin to pass safely through the stomach and be absorbed in the small intestines.
  • carboxylic acids can be used to coat even a poorly or only moderately soluble biologically active agent, thereby to allow delivery and absorption in the intestines.
  • a poorly or moderately soluble biologically active agent is first dissolved in an alcohol and carboxylic acid solution. This solution is then added to a basic solution, which can then be added to or titrated with an acid solution, so that the carboxylic acid and active substance complex forms and precipitates out of solution. The precipitant is then administered to a patient.
  • the active substance can be delivered readily, even if it is insoluble or only moderately soluble.
  • This same method can also be used to formulate biologically active carboxylic acids prior to administration to a patient.
  • stable refers to a precipitated state of the carboxylic acid/active agent complex, which state is sufficiently unchanging so that the complex can be separated, stored, and/or administered to a patient.
  • unstable connotes a state of dissolution, typically in an aqueous solution.
  • complex denotes an aggregation of a precipitated carboxylic acid and a biologically active substance.
  • coated and encapsulated refer to a biologically active substance precipitated with a carboxylic acid.
  • a “moderately soluble” agent is defined as having a solubility of 0.05 to 0.01 moles per liter, while “insoluble” is less than 0.01 moles per liter.
  • biologically active agent biologically active substance
  • active agent active agent
  • active agent active agent
  • acid and “alcohol” refer to pharmaceutically acceptable alcohols and acids, respectively.
  • excipient denotes a usually inert substance that forms a vehicle for a biologically active vehicle.
  • acidic solution denotes one having a sufficient concentration of hydronium ions, that is a sufficiently low pH, to protonate carboxylic acids to such an extent that the carboxylic acid precipitates out of solution and forms a stable complex with the biologically active agent that is present.
  • a “basic solution” is characterized by a sufficiently low enough concentration of hydronium ions, that is a high pH, to cause enough of the present carboxylic acid to become deprotonated or ionized at its functional carboxyl group so that the carboxylic acid dissolves in an aqueous solution.
  • a preferred class of suitable, saturated carboxylic acids for the invention conform to the general formula RCOOH. wherein R is a C 9 to C 30 , preferably C 0 to C 20 , straight or branched chained alkyl, cycloalkyl, or cycloalkyalkyl, optionally substituted by a carboxyl, hydroxyl, or carbonyl oxygen.
  • decanoic (lauric) acid undecanoic acid
  • dodecanoic acid dodecanoic acid
  • tetradecanoic (myristic) acid hexadecanoic (palmitic) acid
  • octadecanoic (stearic) acid eicosanoic (arachidic) acid
  • nonadecanoic acid 2-hydroxydodecanoic acid, 12-hydrocyclodecanoic acid, 12- hydroxystearic acid. 4-tertbutylcyclohexane carboxylic acid, and 2-hexyldecanoic acid.
  • Preferred unsaturated carboxylic acids have the general formula RCOOH, wherein R is a C 9 to C 30 , preferably C 9 to C 20 , straight or branched chained alkyl, cycloalkyl, or cycloalkyalkyl, optionally substituted by a carboxyl, hydroxyl, or carbonyl oxygen.
  • Palmitoleic acid oleic acid, ricinoleic acid, linoleic acid, arachidonic acid, linolenic acid, gamma-linolenic acid, isanic acid, undecylenic acid, cis-5-dodecenoic acid, 10-undecynoic acid, elaidic acid, vaccenic acid, myristoleic acid, eicosenoic acid, eicosatrienoic acid, eicosapentaenoic acid, docosahexaenoic acid, hydnocarpic acid, retinoic acid, and traumatic acid.
  • Preferred steroid ring system carboxylic acids have a steroid ring system and at least one carboxylic acid group.
  • this class includes fusidic acid, apocholic acid, orthocholic acid, chenodeoxycholic acid, hydroxycholic acid, and ursodeoxycholic acid.
  • carboxylic acids which are suitable for this invention are abietic acid, pimaric acid, butibufen, (p-nonylphenoxy)acetic acid, unoprostone, limaprost, 7- hydroxycoumarin-4-acetic acid, 2-(4-isobutylphenyl)butyric acid, levulinic acid, vernolic acid, 4-butylbenzoic acid, 4-tert-butylbenzoic acid, 5 -phenyl valeric acid, 4-(4- methoxyphenyl) -butyric acid, trans-4- ⁇ entylcyclo-hexane carboxylic acid, 4-biphenyl carboxylic acid, 4'-hydroxy-4-biphenyl-carboxylic acid, alpha-(terbutyl)hydrocinamic acid, 4-hexylbenzoic acid, 4-hexyloxybenzoic acid, 4-benzoyl benzoic acid, 4-biphenyl acetic acid, benzilic
  • 4-octylbenzoic acid 4-octoxybenzoic acid, 4- benzyloxy-3-methoxyphenyl acetic acid, 4-nonyloxy-benzoic acid, 4-palmitylbenzoic acid, 4-palmitolyl-benzoic acid, and 4-undecyloxy-benzoic acid.
  • a pharmaceutical agent can be incorporated within the carboxylic acid system at the time of its formation, preferably by including the agent within the mixture of components required to produce the formulation.
  • the ratio of moles of carboxylic acid to bioactive agent in the present invention can range from 2: 1 to 250: 1, preferably from 10: 1 to 30: 1.
  • the basic solution preferably is added slowly, drop-wise and with stirring, into an acidic solution containing a bioactive agent.
  • the latter becomes mildly opalescent and then more and more turbid, finally forming a dense suspension which precipitates gradually, once stirring ceases.
  • This suspension can be administered while in the acidic solution or can be separated from the liquid and further formulated, with one or more excipients.
  • the acidic solution also could be combined with one or more excipients, prior to administration.
  • the suspension can be separated by filtration, evaporation, rotatory evaporation, centrifugation, or decantation, or by any other means known by one skilled in the art.
  • the suspension in a dried or undried state, then can be combined with one or more excipients.
  • the carboxylic acid complex is a composition formulated with the following components: a long-chain, saturated or unsaturated, carboxylic acid dispersed in a weakly basic solution, and a biologically active agent, dispersed in a weakly acidic solution.
  • This composition can be made by titration of one solution into the other to form an acidic solution, which contained the precipitated, encapsulated biologically active agent.
  • Example 1 The present invention is described further below with reference to the following, non-limiting examples.
  • Example 1
  • Carboxylic Acid Strucmres That Contain Insulin Carboxylic acid (CA) is dissolved at 100 mg/ml in ethanol. The AA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml. The mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • CA Carboxylic acid
  • Dodecanoic Acid for the Synthesis of Carboxylic Acid Strucmres That Contain Insulin
  • Dodecanoic acid DDA
  • the DDA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml.
  • the mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • Tetradecanoic acid is dissolved at 100. mg/ml in ethanol. The TDA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml. The mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • TDA Tetradecanoic acid
  • Hexadecanoic Acid for the Synthesis of Carboxylic Acid Structures Containing Insulin
  • Hexadecanoic acid is dissolved at 100 mg/ml in ethanol.
  • the HDA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml.
  • the mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • Octadecanoic Acid for the Synthesis of Carboxylic Acid Strucmres Containing Insulin
  • ODA Octadecanoic acid
  • the ODA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml.
  • the mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • OA Oleic acid
  • Palmitoleic Acid for the Synthesis of Carboxylic Acid Strucmres Containing Insulin Palmitoleic acid (PA) is dissolved at 100 mg/ml in ethanol. The PA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml. The mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • PA Palmitoleic acid
  • Ricinoleic Acid for the Synthesis of Carboxylic Acid Strucmres Containing Insulin Ricinoleic acid (RA) is dissolved at 100 mg/ml in ethanol. The RA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml. The mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • RA Insulin Ricinoleic acid
  • Fusidic Acid for the Synthesis of Carboxylic Acid Strucmres Containing Insulin
  • Fusidic acid (FA) is dissolved at 100 mg/ml in ethanol. The FA solution is then added to 0.25 M K 2 CO 3 to give a final concentration of 5 mg/ml. The mixmre is thoroughly mixed by vortexing and slowly added to an equal volume of 0.5 M citric acid containing 5 mg/ml insulin. The solution was allowed to stir overnight, and was then stored at 4 °C before use.
  • the carboxylic acid transport delivery system has special utility for assisting the delivery of pharmaceutical agents which otherwise would experience a loss of efficacy as a result of instability, inadequate uptake following oral administration, an inappropriate rate of release, and/or insufficient solubility.
  • the pharmaceutical agents comprehended by the present invention particularly include peptide and protein pharmaceuticals that are the subject of proteolytic attack or are unstable at the low pH of the stomach as well as biologically active agents that are insoluble or moderately soluble in an aqueous solution.
  • Therapeutic agents according to the invention can be delivered via oral, nasal, buccal, pulmonary, intravaginally and dermal routes of administration.
  • pharmaceutical agent or “biologically active agent” is not intended to be limited to peptide and protein pharmaceuticals or insoluble and moderately soluble agents but can include therapeutic, prophylactic or diagnostic agents, and organic moieties whose delivery may be aided by incorporation into carboxylic acid systems.
  • This organic moieties include proteins, peptides, polysaccharides. lipopolysaccharides, lipoproteins, glycoproteins, oligonucleotides, or polynucleotides.
  • Species of DNA and RNA (sense or antisense), antibodies, vaccines as well as chemotherapeutic agents are also contemplated.
  • pharmaceutical agent encompasses simple organic or inorganic compounds, nutritional agents or even imaging agents such as metals, radioactive isotopes, radio-opaque or radiolucent agents.
  • traditional chemotherapeutic agents include but are not restricted to hormones, polysaccharides, such as heparin. vasoactive and neuroactive agents, immunomodulating agents, cytotoxic agents, steroids, decongestants, anaesthetics, sedatives, anti- inflammatory agents, anthelmintics.
  • anti-arrhythmic agents antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, anti- epileptics, anti-histamines, anti-hypertensive agents, anti-muscarinic agents, anti- mycobacterial agents, anti-neoplastic agents, immunosuppresants, anti-thyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta- adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti- parkinsonian agents), haemostatis, immunological agents, lipid regulating agents, muscle relaxants.
  • parasympathomimetics parathyroid calcitonin and bisphosphonates, prostaglandins.
  • radio-pharmaceuticals including steroids, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators and zanthines or other agents required to be delivered to a patient for therapeutic, prophylactic or diagnostic purposes.
  • Potential biologically active agents for peptide and protein delivery include alpha antitrypsin, angiogenesis factor, anakinra, antitumor necrosis factor, atriopeptin, calcitonin, cardiac glycosides, epidermal growth factor, erythropoietin, elastase inhibitor, epoetin alpha, epoetin beta, filgastrim, factor VIII, factor IX, granulocyte colony stimulating factor, hirudin, insulin, interferons, interferon-alpha, interferon- gamma, insulin-like growth factor I, insulin-like growth factor I receptor, insulin-like growth factor II, interleukin 2, interleukin 3, interleukin 4.
  • interleukin 5 interleukin 6, interleukin 7, interleukin 8, interleukin 9, interleukin 10, interleukin 11, interleukin 12, interleukin 12 p40, interleukin 12 p70, interleukin 13, interleukin 15, interleukin 16, interleukin 17, interleukin 18/IGIF, LHRH analogs, monoclonal antibodies, neuropeptides, oxytocin, plasminogen activator inhibitors, platelet derived growth factor, platelet-derived growth factor A chain, platelet-derived growth factor AA, platelet-derived growth factor AB, platelet-derived growth factor B chain, platelet- derived growth factor BB.
  • sargramostim sargramostim
  • somatostatin superoxide dismutase
  • stem cell factor tissue plasminogen activator
  • thrombopoietin mmor necrosis factor
  • vasopressin vasopressin
  • wound healing factor Other molecules include polysaccharides such as heparin and heparin sulphate.
  • Additional biologically active agents include ⁇ ckine, amphiregulin, angiogenin, ⁇ 2 -microglobulin, betacellulin, brain-derived neurotrophic factor, CIO, ciliary neurotrophic factor, ciliary neurotrophic factor receptor alpha, CPP32, CRG-2, cytokine-induced neutrophil chemotactic factor 1, cytokine-induced neutrophil chemotactic factor 2 alpha, cytokine-induced neutrophil chemotactic factor 2 beta, cytotoxic t-lymphocyte-associated molecule 4, beta endothelial cell growth factor, endothelin-1, eotaxin, eotaxin-2, epithelial-derived neutrophil attractant 78, erythropoietin receptor, Fas, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7/KGF, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c.
  • fibroblast growth factor 9 fibroblast growth factor acidic, fibroblast growth factor basic, Flt-3 ligand, fractalkine, glial cell line-derived neurotropic factor, granulocyte chemotactic protein, granulocyte colony stimulating factor receptor, granulocyte macrophage colony stimulating factor, growth related protein, growth related protein alpha, growth related protein beta, growth related protein gamma, hemofiltrate CC chemokine 1 , heparin binding epidermal growth factor, hepatocyte growth factor, heregulin alpha, heregulin beta 1, I- 309, interleukin 1 alpha, interleukin 1 beta, interleukin 1 receptor antagonist, IP-10, JE/MCP-1 , KC, keratinocyte growth factor/FGF-7, lactoferrin, leptin, leukemia inhibitory factor, luciferase, macrophage colony stimulating factor, macrophage colony stimulating factor receptor, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein
  • Insoluble and moderately soluble biologically active agents include 17-pregma- 2 , 4-dien-20-y no- [2 , 3 -d] isoxazol- 17-ol(Danazol) , 5, 17,-1 ' -(mehty losulfony 1)- 1 'H-pregn- 20-yno[3,2-c]pyrazol-17-ol(Steroid A), piposulfan, camptothecin, ethyl-3,5- diacetoamido-2,4,6-triiodobenzoate, vitamin E, cyclosporin, propanolol, ibuprofen, fenoprofen, beclomethanzone, beclomethanzone, naproxen, napthalene phenanthrene, 1,4-napthaquinone, 1,2-napthaquinone.
  • insoluble and moderately soluble biologically active agents also includes known analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics including penicillins, anticoagulants, antidepressants, antidiabetic agents, anti-epileptics, anti-histamines.
  • anti-hypertensive agents anti-muscarinic agents, anti-mycobacterial agents, anti-neoplastic agents, immunosuppresants, anti- thyroid agents, antiviral agents, anxiolytic sedatives including hypnotics and neuroleptics, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants including expectorants and mucolytics, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics including anti-parkinsonian agents, haemostatis, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid hormone, calcitonin and bisphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones including steroids, anti-allergic agents, stimulants and anoretics, sympamomimetics, thyroid agents, vasodilators, and zanthines.
  • active agents are not intended to be exhaustive.
  • pharmaceutical agents according to the invention can be in various forms such as charged or uncharged molecules, components of molecular complexes, salts, amines, ethers, esters, amides or other derivatives or pro- biologically active agents of the agents concerned.
  • this invention also relates to a method of controlled biologically active agent release within a patient, which patient is administered a composition comprising a pharmaceutical agent which is entrapped or encapsulated within a carboxylic acid system (CAS) according to the invention.
  • this method can be used for the therapy, prophylaxis or diagnosis of any vertebrate animal, although it is preferred that the animal concerned is a mammal.
  • laboratory animals such as mice, guinea pigs, rabbits, domestic animals such as cats and dogs, farm animals such as horses, cattle, sheep, goats, pigs, captive wild animals such as lions, tigers, elephants or primates such as humans, chimpanzees, baboons, and apes.
  • the effective amount of the pharmaceutical agent delivered when delivered in combination within the CAS according to the invention will depend upon numerous factors which would be readily apparent to a person skilled in the art. For example, the type, age and sex of the vertebrate animal concerned, the disorder that the animal is suffering from, or prone to suffer from, the height and weight of the animal and naturally the type of pharmaceutical agent which is being delivered.
  • the dose will also depend upon the stability of the CAS and the level of control over release of the entrapped or encapsulated pharmaceutical agent, which will be related to the namre of the acid carboxylic acid used to form the CAS. When all of these factors are taken into consideration by a person skilled in the art, the appropriate dose can be determined.
  • compositions according to the invention may be administered in conjunction with one or more pharmaceutically suitable carriers and/or excipients.
  • the namre of the carrier or excipient substance will depend upon numerous factors such as the route of administration, the namre of the cross- linked particle, and the nature of the pharmaceutical agent concerned.
  • appropriate pharmaceutical carriers and excipients we refer to the HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, Second Edition (1994), edited by Ainley Wade and Paul J. Weller, and published by The Pharmaceutical Press (London), the relevant contents of which are incorporated herein by reference.
  • Pharmaceutically acceptable carriers are materials that can be used as a vehicle for administering a medicament because the material is inert or otherwise medically acceptable, as well as compatible with the active agent.
  • a pharmaceutically acceptable carrier can contain conventional additives such as diluents, adjuvants, antioxidants, preservatives and solubilizing agents.
  • composition according to the invention can be administered via either enteral or parenteral routes of administration.
  • administration is via the oral route although, for example, rectal administration or direct administration to the stomach or small intestine is also possible.
  • the compositions according to the invention also can be administered nasally, buccally, transdermally, optically, aurally, vaginally, topically, pulmonary, or directly into an organ or via other parenteral means.
  • suitable formulations for administration include aerosols, capsules, creams, lotions, lozenges, ointments, pills, powders, suppositories, syrups, tablets, tinctures, and unguents.
  • composition should be provided in a suitable dosage form with appropriate carriers and/or excipients, as discussed, for example, in the HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, cited above.
  • Suitable excipients include but are not limited to diluents, emulsions, gelatins, liquors, ointments, oleaginous vehicles, solutions and suspensions.
  • FIGURE 1 shows a modification of serum glucose levels following oral administration of a 1 mg dose of insulin formulated within CAS. Data is presented as the mean AUC (6 hours) + 1 SEM.
  • CAS were formed with deoxycholic acid (DOC), decanoic acid (Deca), dodecanoic acid (Dodeca), tetradecanoic acid (Tetradeca), hexadecanoic acid (Hexadeca) or octadecanoic acid (Octadeca), formulated using either 0.5 M citric acid as the acid phase, or 1.5 M acetic acid (Ac), as the acid phase.
  • DOC deoxycholic acid
  • Deca decanoic acid
  • Dodeca dodecanoic acid
  • Tetradeca tetradecanoic acid
  • Hexadecanoic acid Hexadecanoic acid
  • Octadeca octadecanoic acid
  • FIGURE 1 shows a modification of serum glucose levels following oral administration of a 1 mg dose of insulin formulated within CAS. Data is presented as the mean AUC (6 hours) ⁇ 1 SEM.
  • CAS were formed with oleic acid, palmitoleic acid, ricinoleic acid, or fusidic acid, formulated using 0.5 M citric acid as the acid phase.
  • Figure 2 there was a significant modification of serum glucose when rats were fed insulin incorporated within CAS made of oleic acid, plamitoleic acid, ricinoleic acid, or fusidic acid, formulated using 0.5 M citric acid as the acid phase.

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Abstract

Une composition pharmaceutique ou autre comprenant une substance biologiquement active, destinée à une administration orale, peut être « enrobée » ou « encapsulée » avec de l'acide carboxylique, afin que la substance soit protégée de la protéolyse gastrique et qu'elle soit absorbée au niveau intestinal. Il apparaît que l'acide carboxylique protège l'agent actif de l'environnement protéolytique gastrique, ce qui permet à cet agent de traverser l'estomac en toute sécurité et d'être absorbé par l'intestin grêle. Le complexe acide carboxylique/agent peut être employé pour une administration par voie orale, nasale, buccale ou transdermique d'agents bioactifs modérément solubles voire insolubles.
PCT/IB1999/001872 1998-10-19 1999-10-18 Systemes d'administration orale Ceased WO2000022909A2 (fr)

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US10482798P 1998-10-19 1998-10-19
US60/104,827 1998-10-19

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WO2003082792A1 (fr) * 2002-03-28 2003-10-09 Council Of Scientific And Industrail Research Procede de synthese de l'acide trans-alcenoique et son utilisation
JPWO2002087559A1 (ja) * 2001-04-25 2004-09-09 田辺製薬株式会社 カリウムチャネル開口薬
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